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  • Probiotic LGG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice
    Hepatology (IF 14.971) Pub Date : 2019-09-30
    Yunhuan Liu; Kefei Chen; Fengyuan Li; Zelin Gu; Qi Liu; Liqing He; Tuo Shao; Qing Song; Fenxia Zhu; Lihua Zhang; Mengwei Jiang; Yun Zhou; Shirish Barve; Xiang Zhang; Craig J. McClain; Wenke Feng

    Cholestatic liver disease is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic, Lactobacillus rhamnosus GG (LGG), on hepatic bile acid synthesis, liver injury and fibrosis in bile‐duct ligation (BDL) and Mdr2‐/‐ mice. Global and intestinal specific FXR inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of T‐βMCA, an FXR antagonist, was markedly increased in BDL mice and reduced in LGG‐treated mice, while chenodeoxycholic acid (CDCA), an FXR agonist, was decreased in BDL mice and normalized in LGG‐treated mice. LGG treatment significantly increased the expression of serum and ileum FGF15 and subsequently reduced hepatic CYP7A1 and BA synthesis in BDL and Mdr2‐/‐ mice. At the molecular level, these changes were reversed by global and intestinal specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA de‐conjugation and increased fecal and urine BA excretion both in BDL and Mdr2‐/‐ mice. In vitro studies showed that LGG suppressed the inhibitory effect of T‐βMCA on FXR and FGF19 expression in Caco‐2 cells. Conclusion: LGG supplementation decreases hepatic BA by increasing intestinal FXR/FGF15 signaling pathway‐mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA‐induced liver injury and fibrosis in mice.

    更新日期:2019-10-01
  • Reply letter to Almasi‐Hashiana A et al
    Hepatology (IF 14.971) Pub Date : 2019-09-30
    Sung‐Hsi Huang; Chia‐Jui Yang; Chien‐Ching Hung

    We thank Almasi‐Hashiana et al. for their interest in and constructive comments on our study investigating the factors associated with seroreversion of anti‐hepatitis A antibodies among HIV‐positive patients who had completed 2 doses of hepatitis A vaccination with documented serconversion. In an infectious disease outbreak, the risk of exposure to the infectious agent may evolve with time and location. Thus, these factors were likely to become strong confounders for the outcome of seroreversion in this study. The purpose of the matching in the case‐control analysis of our study was to mitigate the confounding effects.

    更新日期:2019-09-30
  • Letter to the Editor: Methodological Issues Regarding the Matching in Matched Case Control Study
    Hepatology (IF 14.971) Pub Date : 2019-09-30
    Amir Almasi‐Hashiani; Mohammad Ali Mansournia

    We interestingly read a recently published study by Huang SH et al (1). They conducted a case‐control study including 49 seroreverters cases (as case group) and 196 non seroreverters cases (as control) to identify associated factors of seroreversion and followed HIV‐positive adults who had mounted seroresponses after completing two doses of HAV vaccination during a recent outbreak of acute hepatitis A

    更新日期:2019-09-30
  • Sestrin 3 Protects Against Diet‐Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor β Signal Transduction
    Hepatology (IF 14.971) Pub Date : 2019-09-27
    Menghao Huang; Hyeong Geug Kim; Xiaolin Zhong; Chuanpeng Dong; Brian Zhang; Zhigang Fang; Yang Zhang; Xiaoyu Lu; Romil Saxena; Yunlong Liu; Chi Zhang; Suthat Liangpunsakul; X. Charlie Dong

    Sestrin 3 (Sesn3) belongs to the three‐member sestrin protein family. Sestrins have been implicated in antioxidative stress, adenosine monophosphate–activated protein kinase and mammalian target of rapamycin signal transduction, and metabolic homeostasis. However, the role of Sesn3 in the development of nonalcoholic steatohepatitis (NASH) has not been previously studied. In this work, we generated Sesn3 whole‐body knockout and liver‐specific transgenic mice to investigate the hepatic function of Sesn3 in diet‐induced NASH. With only 4 weeks of dietary treatment, Sesn3 knockout mice developed severe NASH phenotype as characterized by hepatic steatosis, inflammation, and fibrosis. Strikingly, after 8‐week feeding with a NASH‐inducing diet, Sesn3 transgenic mice were largely protected against NASH development. Transcriptomic analysis revealed that multiple extracellular matrix–related processes were up‐regulated, including transforming growth factor β (TGF‐β) signaling and collagen production. Further biochemical and cell biological analyses have illustrated a critical control of the TGF‐β–mothers against decapentaplegic homolog (Smad) pathway by Sesn3 at the TGF‐β receptor and Smad3 levels. First, Sesn3 inhibits the TGF‐β receptor through an interaction with Smad7; second, Sesn3 directly inhibits the Smad3 function through protein–protein interaction and cytosolic retention. Conclusion: Sesn3 is a critical regulator of the extracellular matrix and hepatic fibrosis by suppression of TGF‐β–Smad3 signaling.

    更新日期:2019-09-27
  • Reply letter for: HEP‐18‐1513.R3 ‐ Small Dense Low‐Density Lipoprotein Cholesterol Predicts Cardiovascular Events In Liver Transplant Recipients
    Hepatology (IF 14.971) Pub Date : 2019-09-26
    Mohammad Bilal Siddiqui; Mohammad Shadab Siddiqui

    Aberrant lipid metabolism, central to atherosclerosis, is mechanistically influenced by insulin resistance and nonalcoholic fatty liver disease (NAFLD), which favors production and secretion of large very low‐density lipoprotein (VLDL) particles from the liver(1). These large VLDL particles are slowly metabolized in the periphery, leading to formation of atherogenic small dense low‐density lipoprotein (sdLDL) particles(2).

    更新日期:2019-09-26
  • Lipoproteins Sub‐particles and Cardiovascular Risk In liver transplantation: More details, More Significance
    Hepatology (IF 14.971) Pub Date : 2019-09-26
    Pusen Wang; Lin Zhong

    We read with great interest the article of Siddiqui et al.(1) in HEPATOLOGY, which demonstrated that serum concentration of small dense low‐density lipoprotein cholesterol (sdLDL‐C) independently predicted CVD events. Indeed, this study provide a potential useful clinical tool in stratifying patients at risk for CVD events after liver transplantation (LT). We would, however, like to raise the following concerns.

    更新日期:2019-09-26
  • Statin Use and the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B
    Hepatology (IF 14.971) Pub Date : 2019-09-25
    Myung Ji Goh; Dong Hyun Sinn; Seonwoo Kim; Sook Young Woo; Hyun Cho; Wonseok Kang; Geum‐Youn Gwak; Yong‐Han Paik; Moon Seok Choi; Joon Hyeok Lee; Kwang Cheol Koh; Seung Woon Paik

    Statins have pleiotropic effects which may include chemoprevention. Several observational studies have suggested that statins may prevent hepatocellular carcinoma (HCC) but they have not yet been fully studied in patients with chronic hepatitis B virus (HBV) infections. A hospital‐based retrospective cohort of 7,713 chronic HBV‐infected individuals between January 2008 and December 2012 were analyzed. The primary outcome was the development of HCC. Patients who used statins for at least 28 cumulative defined daily doses (cDDD) during the follow‐up period were defined as statin users (n = 713). The association between the use of statin and the incidence of HCC was analyzed using the multivariable Cox regression model with time‐dependent covariates. During a median follow‐up of 7.2 years (min‐max: 0.5‐9.7), HCC newly developed in 702 patients (9.1%). Statin use was associated with a lower risk of HCC (adjusted hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.19‐0.68, adjusted for age, sex, cirrhosis, diabetes, hypertension, serum alanine aminotransferase, cholesterol, HBV DNA level, antiviral treatment, and antiplatelet therapy). The observed benefit of the statin use was dose dependent (adjusted HR (95% CI), 0.63 (0.31‐1.29); 0.51 (0.21‐1.25); 0.32 (0.07,1.36); and 0.17 (0.06, 0.48) for patients with statin use of 28‐365, 366‐730, 731‐1095, and more than 1095 cDDDs, respectively). In subgroup analysis, the association between statin use and reduced risk of HCC was observed in all pre‐specified subgroups analyzed.

    更新日期:2019-09-26
  • Clinical utility of an increase in magnetic resonance elastography in predicting fibrosis progression in NAFLD
    Hepatology (IF 14.971) Pub Date : 2019-09-25
    Veeral H. Ajmera; Amy Liu; Seema Singh; Georg Yachoa; Matthew Ramey; Meera Bhargava; Ava Zamani; Scarlett Lopez; Neeraj Mangla; Ricki Bettencourt; Emily Rizo; Mark Valasek; Cynthia Behling; Lisa Richards; Claude Sirlin; Rohit Loomba

    Cross‐sectional studies have shown that magnetic‐resonance‐elastography (MRE) is accurate in non‐invasive detection of advanced fibrosis in NAFLD. However, there are limited data on the longitudinal association between an increase in liver‐stiffness on MRE and fibrosis progression in NAFLD. Therefore, utilizing a well‐characterized prospective cohort of patients with biopsy‐proven NAFLD, we aimed to examine the longitudinal association between a 15% increase in liver‐stiffness on MRE and fibrosis progression in NAFLD.

    更新日期:2019-09-26
  • Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy
    Hepatology (IF 14.971) Pub Date : 2019-09-25
    Nicholas R. Perkons; Ryan M. Kiefer; Michael C. Noji; Mehrdad Pourfathi; Daniel Ackerman; Sarmad Siddiqui; David Tischfield; Enri Profka; Omar Johnson; Stephen Pickup; Anthony Mancuso; Austin Pantel; Michelle R. Denburg; Gregory J. Nadolski; Stephen J. Hunt; Emma E. Furth; Stephen Kadlecek; Terence P.F. Gade

    Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease—the principal causes of cancer mortality—have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE‐induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. In this study, we characterize and leverage the metabolic reprogramming demonstrated by latent HCC cells in response to TAE‐induced ischemia to enable their detection in vivo using dynamic nuclear polarization magnetic resonance spectroscopic imaging (DNP‐MRSI) of 13Carbon‐labeled substrates. Under TAE‐induced ischemia, latent HCC cells demonstrate reduced metabolism and develop a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP‐MRSI of 1‐13C‐pyruvate and its downstream metabolites, 1‐13C‐lactate and 1‐13C‐alanine, predicted histologic viability. These studies provide a novel paradigm for imaging latent, treatment‐refractory cancer cells that are undetectable using existing clinical imaging paradigms suggesting that DNP‐MRSI provides a unique technology for this application.

    更新日期:2019-09-26
  • Is the total amount as important as localization and type of collagen in liver fibrosis due to steatohepatitis?
    Hepatology (IF 14.971) Pub Date : 2019-09-25
    M A Karsdal; S Detlefsen; S J Daniels; M J Nielsen; A Krag; D Schuppan

    Is liver fibrosis just liver fibrosis? Or do the subtype of collagen, its spatial localization in the liver, its cell of origin, and the time point at which it is synthesized also matter? It is important, since the various collagen subtypes hold different informative values regarding reparative processes in the liver, and as collagens have also emerged as important signaling molecules (1). Novel data have challenged our perception of liver fibrosis and collagens, which may have important implications regarding the development of new biomarkers and anti‐fibrotic interventions. The traditional histological analysis of liver biopsies using histochemical collagen stains, such as the Masson's Trichrome stain or the Sirius Red stain, group all triple helical collagen structures into one gross bucket. Importantly, these stains ignore many other quantitatively minor but nonetheless functionally and structurally relevant collagen and non‐collagen extracellular matrix (ECM) components.

    更新日期:2019-09-26
  • Crigler‐Najjar syndrome type 1: pathophysiology, natural history, and therapeutic frontier
    Hepatology (IF 14.971) Pub Date : 2019-09-25
    Kevin A. Strauss; Charles E. Ahlfors; Kyle Soltys; George V. Mazareigos; Millie Young; Lauren E. Bowser; Michael D. Fox; James E. Squires; Patrick McKiernan; Karlla W. Brigatti; Erik G. Puffenberger; Vincent J. Carson; Hendrik J. Vreman

    We describe the pathophysiology, treatment, and outcome of Crigler‐Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient‐years. Unbound (‘free') bilirubin (Bf) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT) to albumin (A) and validate their molar concentration ratio (BT/A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT/A at least 30% below intravascular BT binding capacity (i.e. BT/A=1.0). Categorical clinical outcomes were ascertained by chart review, and a novel measure was used to quantify liver fibrosis. Unbound bilirubin had a non‐linear relationship to BT (R2 = 0.71) and BT/A (R2 = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin‐albumin equilibrium association binding costant (R2 = 0.69), which varied 10–fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3±1.1 mg/dL•day. Four (14%) neonates developed kernicterus between 14 and 45 days of age; peak BT ≥30 mg/dL and BT/A ≥1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5‐fold. Consistent phototherapy with 33–103 µW/cm2•nm for 9.2 ± 1.1 hours/day kept BT and BT/A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by age 18 years. Liver transplantation (n=17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.

    更新日期:2019-09-26
  • Diet associations with nonalcoholic fatty liver disease in an ethnically diverse population: the Multiethnic Cohort
    Hepatology (IF 14.971) Pub Date : 2019-09-25
    Mazen Noureddin; Shira Zelber‐Sagi; Lynne R. Wilkens; Jacqueline Porcel; Carol J. Boushey; Loïc Le Marchand; Hugo R. Rosen; Veronica Wendy Setiawan

    Epidemiological data on dietary risk factors for NAFLD from population‐based studies, particularly in an ethnically diverse population, are scarce. We examined dietary factors in relation to NAFLD risk in African Americans, Japanese Americans, Latinos, Native Hawaiians, and whites in the Multiethnic Cohort (MEC). A nested case‐control analysis was conducted within the MEC, a large prospective study with >215,000 older‐adult participants in Hawaii and California. NAFLD was identified using Medicare claims data, and controls were selected among participants without liver disease and individually matched to cases by birth year, sex, ethnicity, and length of Medicare enrollment. Diet was assessed at baseline via a validated quantitative food frequency questionnaire. Diet‐NAFLD associations were quantified by odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable conditional logistic regression. The study consisted of 2,974 NAFLD cases (518 with cirrhosis; 2,456 without cirrhosis) and 29,474 matched controls. Red meat (P trend=0.010), processed red meat (P trend= 0.004), poultry (P trend= 0.005) and cholesterol (P trend= 0.005) intakes were positively associated with NAFLD, while dietary fiber intake (P trend=0.003) was inversely associated with risk. Stronger associations were observed between red meat and cholesterol and NAFLD with cirrhosis than without cirrhosis (P heterogeneity ≤0.014). Conclusion Dietary factors are independently associated with NAFLD and NAFLD‐related cirrhosis in a multiethnic population. Decreasing the consumption of cholesterol, red and processed meat and poultry and increasing consumption of fiber may reduce the risk for NAFLD and related advanced liver disease.

    更新日期:2019-09-26
  • A novel deactivation factor of fibrogenic hepatic stellate cells induces regression of liver fibrosis in mice
    Hepatology (IF 14.971) Pub Date : 2019-09-24
    Yasuhiro Nakano; Akihide Kamiya; Hideaki Sumiyoshi; Kota Tsuruya; Tatehiro Kagawa; Yutaka Inagaki

    Hepatic stellate cells (HSCs), a key player in the progression of liver fibrosis, are activated by various inflammatory stimuli and converted to myofibroblast‐like cells with excessive collagen production. Despite many attempts to suppress activation of HSCs or inhibit collagen production in activated HSCs, their clinical applications have not been established yet. Recently, the deactivation of HSCs has been reported as a mechanism underlying the reversibility of experimental liver fibrosis. In the present study, we have identified Tcf21 as a novel deactivation factor of fibrogenic HSCs by screening transcription factors whose expression is up‐regulated in parallel to the differentiation of fetal HSCs. Expression of Tcf21 in HSCs remarkably decreased during culture‐induced activation in vitro and in murine and human fibrotic liver tissue in vivo. This reduced Tcf21 expression was recovered during the spontaneous regression of murine liver fibrosis. Tcf21 was also examined for its effects by adeno‐associated viruses serotype 6 (AAV6)‐mediated Tcf21 gene transfer into cultured activated HSCs and mice with carbon tetrachloride‐ or methionine‐choline deficient diet‐induced liver fibrosis. Overexpression of Tcf21 in activated HSCs not only suppressed fibrogenic gene expression, but also restored cells, at least in part, to a quiescent phenotype, both in vitro and in vivo. These phenotypic changes of HSCs were accompanied by the regression of steatohepatitis and fibrosis, and improved hepatic architecture and function.

    更新日期:2019-09-25
  • MicroRNA‐210 promotes bile acid‐induced cholestatic liver injury by targeting mixed‐lineage leukemia‐4 methyltransferase in mice
    Hepatology (IF 14.971) Pub Date : 2019-09-24
    Young‐Chae Kim; Hyunkyung Jung; Sunmi Seok; Yang Zhang; Jian Ma; Tiangang Li; Byron Kemper; Jongsook Kim Kemper

    Bile acids (BAs) are important regulators of metabolism and energy balance, but excess BAs cause cholestatic liver injury. The histone methyltransferase, Mixed‐lineage leukemia‐4 (MLL4), is a transcriptional coactivator of the BA‐sensing nuclear receptor, Farnesoid‐X‐Receptor (FXR), and epigenetically upregulates FXR targets important for the regulation of BA levels, Small Heterodimer Partner (SHP) and Bile Salt Export Pump (BSEP). MLL4 expression is aberrantly downregulated and BA homeostasis is disrupted in cholestatic mice, but the underlying mechanisms are unclear. Here, we examined whether elevated microRNA‐210 (miR‐210) in cholestatic liver promotes BA‐induced pathology by inhibiting MLL4 expression. MiR‐210 was the most highly elevated miR in hepatic SHP‐downregulated mice with elevated hepatic BA levels. MLL4 was identified as a direct target of miR‐210 and overexpression of miR‐210 inhibited MLL4, and subsequently, BSEP and SHP expression, resulting in defective BA metabolism and hepatotoxicity with inflammation. MiR‐210 levels were elevated in cholestatic mouse models, and in vivo silencing of miR‐210 ameliorated BA‐induced liver pathology and decreased hydrophobic BA levels in a MLL4‐dependent manner. In gene expression studies, SHP inhibited miR‐210 expression by repressing a transcriptional activator, Kruppel‐like factor‐4 (KLF4). In primary biliary cholangitis/cirrhosis (PBC) patients, hepatic levels of miR‐210 and KLF4 were highly elevated, whereas nuclear levels of SHP and MLL4 were reduced. In conclusion, hepatic miR‐210 is physiologically regulated by SHP, but is elevated in cholestatic mice and PBC patients, promoting BA‐induced liver injury in part by targeting MLL4. The miR‐210/MLL4 axis is a potential target for the treatment of BA‐associated hepatobiliary disease.

    更新日期:2019-09-25
  • Comparison of risk scores in the PSC arena
    Hepatology (IF 14.971) Pub Date : 2019-09-24
    EC Goode; GM Hirschfield; SM Rushbrook

    Primary sclerosing cholangitis (PSC) is a rare liver disease with high clinical burden and significant heterogeneity in outcome. The UK‐PSC risk scores(1), based upon a national observational cohort study of >1000 patients from across the UK, provide a robust evaluation of PSC risk for individual patients based on clinical predictors of outcome.

    更新日期:2019-09-25
  • Fair comparisons in the arena of risk scores
    Hepatology (IF 14.971) Pub Date : 2019-09-23
    Junfeng Wang; Ronald B. Geskus; Mariska M.G. Leeflang; Cyriel Y. Ponsioen

    We congratulate Goode and colleagues on their work(1). We are happy to see several research groups are working on this topic, underscoring the importance of the need for predicting outcome of PSC. The authors mention the Amsterdam‐Oxford PSC score, which contains similar variables and evaluates almost the same outcomes and state that it has a moderate C statistic of 0.68, and suggest the UK‐PSC score is superior due to its C‐statistic of 0.80.

    更新日期:2019-09-23
  • HBx protein contributes to liver carcinogenesis by H3K4me3 modification through stabilizing WD repeat domain 5 protein
    Hepatology (IF 14.971) Pub Date : 2019-09-22
    Weiwu Gao; Zhengcai Jia; Yi Tian; Penghui Yang; Hui Sun; Chenhui Wang; Yi Ding; Mengjie Zhang; Yi Zhang; Di Yang; Zhiqiang Tian; Jian Zhou; Zhihua Ruan; Yuzhang Wu; Bing Ni

    Cancer is typically considered as a genetic and epigenetic disease. While numerous studies have indicated that aberrant structure, function or expression level of epigenetic enzymes contribute to many tumor types, precisely how the epigenetic mechanisms are involved in the hepatitis B virus (HBV)‐induced hepatocellular carcinoma (HCC) remains unknown. In this study, we found that the WD repeat domain 5 protein (WDR5)—a core subunit of histone H3 lysine 4 methyltransferase complexes, which catalyze the generation of histone H3 lysine 4 trimethylation (H3K4me3) modification—is highly expressed in HBV‐related HCC and promotes HCC development. WDR5 plays a critical role in HBV‐driven cell proliferation and tumor growth in mice, and the WDR5‐0103 small molecule inhibitor of WDR5 activity compromises HBV‐ and HBx‐driven tumor proliferation. The aberrantly high WDR5 protein level was found to involve the HBV x protein (HBx) through its stabilization of the WDR5 protein by inhibiting the interaction between the damage‐specific DNA binding protein 1/ cullin‐4 (DDB1‐CUL4) and WDR5, causing decreased ubiquitination of the WDR5 protein. HBx was found to colocalize with WDR5 on chromatin genome‐wide and promotes genome‐wide H3K4me3 modification via WDR5. Furthermore, the recruitment of HBx to promoters of target genes relied on its interaction with WDR5, through its α‐helix domain. WDR5 was also found to promote HBV transcription via H3K4 modification of cccDNA minichromosome, and WDR5‐0103 was able to inhibit HBV transcription. Finally, the in vitro and in vivo data further proved that HBx exerted its tumor promoting function in a WDR5‐dependent manner.

    更新日期:2019-09-23
  • Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps
    Hepatology (IF 14.971) Pub Date : 2019-09-23
    Amedeo Lonardo; Fabio Nascimbeni; Stefano Ballestri; DeLisa Fairweather; Sanda Win; Tin A. Than; Manal F. Abdelmalek; Ayako Suzuki

    Despite tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex differences in NAFLD remains insufficient. This review summarizes the current knowledge on sex differences in NAFLD, identifies gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate the sex differences observed in patients, with more severe steatosis and steatohepatitis, more proinflammatory/profibrotic cytokines, and a higher incidence of hepatic tumors in male than female subjects. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex‐specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use. Conclusion: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD, suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines; adequate consideration of sex differences, sex hormones/menopausal status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.

    更新日期:2019-09-23
  • RPB5‐mediating protein promotes cholangiocarcinoma tumorigenesis and drug resistance by competing with NRF2 for KEAP1 binding
    Hepatology (IF 14.971) Pub Date : 2019-09-21
    Zheng‐Hua Wan; Tian‐Yi Jiang; Yuan‐Yuan Shi; Yu‐Fei Pan; Yun‐Kai Lin; Yun‐Han Ma; Chun Yang; Xiao‐Fan Feng; Li‐Feng Huang; Xiao‐Ni Kong; Zhi‐Wen Ding; Ye‐Xiong Tan; Li‐Wei Dong; Hong‐Yang Wang

    Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is mainly regulated by NRF2 during tumorigenesis. Here, we demonstrated that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. RMP‐overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 via the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP‐KEAP1‐NRF2 axis promotes ICC tumorigenesis, metastasis and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.

    更新日期:2019-09-22
  • The novel tumor suppressor IRF2BP2 regulates Hippo pathway in liver cancer via a feedback loop
    Hepatology (IF 14.971) Pub Date : 2019-09-20
    Xue Feng; Tiantian Lu; Jinhui Li; Ruizeng Yang; Liqiao Hu; Yi Ye; Feifei Mao; Lingli He; Jinjin Xu; Zuoyun Wang; Yingbin Liu; Yonglong Zhang; Hongbin Ji; Yun Zhao; Shuqun Cheng; Wei Tian; Lei Zhang

    The conserved Hippo pathway regulates organ size, tissue homeostasis and tumorigenesis. IRF2BP2 was originally identified as a transcriptional co‐repressor. However, the association between IRF2BP2 and Hippo pathway remains largely unknown. In addition, the biological function and the regulation mechanism of IRF2BP2 in liver cancer are poorly understood. In this study, we uncovered the clinical significance of IRF2BP2 in suppressing hepatocellular carcinogenesis. We showed that IRF2BP2, a direct target repressed by the YAP‐TEAD4 transcriptional complex, inhibited YAP activity via a feedback loop. IRF2BP2 stabilized VGLL4, and further enhanced VGLL4’s inhibitory function on YAP. Moreover, liver‐specific IRF2BP2 overexpression suppressed tumor formation induced by Hippo pathway inactivation. These results revealed the important role of IRF2BP2 in repressing liver cancer progression, and highlighted a feedback loop underlying Hippo pathway in organ size control and tumorigenesis.

    更新日期:2019-09-21
  • Targeting HDAC6 Reprograms TH17 Pathogenicity and Facilitates Immunotherapies for Hepatocellular Carcinoma
    Hepatology (IF 14.971) Pub Date : 2019-09-20
    Weinan Qiu; Bin Wang; Yanan Gao; Yuan Tian; Meijie Tian; Yuanying Chen; Li Xu; Tso‐Pang Yao; Peng Li; Pengyuan Yang

    Hepatocellular carcinoma (HCC) often accompanies with resistance to immunotherapies despite the presence of tumor‐infiltrating lymphocytes. Here we report that HDAC6 represses TH17 cell pathogenicity and antitumor immune response dependent on its deacetylase activity. Adoptive transfer of HDAC6‐deficient TH17 cell impedes HCC growth dependent on elevated IL‐17A via enhancing the production of antitumor cytokine and CD8+ T cell‐mediated antitumor responses. Intriguingly, HDAC6‐depleted T cells triggers PD‐1‐PD‐L1 expression to achieve a strong synergistic effect to sensitize advanced HCC to immune checkpoint blocker, while blockade of IL‐17A partially suppresses it. Mechanistically, HDAC6 limits TH17 pathogenicity and antitumor effect through regulating FoxO1. HDAC6 binds and deacetylates cytosolic FoxO1 at K242, which is required for its nuclear translocation and stabilization to repress RoRγt, the transcription factor of TH17 cell. This regulation of HDAC6 for murine and human TH17 cell is highly conserved.

    更新日期:2019-09-21
  • Near infrared spectroscopy reveals brain hypoxia and cerebrovascular dysregulation in primary biliary cholangitis
    Hepatology (IF 14.971) Pub Date : 2019-09-19
    Chris C. Duszynski; V. Avati; A.P. Lapointe; F. Scholkmann; J.F. Dunn; M.G. Swain

    Primary Biliary Cholangitis (PBC) is an autoimmune cholestatic liver disease linked to symptoms including fatigue and altered mood/cognition, indicating that chronic liver inflammation associated with PBC can impact brain function. We employed near infrared spectroscopy (NIRS), a non‐invasive neuroimaging technique, to determine whether PBC patients exhibit reduced cerebral oxygen saturation (StO2) and altered patterns of microvascular cerebral blood perfusion, and whether these alterations were associated with clinical phenotype. This observational case‐control study was conducted at a tertiary hospital clinic (University of Calgary Liver Unit). Thirteen females with non‐cirrhotic PBC, seven females with cirrhotic PBC, and eleven healthy female controls were recruited via physician referral and word of mouth, respectively. Near infrared spectroscopy was used to measure cerebral hemoglobin and oxygen saturation. A wavelet phase coherence method was used to estimate the coherent frequency coupling of temporal changes in cerebral hemodynamics. The PBC group demonstrated significantly reduced cerebral StO2 (p = 0.01, d = 0.84), indicating cerebral hypoxia, significantly increased cerebral deoxy‐hemoglobin (HHb) concentration (p < 0.01, d = 0.86), and significantly reduced hemodynamic coherence in the low‐frequency band (0.08‐0.15 Hz) for oxygenated hemoglobin (O2Hb) concentration (p = 0.02, d = 0.99) and tHb concentration (p = 0.02, d = 0.50), indicating alterations in cerebrovascular activity. Complete biochemical response to ursodexycholic acid (UDCA) therapy in early PBC patients was associated with increased cerebral tHb concentration and decreased hemodynamic coherence.

    更新日期:2019-09-19
  • Adjuvant Treatment of Hepatocellular Carcinoma: Prospect of Immunotherapy
    Hepatology (IF 14.971) Pub Date : 2019-09-19
    Zachary J. Brown; Tim F. Greten; Bernd Heinrich

    Although patients undergo procedures with curative intent for early‐stage hepatocellular carcinoma (HCC), up to 70% of patients may have disease recurrence in the liver at 5 years. Thus far, no therapy has proven to be effective in the adjuvant setting. Here, we discuss the application of immune‐based therapies in the adjuvant setting for HCC, focusing on the underlying rationale for immunotherapies, which patients may benefit from an immune‐based therapy, and what type of immune therapy should be implemented.

    更新日期:2019-09-19
  • Portal Pressure in Non‐Cirrhotic Portal Hypertension: To Measure or Not to Measure
    Hepatology (IF 14.971) Pub Date : 2019-09-18
    Ashish Kumar; Praveen Sharma; Anil Arora

    We read with interest the article by Da et al. (1) on hepatic venous pressure gradient (HVPG) measurement in patients with non‐cirrhotic portal hypertension (NCPH). The authors on the basis of HVPG measurement in a cohort of 53 patients had concluded that it is not useful in patients suspected to have NCPH.

    更新日期:2019-09-18
  • REPLY: Portal Pressure in Non‐Cirrhotic Portal Hypertension: To Measure or Not to Measure
    Hepatology (IF 14.971) Pub Date : 2019-09-18
    Ben L. Da; Christopher Koh; Theo Heller

    We appreciate the interest in our work and the commentary provided by Professor Kumar and colleagues. To clarify, we do believe that hepatic venous pressure gradient (HVPG) measurement is a viable clinical tool that can be used in addition to liver biopsy in distinguishing non‐cirrhotic portal hypertension (NCPH) versus cirrhosis. However, this is rarely necessary unless tissue sample obtained during the biopsy is insufficient. Performance of HVPG measurements, compared to percutaneous liver biopsy, subject patients to prolonged procedure times, requires additional allocation of medical resources, all while resulting in smaller and narrower cores that make histologic interpretation less reliable.(1) The latter being the most crucial liability as the tissue itself is the gold standard in differentiating NCPH from cirrhosis.

    更新日期:2019-09-18
  • Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3
    Hepatology (IF 14.971) Pub Date : 2019-09-17
    Jing Fang; Yan‐Xiao Ji; Peng Zhang; Lin Cheng; Yue Chen; Jun Chen; Yanfang Su; Xu Cheng; Yan Zhang; Tianyu Li; Xuehai Zhu; Xiao‐Jing Zhang; Xiang Wei

    Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decade, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor‐2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically downregulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown. Herein, using gain‐ and loss‐of‐function approaches in mice, we demonstrated that while hepatocyte‐specific Irf2bp2 knockout exacerbated high‐fat diet‐induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout‐exaggerated hepatosteatosis in vitro.

    更新日期:2019-09-18
  • Hepatocyte Elovl6 determines ceramide acyl‐chain length and hepatic insulin sensitivity in mice
    Hepatology (IF 14.971) Pub Date : 2019-09-17
    Takashi Matsuzaka; Motoko Kuba; Saori Koyasu; Yuta Yamamoto; Kaori Motomura; Sundaram Arulmozhiraja; Hiroshi Ohno; Rahul Sharma; Takuya Shimura; Yuka Okajima; Song‐iee Han; Yuichi Aita; Yuhei Mizunoe; Yoshinori Osaki; Hitoshi Iwasaki; Shigeru Yatoh; Hiroaki Suzuki; Hirohito Sone; Yoshinori Takeuchi; Naoya Yahagi; Takafumi Miyamoto; Motohiro Sekiya; Yoshimi Nakagawa; Masatsugu Ema; Satoru Takahashi; Hiroaki Tokiwa; Hitoshi Shimano

    Dysfunctional hepatic lipid metabolism is a cause of non‐alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes (T2D). ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity‐induced insulin resistance by modifying hepatic C16/C18‐related FA composition. To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver‐specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high‐fat diet‐induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high‐sucrose diet (HSD), which induces lipogenesis. Hepatic patatin‐like phospholipase domain‐containing protein 3 (Pnpla3) expression was downregulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD‐fed LKO mice. Lipidomic analyzes showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to its biological inhibitor I2PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6‐ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum (ER) and a Pnpla3‐CerS4 complex on lipid droplets (LDs). Consistent with this, liver‐specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity, and ameliorated insulin resistance.

    更新日期:2019-09-18
  • Hypoxia‐Inducible Factor (HIF)‐2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury via the Production of Interleukin‐6
    Hepatology (IF 14.971) Pub Date : 2019-09-17
    Rachel Y. Gao; Meng Wang; Qihui Liu; Dechun Feng; Yankai Wen; Yang Xia; Sean P. Colgan; Holger K. Eltzschig; Cynthia Ju

    Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one‐third of patients in the United States. The effectiveness of the only antidote, N‐acetylcysteine (NAC), declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover novel targets for therapeutic interventions. We observed that APAP challenge caused the stabilization of hypoxia‐inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particular HIF‐2α. Genetic deletion of the HIF‐2α gene in myeloid cells (HIF‐2α mye/‐) markedly exacerbated APAP‐induced liver injury (AILI) without affecting APAP bio‐activation and detoxification. In contrast, hepatic and serum levels of the hepato‐protective cytokine interleukin (IL)‐6, its downstream signal transducer and transcription factor 3 (STAT3) activation in hepatocytes, as well hepatic MΦs IL‐6 expression were markedly reduced in HIF‐2α mye/‐ mice compared to WT mice post APAP challenge. In vitro experiments revealed that hypoxia induced IL‐6 production in hepatic MΦs and that such induction was abolished in HIF‐2α‐deleted hepatic MΦs. Restoration of IL‐6 by administration of exogenous IL‐6 ameliorated AILI in HIF‐2α mye/‐ mice. Finally, IL‐6‐mediated hepatoprotection against AILI was abolished in hepatocyte‐specific IL‐6 receptor knockout mice.

    更新日期:2019-09-18
  • γδ T cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming
    Hepatology (IF 14.971) Pub Date : 2019-09-17
    Alejandro Torres‐Hernandez; Wei Wang; Yuri Nikiforov; Karla Tejada; Luisana Torres; Aleksandr Kalabin; Salma Adam; Jingjing Wu; Lu Lu; Ruonan Chen; Aaron Lemmer; Jimmy Camargo; Mautin Hundeyin; Brian Diskin; Berk Aykut; Emma Kurz; Juan A. Kochen Rossi; Mohammed Khan; Miguel Liria; Gustavo Sanchez; Nan Wu; Wenyu Su; Steven Adams; Muhammad Israr Ul Haq; Mohammad Saad Farooq; Varshini Vasudevaraja; Joshua Leinwand; George Miller

    The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis. We found that in steatohepatitis, γδT cells are recruited to the liver by CCR2, CCR5, and NOD2 signaling and are skewed towards an IL‐17A+ phenotype in an ICOS‐ICOSL dependent manner. γδT cells exhibit a distinct Vγ4+, PD1+, Ly6C+CD44+ phenotype in steatohepatitis. Moreover, γδT cells upregulate both CD1d, which is necessary for lipid‐based antigens presentation, and the free fatty acid receptor CD36. γδT cells are stimulated to express IL‐17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet‐induced steatohepatitis and accelerates disease resolution. We demonstrate that hepatic γδT cells exacerbate steatohepatitis, independent of IL‐17 expression, by mitigating conventional CD4+ T cell expansion and modulating their inflammatory program via CD1d‐dependent VEGF expression.

    更新日期:2019-09-18
  • Immunomodulatory mechanism of acyclic nucleoside phosphates in treatment of hepatitis B virus infection
    Hepatology (IF 14.971) Pub Date : 2019-09-17
    Kazumoto Murata; Senko Tsukuda; Futoshi Suizu; Akihiro Kimura; Masaya Sugiyama; Koichi Watashi; Masayuki Noguchi; Masashi Mizokami

    Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic and novel therapies are desired. It has been believed that all NUCs have similar function to inhibit HBV reverse‐transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)‐λ3 in the gastrointestinal tract suggests that ANPs are not only distinct in their structures but also in their functions from nucleoside analogs (lamivudine and entecavir). Since enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS‐mediated cytokine profile in PBMCs. This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS‐mediated interleukin (IL)‐10 production, which reciprocally induced IL‐12p70 and tumor necrosis factor‐α production in a dose‐dependent manner. Furthermore, the combination of IFN‐α and ANPs synergistically enhanced LPS‐mediated IL‐12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS‐mediated IL‐10 production.

    更新日期:2019-09-18
  • FGF19‐mediated upregulation of SOX18 promotes hepatocellular carcinoma metastasis by transactivating FGFR4 and FLT4
    Hepatology (IF 14.971) Pub Date : 2019-09-16
    Jie Chen; Feng Du; Yunzhi Dang; Xiaowei Li; Meirui Qian; Weibo Feng; Chenyang Qiao; Daiming Fan; Yongzhan Nie; Kaichun Wu; Limin Xia

    The poor prognosis of patients with hepatocellular carcinoma (HCC) is mainly attributed to its high rate of metastasis and recurrence. However, the molecular mechanisms underlying HCC metastasis need to be elucidated. The SRY‐related HMG box (SOX) family proteins, which are a group of highly conserved transcription factors, play important roles in cancer initiation and progression. Here, we report a novel role of SOX18, a member of the SOX family, in promoting HCC invasion and metastasis. The elevated expression of SOX18 was positively correlated with poor tumor differentiation, higher TNM stage, and poor prognosis. The overexpression of SOX18 promoted HCC metastasis by upregulating metastasis‐related genes, including fibroblast growth factor receptor 4 (FGFR4) and fms‐related tyrosine kinase 4 (FLT4). Knockdown of both FGFR4 and FLT4 significantly decreased SOX18‐mediated HCC invasion and metastasis, while the stable overexpression of FGFR4 and FLT4 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. Fibroblast growth factor 19 (FGF19), which is the ligand of FGFR4, upregulated SOX18 expression. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the FGF19‐FGFR4 pathway relied on the p‐FRS2/p‐GSK3β/β‐catenin pathway. SOX18 knockdown significantly reduced FGF19‐enhanced HCC invasion and metastasis. Furthermore, BLU9931, a specific FGFR4 inhibitor, significantly reduced the SOX18‐mediated HCC invasion and metastasis. In human HCC tissues, SOX18 expression was positively correlated with FGF19, FGFR4 and FLT4 expression, and patients that coexpressed FGF19/SOX18, SOX18/FGFR4, or SOX18/FLT4 had the worst prognosis.

    更新日期:2019-09-18
  • MELD‐GRAIL‐Na: Glomerular filtration rate and mortality on Liver‐Transplant Waiting List
    Hepatology (IF 14.971) Pub Date : 2019-09-16
    Sumeet K. Asrani; Linda W. Jennings; WR Kim; Patrick Kamath; Josh Levitsky; Mitra K. Nadim; Giuliano Testa; Michael Leise; James F. Trotter; Goran Klintmalm

    Among patients with cirrhosis awaiting liver transplantation, prediction of waitlist (WL) mortality is adjudicated by Model for End Stage liver disease‐sodium (MELD‐Na) score. Replacing serum creatinine (Scr) with estimated glomerular filtration rate (eGFR) in the MELD‐Na score may improve prediction of WL mortality, especially for women and highest disease severity.

    更新日期:2019-09-16
  • Paneth cell dysfunction mediates alcoholic steatohepatitis through promoting bacterial translocation in mice: role of zinc deficiency
    Hepatology (IF 14.971) Pub Date : 2019-09-14
    Wei Zhong; Xiaoyuan Wei; Liuyi Hao; Tai‐Du Lin; Ruichao Yue; Xinguo Sun; Wei Guo; Haibo Dong; Tianjiao Li; Ali R. Ahmadi; Zhaoli Sun; Qibin Zhang; Jiangchao Zhao; Zhanxiang Zhou

    Microbial dysbiosis is associated with alcoholic hepatitis (AH) with the mechanisms yet to be elucidated. The present study aimed to determine the effects of alcohol and zinc deficiency on Paneth cell (PC) antimicrobial peptides ‐ α‐defensins, and to define the link between PC dysfunction and AH. Translocation of pathogen‐associated molecular patterns (PAMPs) was determined in patients with severe AH and in a mouse model of alcoholic liver disease. Microbial composition and PC function were examined in mice. The link between α‐defensin dysfunction and AH was investigated in α‐defensin deficient mice. Synthetic human α‐defensin 5 (HD5) was orally given to the alcohol‐fed mice to test the therapeutic potential. The role of zinc deficiency in α‐defensin was evaluated in acute and chronic mouse models of zinc deprivation. Hepatic inflammation was associated with PAMP translocation, and lipocalin‐2 (LCN2) and CXCL1 elevation in AH patients. Antibiotic treatment, lipopolysaccharide injection to mice, and in vitro experiments showed that PAMPs, but not alcohol, directly induced LCN2 and CXCL1. Chronic alcohol feeding caused systemic dysbiosis and PC α‐defensin reduction in mice. Knockout of functional α‐defensins synergistically affected alcohol‐perturbed bacterial composition and gut barrier, and exaggerated PAMP translocation and liver damage. Administration of HD5 effectively altered cecal microbial composition, especially increased Akkermansia muciniphila, and reversed alcohol‐induced deleterious effects. Zinc regulated PC homeostasis and α‐defensins function at multiple levels, and dietary zinc deficiency exaggerated the deleterious effect of alcohol on PC bactericidal activity

    更新日期:2019-09-16
  • The engineered anti‐GPC3 immunotoxin, HN3‐ABD‐T20, produces regression in mouse liver cancer xenografts via prolonged serum retention
    Hepatology (IF 14.971) Pub Date : 2019-09-14
    Bryan D. Fleming; Daniel J. Urban; Matthew Hall; Thomas Longerich; Tim Greten; Ira Pastan; Mitchell Ho

    Treatment of hepatocellular carcinomas (HCC) using our glypican‐3 (GPC3)‐targeting human nanobody (HN3) immunotoxins causes potent tumor regression by blocking protein synthesis and down‐regulating the Wnt signaling pathway. However, immunogenicity and a short serum half‐life may limit the ability of immunotoxins to transition to the clinic. To address these concerns, we engineered HN3‐based immunotoxins to contain various deimmunized Pseudomonas exotoxin (PE) domains. This included HN3‐T20, which was modified to remove T‐cell epitopes and contains a PE domain II truncation. We compared them to our previously reported B cell deimmunized immunotoxin (HN3‐mPE24) and our original HN3‐immunotoxin with a wild‐type PE domain (HN3‐PE38). All of our immunotoxins displayed high affinity to human GPC3, with HN3‐T20 having a KD value of 7.4 nM. HN3‐T20 retained 73% enzymatic activity when compared to the wild‐type immunotoxin in an ADP‐ribosylation assay. Interestingly, a real‐time cell growth inhibition assay demonstrated that a single dose of HN3‐T20 at 62.5 ng/ml (1.6 nM) was capable of inhibiting nearly all cell proliferation during the 10‐day experiment. To enhance HN3‐T20’s serum retention, we tested the effect of adding a streptococcal albumin binding domain (ABD) and a llama single‐domain antibody fragment specific for mouse and human serum albumin (ALB1). For the detection of immunotoxin in mouse serum, we developed a highly sensitive ELISA and found that HN3‐ABD‐T20 had a 45‐fold higher serum half‐life than HN3‐T20 (326 min vs 7.3 minutes); consequently, addition of an albumin binding domain resulted in HN3‐ABD‐T20 mediated tumor regression at 1 mg/kg. Conclusion These data show that albumin binding deimmunized HN3‐T20 immunotoxins are high potency therapeutics ready to be evaluated in clinical trials for the treatment of liver cancer.

    更新日期:2019-09-16
  • Hepatology Elsewhere
    Hepatology (IF 14.971) Pub Date : 2019-09-13
    Heung Bae Kim; Scott A. Elisofon

    The paper from LeeVan et al entitled “Biliary‐Enteric Drainage vs Primary Liver Transplant as Initial Treatment for Children with Biliary Atresia” is a retrospective cohort study that examines long‐term outcomes for children with biliary atresia (BA) through analysis of information obtained from the California Office of Statewide Health Planning and Development (OSHPD), an administrative database. Specifically, the authors compare outcomes between a cohort of BA patients who underwent a biliary enteric drainage (BED) procedure (presumably a Kasai hepatoportoenterostomy) as the primary therapy to those who underwent a primary liver transplant (pLT) without a previous BED.

    更新日期:2019-09-14
  • Highly elevated plasma γ‐glutamyltransferase elevations: a trait caused by GGT1 transmembrane mutations
    Hepatology (IF 14.971) Pub Date : 2019-09-13
    Alessandro de Grandi; Maria Franzini; Štefan Rosipal; Rastislav Rosipal; Marianna Debreova; Alessandro Corti; Elisabeth Ruetzler‐Dichtl; Sabine Scholl‐Bürgi; Aldo Paolicchi; Alfonso Pompella; Michele Emdin; Germano Zampa; Heiko Witt; Heinz Zoller; Herbert Tilg; Ertan Mayatepek; Diran Herebian; Peter P. Pramstaller; Thomas Müller; Andreas R. Janecke

    Assay of γ‐glutamyl transferase (GGT) activity is a widely used test to indicate and monitor liver and biliary tract injury. We observed dominant inheritance of highly elevated plasma GGT levels, designated GGTemia, in two unrelated families. Neither clinical symptoms nor alterations of GGT substrates were associated with GGTemia. A plasma GGT fractions pattern distinguishes this trait from common liver diseases. Heterozygous GGT1 mutations that disrupt the GGT1 transmembrane domain were identified. We establish GGTemia as a benign condition; GGT1 mutation testing can prevent repeated and invasive diagnostic workup in such patients.

    更新日期:2019-09-14
  • Predicting Heart Failure After TIPS: Still More Questions Than Answers
    Hepatology (IF 14.971) Pub Date : 2019-09-13
    Anna Baiges; Juan Carlos Garcia‐Pagán

    The transjugular intrahepatic portosystemic shunt (TIPS) is a percutaneous imaging‐guided procedure that effectively reduces portal pressure by diverting blood from the portal to the systemic circulation. Despite being a very effective treatment for portal hypertension–related complications, the use of TIPS was hampered for many years by the high rate of TIPS dysfunction, an issue that has become almost anecdotal since the introduction of covered stents.(1)(1)(1) Currently, development of post‐TIPS hepatic encephalopathy and, much less frequently, post‐TIPS liver and cardiac failure remain as the major complications of TIPS, limiting its use. Until effective preventive and/or therapeutic strategies are available, adequate patient selection is the best existing approach to diminish the rate of these TIPS complications.

    更新日期:2019-09-14
  • Editorial: The 20% Rule of NASH Progression: The Natural History of Advanced Fibrosis and Cirrhosis due to NASH
    Hepatology (IF 14.971) Pub Date : 2019-09-13
    Rohit Loomba; Leon A. Adams

    The global epidemic of obesity has led to the rise of non‐alcoholic fatty liver disease (NAFLD) as a significant cause of cirrhosis, end‐stage liver disease and need for liver transplantation.(1) NAFLD is common, with a global estimate of 25% of adults (2), however only a small proportion will progress to cirrhosis and develop liver related morbidity. As with other chronic liver diseases, the severity of underlying liver fibrosis aids prediction of outcome, with patients with bridging fibrosis or cirrhosis being at greatest risk of future liver related morbidity.(3) Nonetheless, key questions remain largely unanswered including what proportion of subjects develop progressive disease, how fast this occurs, and how to identify and monitor these individuals.

    更新日期:2019-09-14
  • A prospective study identifying predictive factors of cardiac decompensation after TIPS: the Toulouse algorithm
    Hepatology (IF 14.971) Pub Date : 2019-09-12
    Chloé Billey; Sophie Billet; Marie Angèle Robic; Thomas Cognet; Maeva Guillaume; Jean Pierre Vinel; Jean Marie Péron; Olivier Lairez; Christophe Bureau

    Transjugular intrahepatic portosystemic shunt (TIPS) is now a standard for the treatment of portal hypertension related complications. After TIPS procedure, the incidence and the risk factors of cardiac decompensation are poorly known. The main objectives were to measure the incidence of the onset of cardiac decompensation after TIPS and to identify the predictive factors.

    更新日期:2019-09-12
  • EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
    Hepatology (IF 14.971) Pub Date : 2019-09-12
    Laurent Gouya; Paolo Ventura; Manisha Balwani; D. Montgomery Bissell; David C. Rees; Ulrich Stölzel; John D. Phillips; Raili Kauppinen; Janneke G. Langendonk; Robert J. Desnick; Jean‐Charles Deybach; Herbert L. Bonkovsky; Charles Parker; Hetanshi Naik; Michael Badminton; Penelope E. Stein; Elisabeth Minder; Jerzy Windyga; Radan Bruha; Maria Domenica Cappellini; Eliane Sardh; Pauline Harper; Sverre Sandberg; Aasne K. Aarsand; Janice Andersen; Félix Alegre; Aneta Ivanova; Neila Talbi; Amy Chan; William Querbes; John Ko; Craig Penz; Shangbin Liu; Tim Lin; Amy Simon; Karl E. Anderson

    Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0‐52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0‐37.0]). Elevated levels of hepatic δ‐aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ‐aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day‐to‐day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

    更新日期:2019-09-12
  • A Novel hMTR4‐PDIA3P1‐miR‐125/124‐TRAF6 Regulatory Axis and Its Function in NF‐KB Signaling and Chemoresistance
    Hepatology (IF 14.971) Pub Date : 2019-09-11
    Chen Xie; Li‐Zhen Zhang; Zhan‐Li Chen; Wang‐Jing Zhong; Jian‐Hong Fang; Ying Zhu; Man‐Huan Xiao; Zhi‐Wei Guo; Na Zhao; Xionglei He; Shi‐Mei Zhuang

    We found that lncRNA PDIA3P1 (protein disulfide isomerase family A member 3 pseudogene 1) was up‐regulated in multiple cancer types and upon treatment with DNA‐damaging chemotherapeutic agents, like doxorubicin (Dox). Higher PDIA3P1 level was associated with poorer recurrence‐free survival of human hepatocellular carcinoma (HCC). Both gain‐ and loss‐of‐function studies revealed that PDIA3P1 protected cancer cells from Dox‐induced apoptosis and allowed tumor xenografts to grow faster and to be more resistant to Dox treatment. Mechanistically, miR‐125a/b and miR‐124 suppressed the expression of tumor necrosis factor receptor–associated factor 6 (TRAF6), but PDIA3P1 bound to miR‐125a/b/miR‐124 and relieved their repression on TRAF6, leading to activation of the nuclear factor‐KB (NF‐KB) pathway. Consistently, the effect of PDIA3P1 inhibition in promoting Dox‐triggered apoptosis was antagonized by silencing the inhibitor of KBα (IKBαor overexpressing TRAF6. Administration of BAY 11‐7085, an NF‐KB inhibitor, attenuated PDIA3P1‐induced resistance to Dox treatment in mouse xenografts. Moreover, up‐regulation of PDIA3P1 was significantly correlated with elevation of TRAF6, phosphorylated p65, or NF‐KB downstream anti‐apoptosis genes in human HCC tissues. These data indicate that enhanced PDIA3P1 expression may confer chemoresistance by acting as a microRNA (miRNA) sponge to increase TRAF6 expression and augment NF‐KB signaling. Subsequent investigations into the mechanisms of PDIA3P1 up‐regulation revealed that human homologue of mRNA transport mutant 4 (hMTR4), which promotes RNA degradation, could bind to PDIA3P1, and this interaction was disrupted by Dox treatment. Overexpression of hMTR4 attenuated Dox‐induced elevation of PDIA3P1, whereas silencing hMTR4 increased PDIA3P1 level, suggesting that Dox may up‐regulate PDIA3P1 by abrogating the hMTR4‐mediated PDIA3P1 degradation

    更新日期:2019-09-12
  • Discovery and validation of a biomarker model (preserve) predictive of renal outcomes after liver transplantation
    Hepatology (IF 14.971) Pub Date : 2019-09-11
    Josh Levitsky; Sumeet K. Asrani; Goran Klintmalm; Thomas Schiano; Adyr Moss; Kenneth Chavin; Charles Miller; Kexin Guo; Lihui Zhao; Linda W. Jennings; Merideth Brown; Brian Armstrong; Michael Abecassis

    A high proportion of patients develop chronic kidney disease after liver transplantation. We aimed to develop clinical/protein models to predict future GFR deterioration in this population. In independent multicenter discovery (CTOT14) and single center validation (BUMC) cohorts, we analyzed kidney injury proteins in serum/plasma samples at month 3 after liver transplant in recipients with preserved GFR who demonstrated subsequent GFR deterioration vs. preservation by year 1, and year 5 in the BUMC cohort. In CTOT14, we also examined correlations between serial protein levels and GFR over the first year. A month 3 predictive model was constructed from clinical and protein level variables using the CTOT14 cohort (n=60). Levels of β2‐microglobulin and CD40 antigen and presence of HCV infection predicted early (year 1) GFR deterioration (AUC 0.814). We observed excellent validation of this model (AUC 0.801) in the BUMC cohort (n=50) who had both early and late (year 5) GFR deterioration. At an optimal threshold, the model had the following performance characteristics in CTOT14 and BUMC, respectively: accuracy (0.75, 0.8), sensitivity (0.71, 0.67), specificity (0.78, 0.88), positive predictive value (0.74, 0.75) and negative predictive value (0.76, 0.82). In the serial CTOT14 analysis, several proteins, including β2‐microglobulin and CD40, correlated with GFR changes over the first year. Conclusion: We have validated a clinical/protein model (PRESERVE) that early after liver transplantation can predict future renal deterioration vs. preservation with high accuracy. This model may help select recipients at higher risk for subsequent chronic kidney disease for early, proactive renal sparing strategies.

    更新日期:2019-09-12
  • Acute Liver Failure from Exertional Heatstroke Can Result in Excellent Long‐term Survival with Liver Transplantation
    Hepatology (IF 14.971) Pub Date : 2019-09-11
    Xia Bi; Adam Deising; Catherine Frenette

    The incidence of heat‐related illnesses has been on the rise due to global climate change [1]. Active‐duty service members are at an increased risk of heat related illness due to the physical demands placed upon them in austere training environments [2,3]. Exertional heatstroke (EHS) is the most serious form of heat illness that may rarely progress to acute liver failure (ALF). Although a prior case series has documented variables associated with prognosis [4], the long­term outcomes of those transplanted for EHS remain largely unknown. Here, we present a case series of patients who suffered from EHS­induced ALF and describe the clinical characteristics and long­term outcomes associated with the condition.

    更新日期:2019-09-12
  • Vitamin D receptor activation in liver macrophages ameliorates hepatic inflammation, steatosis, and insulin resistance in mice
    Hepatology (IF 14.971) Pub Date : 2019-09-11
    Bingning Dong; Ying Zhou; Wei Wang; Jessica Scott; Kang Ho Kim; Zhen Sun; Qi Guo; Yang Lu; Naomi M. Gonzales; Huaizhu Wu; Sean Hartig; Robert Brian York; Feng Yang; David D. Moore

    Obesity‐induced chronic inflammation is a key component in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Increased secretion of pro‐inflammatory cytokines by macrophages in metabolic tissues promotes disease progression. In the diet induced obesity mouse (DIO) model, activation of liver resident macrophages, or Kupffer cells (KC), drives inflammatory responses, which recruits circulating macrophages and promotes fatty liver development, and ultimately contributes to impaired hepatic insulin sensitivity. Hepatic macrophage express the highest level of Vitamin D receptor (VDR) among non‐parenchymal cells, while VDR expression is very low in hepatocytes. VDR activation exerts anti‐inflammatory effects in immune cells. Here we found that VDR activation exhibits strong anti‐inflammatory effects in mouse hepatic macrophages, including those isolated from DIO livers, while mice with genetic loss of Vdr developed spontaneous hepatic inflammation at 6 months of age. Under the chronic inflammation conditions of the DIO model, VDR activation by the vitamin D analog calcipotriol reduced liver inflammation and hepatic steatosis, significantly improving insulin sensitivity. The hyperinsulinemic euglycemic clamp revealed that VDR activation greatly increased the glucose infusion rate, while hepatic glucose production was remarkably decreased. Glucose uptake in muscle and adipose did not show similar effects, suggesting that improved hepatic insulin sensitivity is the primary contributor to the beneficial effects of VDR activation. Finally, specifically ablating liver macrophages by treatment with clodronate liposomes largely abolished the beneficial metabolic effects of calcipotriol, confirming that VDR activation in liver macrophages is required for the anti‐diabetic effect. Conclusion: Activation of liver macrophage VDR by vitamin D ligands ameliorates liver inflammation, steatosis and insulin resistance. Our results suggest novel therapeutic paradigms for treatment of NAFLD and T2D.

    更新日期:2019-09-11
  • PDLIM1 inhibits tumor metastasis through activating Hippo signaling in hepatocellular carcinoma
    Hepatology (IF 14.971) Pub Date : 2019-09-11
    Zhao Huang; Jian‐Kang Zhou; Kui Wang; Haining Chen; Siyuan Qin; Jiayang Liu; Maochao Luo; Yan Chen; Jingwen Jiang; Li Zhou; Lei Zhu; Juan He; Jiao Li; Wenchen Pu; Yanqiu Gong; Jianbo Li; Qin Ye; Dandan Dong; Hongbo Hu; Zongguang Zhou; Lunzhi Dai; Canhua Huang; Xiawei Wei; Yong Peng

    Tumor metastasis is a major factor of high recurrence and mortality in hepatocellular carcinoma (HCC), but its underlying mechanism remains elusive. Here we report that PDZ and LIM domain protein 1 (PDLIM1) is significantly downregulated in metastatic human HCC tissues, which predicts unfavorable prognosis, suggesting that PDLIM1 may play an important inhibitory role during HCC metastasis. Functional studies indicate that PDLIM1 knockdown induces epithelial‐to‐mesenchymal transition (EMT) of HCC cells, elevates their invasive capacity and promotes metastasis in vitro and in vivo, whereas overexpression of PDLIM1 exhibits opposite phenotypes. Mechanistically, PDLIM1 competitively binds to the cytoskeleton cross‐linking protein ACTN4, leading to the disassociation of ACTN4 from F‐actin, thus preventing F‐actin overgrowth. In contrast, loss of PDLIM1 induces excessive F‐actin formation, resulting in dephosphorylation of LATS1 and activation of YAP, thereby promoting HCC metastasis. Moreover, Asn145 (N145) of PDLIM1 is critical for its interaction with ACTN4, and N145A mutation abolishes its regulatory function in Hippo signaling and HCC metastasis.

    更新日期:2019-09-11
  • Hepatocyte Stress Increases Expression of YAP and TAZ in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis
    Hepatology (IF 14.971) Pub Date : 2019-09-10
    Meghan Mooring; Brendan H. Fowl; Shelly Z.C. Lum; Ye Liu; Kangning Yao; Samir Softic; Rory Kirchner; Aaron Bernstein; Aatur D. Singhi; Daniel G. Jay; C. Ronald Kahn; Fernando D. Camargo; Dean Yimlamai

    Activated hepatocytes are hypothesized to be a major source of signals that drive cirrhosis, but the biochemical pathways that convert hepatocytes into such a state are unclear. We examined the role of the Hippo pathway transcriptional coactivators, YAP/TAZ in hepatocytes to facilitate cell‐cell interactions that stimulate liver inflammation and fibrosis. Using a variety of genetic, metabolic and liver injury models in mice, we manipulated Hippo signaling in hepatocytes and examined its effects in non‐parenchymal cells to promote liver inflammation and fibrosis. YAP expressing hepatocytes rapidly and potently activate the expression of proteins that promote fibrosis (COL1A1, TIMP1, PDGFc, TGFβ2) and inflammation (TNF, IL1β). They stimulate expansion of myofibroblasts and immune cells followed by aggressive liver fibrosis. In contrast, hepatocyte‐specific YAP and YAP/TAZ knockouts exhibit limited myofibroblast expansion, less inflammation, and decreased fibrosis after carbon tetrachloride injury despite a similar degree of necrosis as controls. We identified CYR61 as a chemokine that is upregulated by hepatocytes during liver injury but is expressed at significantly lower levels in mice with hepatocyte‐specific deletion of YAP or TAZ. Gain and loss of function experiments with CYR61 in vivo point to it being a key chemokine controlling liver fibrosis and inflammation in the context of YAP/TAZ. There is a direct correlation between levels of YAP/TAZ and CYR61 in liver tissues of high‐grade NASH patients.

    更新日期:2019-09-11
  • Utilization of HCV‐Viremic Organs for HCV Negative Recipients: Is Practice Speeding Past the Evidence?
    Hepatology (IF 14.971) Pub Date : 2019-09-10
    Elizabeth C. Verna; Demetra Tsapepas; Jean C. Emond; Robert S. Brown; Sumit Mohan

    Over nearly 3 decades, organs from donors with hepatitis C virus (HCV) have been widely used for recipients with HCV without detrimental impact on recurrence, graft survival, or the incidence of cholestatic hepatitis. The recent availability of highly effective antiviral therapy has dramatically decreased the number of HCV‐viremic transplant candidates, contributing to underutilization of HCV‐viremic donors in recent years. Combined with an increase in HCV‐viremic donors due to opioid overdose death, experts have proposed the use of HCV‐viremic donors in HCV‐negative transplant recipients with post‐transplant DAA therapy.

    更新日期:2019-09-11
  • Monoacylglycerol lipase inhibition protects from liver injury in mouse models of sclerosing cholangitis
    Hepatology (IF 14.971) Pub Date : 2019-09-10
    Matteo Tardelli; Francesca V. Bruschi; Claudia D. Fuchs; Thierry Claudel; Nicole Auer; Victoria Kunczer; Maximilian Baumgartner; Onne A.H.O. Ronda; Henk Jan Verkade; Tatjana Stojakovic; Hubert Scharnagl; Aida Habib; Robert Zimmermann; Sophie Lotersztajn; Michael Trauner

    Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FA) and converting 2‐arachidonoylglycerol into arachidonic acid (AA), thus providing ligands for nuclear receptors (NRs) as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis (SC), a disease so far lacking effective pharmacological therapy. To this aim we analyzed the effects of 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) feeding to induce SC in wild type (WT) and knockout (MGL‐/‐) mice and tested pharmacological inhibition with JZL184 in the Mdr2‐/‐ mouse model of SC. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL‐/‐ mice were protected from DDC‐induced biliary fibrosis and inflammation with reduced serum liver enzymes, increased FA/BA metabolism and β‐oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC‐fed WT mice and protected Mdr2‐/‐ from spontaneous liver injury, with improved liver enzymes, inflammation and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E2 accumulation in the intestine upregulating peroxisome proliferator activated receptor (PPAR) ‐α and ‐γ activity, thus reducing inflammation. Conclusions: Collectively, our study unravels MGL as a novel metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for SC.

    更新日期:2019-09-11
  • Wnt/β‐Catenin signaling plays a protective role in the Mdr2 KO murine model of cholestatic liver disease
    Hepatology (IF 14.971) Pub Date : 2019-09-06
    Tirthadipa Pradhan‐Sundd; Karis Kosar; Harvinder Saggi; Rong Zhang; Ravi Vats; Pamela Cornuet; Sydney Green; Sucha Singh; Gang Zeng; Prithu Sundd; Kari Nejak‐Bowen

    The Wnt/β‐catenin signaling pathway has a well‐described role in liver pathobiology. Its suppression was recently shown to decrease bile acid (BA) synthesis, thus preventing the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL). To generalize these observations, we suppressed β‐catenin in Mdr2 knockout (KO) mice, which develop sclerosing cholangitis due to regurgitation of BA from leaky ducts. When β‐catenin was knocked down (KD) in KO for 2 weeks, hepatic and biliary injury were exacerbated in comparison to KO given placebo, as shown by serum biochemistry, ductular reaction, inflammation, and fibrosis. Simultaneously, KO/KD livers displayed increased oxidative stress and senescence and an impaired regenerative response. Although total liver BA levels were similar between KO/KD and KO, there was significant dysregulation of BA transporters and BA detoxification/synthesis enzymes in KO/KD compared to KO alone. Multiphoton intravital microscopy revealed a mixing of blood and bile in the sinusoids, and validated the presence of increased serum BA in KO/KD mice. Although hepatocyte junctions were intact, KO/KD livers had significant canalicular defects, which resulted from loss of hepatocyte polarity. Thus, in contrast to the protective effect of β‐catenin KD in BDL model, β‐catenin KD in Mdr2 KO aggravated rather than alleviated injury by interfering with expression of BA transporters, hepatocyte polarity, canalicular structure, and the regenerative response. The resulting imbalance between ongoing injury and restitution led to worsening of the Mdr2 KO phenotype, suggesting caution in targeting β‐catenin globally for all cholestatic conditions.

    更新日期:2019-09-06
  • Liver Transplantation in Unauthorized Immigrants in the United States
    Hepatology (IF 14.971) Pub Date : 2019-09-05
    Brian P. Lee; Norah A. Terrault

    Eleven million unauthorized immigrants reside in the US, and may account for 3% of deceased organ donors. Recently introduced Federal and state legislation propose to address access to organ transplantation among unauthorized immigrants. The national landscape of liver transplantation (LT) for unauthorized immigrants is unknown. We included all US LT recipients between March 2012 and December 2018, linked to Pew Center of Research data to estimate the population of unauthorized immigrants in each US state and by country of origin, based on US Census data. We categorized patients as unauthorized immigrants versus US citizens/residents. The main outcome measures were: (i) Proportion of LTs performed for unauthorized immigrants compared to proportion of unauthorized immigrants among total population in each US state; (ii) Graft failure and death post‐LT. Of 43,192 LT recipients, 43,026 (99.6%) were US citizens/residents, and 166 (0.4%) were unauthorized immigrants. Among unauthorized immigrants, most LTs were performed in California (47%) and New York (18%). The absolute difference in proportion of LTs performed for unauthorized immigrants compared to the proportion of unauthorized immigrants among the total population differed among states, ranging from +20% in California to ‐12% in Texas. The most common countries of birth among LT recipients who were unauthorized immigrants were Mexico (52%), Guatemala (7%), China (6%), El Salvador (5%), and India (5%). In competing risk analysis, unauthorized immigration status (vs. US citizens/residents) was associated with similar risk of graft failure (sHR 0.74, 95% CI:0.40 to 1.34, p=0.38) and death (sHR 0.68, 95%:CI 0.36 to 1.29, p=0.23).

    更新日期:2019-09-06
  • The unexpected role of neutrophils for resolving liver inflammation by transmitting microRNA‐223 to macrophages
    Hepatology (IF 14.971) Pub Date : 2019-09-04
    Adrien Guillot; Frank Tacke

    Neutrophils are commonly recognized as prototypic inflammatory cells: They invade the liver upon injury, have a short half‐life in inflamed tissue and aggravate injury as well as inflammatory reactions. This has been conclusively demonstrated for acute acetaminophen injury in mice, where myeloid‐cell specific receptor for advanced glycation end products (RAGE)‐deficiency dramatically altered neutrophil recruitment to necrotic areas, and high‐mobility group box 1 (HMGB1) epithelial cell deficiency in the liver prevented all acetaminophen‐induced mortality.

    更新日期:2019-09-05
  • Retraction statement: Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice
    Hepatology (IF 14.971) Pub Date : 2019-09-04

    Qian Sun, Patricia Loughran, Richard Shapiro, Indira H. Shrivastava, Daniel J. Antoine, Tunliang Li, Zhengzheng Yan, Jie Fan, Timothy R. Billiar, and Melanie J. Scott. Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice. Hepatology 2017, doi: 10.1002/hep.28893.

    更新日期:2019-09-05
  • Tumor‐Derived PGLYRP2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma
    Hepatology (IF 14.971) Pub Date : 2019-09-03
    Zongyi Yang; Jia Feng; Li Xiao; Xi Chen; Yuanfei Yao; Yiqun Li; Yu Tang; Shuai Zhang; Min Lu; Yu Qian; Hongjin Wu; Ming Shi

    Hepatocellular carcinoma (HCC) is linked to immunosuppression. Relieving immunosuppression has been becoming an attractive strategy to improve the efficacy of cancer immunotherapy. PGLYRP2 is a pattern recognition receptor, which is specifically expressed in liver and implicated in regulation of innate immunity and immunosurveillance. However, the role of hepatic PGLYRP2 in modulating immune responses against HCC remains to be investigated. In this study, we aimed to investigate whether PGLYRP2 is able to influence HCC progression through regulating host antitumor immune responses. Here we demonstrated that PGLYRP2 was down‐regulated in HCC, which was linked with poor prognosis in patients (p<0.001). PGLYRP2 overexpression in HCC cells significantly enhanced antitumor immune responses in immune‐competent mice, and elevated immune response rates of PBMCs against HCC. Mechanistically, DNMT3A‐mediated promoter hypermethylation was responsible for the downregulation of PGLYRP2 in HCC. PGLYRP2 promoted production of chemokine CCL5 in HCC via binding to CCL5 promoter, which contributed to the enhanced antitumor immunity. Conclusions: we provide evidence that tumor‐derived PGLYRP2 acts as a candidate biomarker for adequate immune response against HCC and improved patient outcomes, indicating the importance of hepatic PGLYRP2 in cancer immunosurveillance and in designing novel immunotherapeutic approaches.

    更新日期:2019-09-04
  • Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants
    Hepatology (IF 14.971) Pub Date : 2019-06-05
    Sanne Brun Jensen; Ulrik Fahnøe; Long V. Pham; Stéphanie Brigitte Nelly Serre; Qi Tang; Lubna Ghanem; Martin Schou Pedersen; Santseharay Ramirez; Daryl Humes; Anne Finne Pihl; Jonathan Filskov; Christina Søhoel Sølund; Julia Dietz; Slim Fourati; Jean‐Michel Pawlotsky; Christoph Sarrazin; Nina Weis; Kristian Schønning; Henrik Krarup; Jens Bukh; Judith Margarete Gottwein

    Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance–associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1‐4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156‐RASs were not maintained. For genotypes 1 and 2, persistence of 156‐RASs depended on genome‐wide substitution networks, co‐selected under continued PI treatment and identified by next‐generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156‐RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre‐existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156‐RASs, we observed genome‐wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1‐6 revealed 156‐RASs as key determinants of high‐level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1‐3 156‐variants, which might pose a threat to clinically relevant combination treatments.

    更新日期:2019-08-31
  • The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS‐9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis
    Hepatology (IF 14.971) Pub Date : 2019-03-10
    Michael Trauner; Aliya Gulamhusein; Bilal Hameed; Stephen Caldwell; Mitchell L. Shiffman; Charles Landis; Bertus Eksteen; Kosh Agarwal; Andrew Muir; Simon Rushbrook; Xiaomin Lu; Jun Xu; Jen‐Chieh Chuang; Andrew N. Billin; Georgia Li; Chuhan Chung; G. Mani Subramanian; Robert P. Myers; Christopher L. Bowlus; Kris V. Kowdley

    Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double‐blind, placebo‐controlled study, we tested the safety and efficacy of cilofexor (formerly GS‐9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large‐duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α‐hydroxy‐4‐cholesten‐3‐one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288‐439) and 0.7 mg/dL (0.5‐1.0), respectively. Dose‐dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction −21%; P = 0.029 versus placebo), gamma‐glutamyl transferase (−30%; P < 0.001), alanine aminotransferase (ALT) (−49%; P = 0.009), and aspartate aminotransferase (−42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid–treated and untreated patients. At week 12, cilofexor‐treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyl transferase, tissue inhibitor of metalloproteinase 1, C‐reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo‐treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12‐week, randomized, placebo‐controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.

    更新日期:2019-08-31
  • Efficacy of Granulocyte Colony‐stimulating Factor in the Management of Steroid‐Nonresponsive Severe Alcoholic Hepatitis: A Double‐Blind Randomized Controlled Trial
    Hepatology (IF 14.971) Pub Date : 2019-03-25
    Saggere Muralikrishna Shasthry; Manoj Kumar Sharma; Varsha Shasthry; Apurva Pande; Shiv Kumar Sarin

    Severe alcoholic hepatitis (SAH) is often a progressive disease with high mortality and limited steroid responsiveness. Management options of steroid nonresponsive SAH (day 7 Lille score > 0.45) are limited. We assessed the efficacy and safety of granulocyte colony‐stimulating factor (G‐CSF) in steroid nonresponders. A randomized, double‐blind, single‐center trial (NCT01820208) was conducted between March 2013 and June 2016 in patients with histologically proven SAH, nonresponsive to 40 mg/day of prednisolone were randomized to G‐CSF (12 doses, 300 μg each in 28 days) or placebo. Responders were continued with prednisolone. Of the 430 patients with SAH, 132 received steroid therapy. Of these, 33 (25%) were nonresponders and were randomized to G‐CSF or placebo (14 in each group after exclusions). The baseline characteristics of both groups were comparable. The 28‐day mortality was comparable between the groups (21.4%, G‐CSF; 28.6%, placebo; P = 0.69). At 90 days, in the G‐CSF but not in the placebo group, the Model for End‐Stage Liver Disease reduced from 24.6 ± 3.9 to 19.4 ± 3.7 (P = 0.002) and Maddrey’s discriminant function from 74.8 ± 22.8 to 57.4 ± 31 (P = 0.26). Infections were less common (28% versus 71%; P < 0.001) with lower 90‐day mortality (35.7% versus 71.4%; P = 0.04) in the G‐CSF than in the placebo group. On Cox regression analysis, receiving G‐CSF (hazard ratio, 0.37; SD, 0.14‐0.98; P = 0.04), and high baseline serum creatinine (hazard ratio, 4.12; SD, 1.7‐10.3; P = 0.002) predicted day‐90 outcomes in steroid nonresponsive SAH. Patients tolerated G‐CSF without any major adverse events. Conclusion: Approximately one‐quarter of patients with SAH do not respond to corticosteroid therapy. Administration of G‐CSF is safe and helps to reduce the disease severity and 90‐day mortality in these patients.

    更新日期:2019-08-31
  • Association Between Nonalcoholic Fatty Liver Disease and Reduced Bone Mineral Density in Children: A Meta‐Analysis
    Hepatology (IF 14.971) Pub Date : 2019-03-18
    Alessandro Mantovani; Davide Gatti; Giacomo Zoppini; Giuseppe Lippi; Enzo Bonora; Christopher D. Byrne; Valerio Nobili; Giovanni Targher

    Recent cross‐sectional studies have examined the association between nonalcoholic fatty liver disease (NAFLD) and bone mineral density (BMD) in children or adolescents, but these have produced conflicting results. We performed a systematic review and meta‐analysis of these published studies to quantify the magnitude of the association, if any, between NAFLD and BMD. We searched publication databases from January 2000 to September 2018, using predefined keywords to identify relevant observational studies conducted in children or adolescents in whom NAFLD was diagnosed either by imaging or by histology and BMD Z score was measured by dual‐energy X‐ray absorptiometry. Data from selected studies were extracted, and a meta‐analysis was performed using random‐effects modeling. A total of eight observational cross‐sectional or case–control studies enrolling 632 children and adolescents (mean age 12.8 years), 357 of whom had NAFLD, were included in the final analysis. Meta‐analysis showed significant differences in whole‐body or lumbar BMD Z scores between children/adolescents with and without NAFLD (n = 6 studies; pooled weighted mean difference [WMD], –0.48; 95% confidence interval [CI], –0.74 to –0.21; I2 = 55.5%), as well as between those with biopsy‐confirmed nonalcoholic steatohepatitis (NASH) and those with no‐NASH (n = 4 studies; pooled WMD, –0.27; 95% CI, –0.40 to –0.13; I2 = 0%). The aforementioned WMDs in BMD Z scores were independent of common clinical risk factors, such as age, sex, race/ethnicity, and body mass index. Sensitivity analyses did not modify these findings. Funnel plot and Egger test did not reveal significant publication bias. Conclusion: This meta‐analysis shows that the presence and severity of NAFLD are significantly associated with reduced whole‐body BMD Z scores in children and adolescents; however, the observational design of the studies included does not allow for proving causality.

    更新日期:2019-08-31
  • Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma
    Hepatology (IF 14.971) Pub Date : 2019-03-15
    Jian‐Hong Fang; Li Xu; Li‐Ru Shang; Chu‐Zhi Pan; Jin Ding; Yun‐Qiang Tang; Hui Liu; Chu‐Xing Liu; Jia‐Lin Zheng; Yao‐Jun Zhang; Zhong‐Guo Zhou; Jing Xu; Limin Zheng; Min‐Shan Chen; Shi‐Mei Zhuang

    Sorafenib is the most recommended first‐line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC‐mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+/VETC–) was investigated. Kaplan‐Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio [HR] = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC‐ patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+, but not VETC–, patients. Further mechanistic investigations showed that VETC+ and VETC– HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal‐regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC‐pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC– irrespective of levels of pERK/EC‐pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC– HCCs may not result from activation of Raf/mitogen‐activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+, but not VETC–, patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.

    更新日期:2019-08-31
  • Stereotactic Radiofrequency Ablation of Hepatocellular Carcinoma: a Histopathological Study in Explanted Livers
    Hepatology (IF 14.971) Pub Date : 2019-02-14
    Reto Bale; Peter Schullian; Gernot Eberle; Daniel Putzer; Heinz Zoller; Stefan Schneeberger; Claudia Manzl; Patrizia Moser; Georg Oberhuber

    This retrospective study was performed to evaluate the efficacy of three‐dimensional (3D)‐navigated multiprobe radiofrequency ablation (RFA) with intraprocedural image fusion for treatment of hepatocellular carcinoma (HCC) by histopathological examination. From 2009 to 2018, 97 patients (84 men, 13 women; median age, 60 years; range, 1‐71) were transplanted after bridging therapy of 195 HCCs by stereotactic RFA (SRFA). The median interval between the first SRFA and transplantation was 6.8 months (range, 0‐71). The rate of residual vital tissue (RVT) could be assessed in 188 of 195 lesions in 96 of 97 patients by histological examination of the explanted livers using hematoxylin and eosin (H&E) and Tdt‐mediated UTP nick‐end labeling (TUNEL) stains. Histopathological results were compared with the findings of the last computed tomography (CT) imaging before liver transplantation (LT). Median number and size of treated tumors were 1 (range, 1‐8) and 2.5 cm (range, 1‐8). Complete radiological response was achieved in 186 of 188 nodules (98.9%) and 94 of 96 patients (97.9%) and complete pathological response in the explanted liver specimen in 183 of 188 nodules (97.3%) and 91 of 96 patients (94.8%), respectively. In lesions ≥3 cm, complete tumor cell death was achieved in 50 of 52 nodules (96.2%). Residual tumor did not correlate with tumor size (P = 0.5). Conclusion: Multiprobe SRFA with intraprocedural image fusion represents an efficient, minimally invasive therapy for HCC, even with tumor sizes larger than 3 cm, and without the need of a combination with additional treatments. The results seem to justify the additional efforts related to the stereotactic approach.

    更新日期:2019-08-31
  • Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice
    Hepatology (IF 14.971) Pub Date : 2019-05-13
    Congwen Wei; Xiaoli Yang; Ning Liu; Jin Geng; Yanhong Tai; Zhenyu Sun; Gangwu Mei; Pengyu Zhou; Yumeng Peng; Chenbin Wang; Xiaoli Zhang; Pingping Zhang; Yunqi Geng; Yujie Wang; Xiaotong Zhang; Xin Liu; Yanhong Zhang; Feixiang Wu; Xiang He; Hui Zhong

    The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor‐promoting inflammation by up‐regulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of Golgi protein 73 (GP73), a Golgi‐associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Through GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor‐associated macrophage (TAM) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with glucose‐regulated protein 78 (GRP78) expression and TAM density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth, and prolonged survival in two mouse HCC models. Conclusion: Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals.

    更新日期:2019-08-31
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