ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation

doi:10.1016/j.jhep.2019.12.004

Journal of Hepatology

Volume 72, Issue 5, May 2020, Pages 976-989

https://doi.org/10.1016/j.jhep.2019.12.004 Get rights and content

Highlights

•
ARRB1 is downregulated in NASH samples from both patients and mouse models.
•
ARRB1 deficiency accelerates NASH development by increasing lipogenesis and decreasing β-oxidation.
•
ARRB1 protects against NASH by facilitating GDF15 precursor maturation and secretion.
•
ARRB1 could serve as a novel potential target for NASH treatment.

Background & Aims

Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation. The causal mechanism underlying NASH is not fully elucidated. This study investigated the role of β-Arrestin1 (ARRB1) in the progression of NASH.

Methods

Liver tissue from patients with NASH and controls were obtained to evaluate ARRB1 expression. NASH models were established in Arrb1-knockout and wild-type mice fed either a high-fat diet (HFD) for 26 weeks or a methionine/choline-deficient (MCD) diet for 6 weeks.

Results

ARRB1 expression was reduced in liver samples from patients with NASH. Reduced Arrb1 levels were also detected in murine NASH models. Arrb1 deficiency accelerated steatohepatitis development in HFD-/MCD-fed mice (accompanied by the upregulation of lipogenic genes and downregulation of β-oxidative genes). Intriguingly, ARRB1 was found to interact with growth differentiation factor 15 (GDF15) and facilitated the transportation of GDF15 precursor (pro-GDF15) to the Golgi apparatus for cleavage and maturation. Treatment with recombinant GDF15 ablated the lipid accumulation in the presence of Arrb1 deletion both in vitro and in vivo. Re-expression of Arrb1 in the NASH models ameliorated the liver disease, and this effect was greater in the presence of pro-GDF15 overexpression. By contrast, the effect of pro-GDF15 overexpression alone was impaired in Arrb1-deficient mice. In addition, the severity of liver disease in patients with NASH was negatively correlated with ARRB1 expression.

Conclusion

ARRB1 acts as a vital regulator in the development of NASH by facilitating the translocation of GDF15 to the Golgi apparatus and its subsequent maturation. Thus, ARRB1 is a potential therapeutic target for the treatment of NASH.

Lay summary

Non-alcoholic steatohepatitis (NASH) is associated with the progressive dysfunction of lipid metabolism and a consequent inflammatory response. Decreased ARRB1 is observed in patients with NASH and murine NASH models. Re-expression of Arrb1 in the murine NASH model ameliorated liver disease, an effect which was more pronounced in the presence of pro-GDF15 overexpression, highlighting a promising strategy for NASH therapy.

Graphical abstract

Introduction

Metabolic disorders, including obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD), have become a public health issue worldwide as a result of dramatic changes to human lifestyles and dietary choices.¹^,² Excessive nutritional intake and decreased energy expenditure appear to be crucial in the pathogenesis of NAFLD. This disease comprises a spectrum of liver diseases, ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and liver cancer.³^,⁴ NASH is associated with reprogrammed hepatic metabolic profiles that lead to excessive lipid accumulation in the liver and imbalances in lipid metabolism and lipid catabolism.⁵^,⁶ More advanced NASH is associated with impaired lipid metabolism, leading to the accumulation of triglycerides and other lipids in hepatocytes.⁷ Lipotoxicity in the liver is the primary insult that initiates and propagates damage leading to hepatocyte injury and resulting inflammation.⁸ Hepatic lipid homeostasis is fine-tuned by a complex machinery comprising hormones, signaling and/or transcriptional pathways, and downstream genes associated with lipogenesis and lipolysis.⁹ Although many molecular regulatory networks have been described, the underlying mechanisms initiating the metabolic rearrangement and inflammatory response underlying NASH remain incompletely elucidated.

β-Arrestin1 (ARRB1), originally identified as a negative regulator of G-protein-coupled receptor (GPCR) signaling, has been demonstrated to function as molecular scaffold that regulates cellular function by interacting with other partner proteins, and is involved in multiple physiological process, including immune response, tumorigenesis, and inflammation.[10], [11], [12], [13] ARRB1 has also been found to regulate the NF-κB pathway in multiple inflammatory disease models.¹⁴^,¹⁵ In addition, previous research showed that ARRB1 is involved in regulating hepatocellular carcinoma aggressiveness by mediating the desensitization and internalization of CD97.¹⁶ Moreover, ARRB1 partially represses diet-induced obesity and improves glucose tolerance by interacting with peroxisome proliferator-activated receptor (PPAR)-γ in preadipocytes.¹⁷ However, the regulatory roles of ARRB1 in hepatic inflammation and lipid metabolism disorder during the progression of NASH remain unknown.

The regulation of energy balance in the liver and other peripheral tissues is influenced by humoral factors that impact various metabolic activities, such as lipolysis and lipogenesis. The dysregulation of hormones or cytokines, including leptin, adiponectin, and insulin, contributes to metabolic disorders and hepatic lipid accumulation. Thus, more comprehensive elucidation of the causal mechanism underlying abnormal expression of these hormones or cytokines could enable the development of new therapeutic approaches for NASH. Growth Differentiation Factor 15 (GDF15; also known as Macrophage Inhibitor 1), is predominantly expressed in the liver and is a member of the Transforming Growth Factor (TGF)-beta superfamily.¹⁸ GDF15 is initially translated to GDF15 precursor (pro-GDF15) in dimeric form and is subsequently cleaved and secreted as mature GFD15 dimers.¹⁹^,²⁰ Recent studies showed that GDF15 activates AKT, ERK1/2, and PLCγ by binding GDNF-Family Receptor-α-Like (GFRAL) and through a GFRAL-RET complex present in cells, thus, reducing food intake, driving weight loss, and enhancing glucose homeostasis.¹⁸^,[21], [22], [23] In addition, GDF15 alleviates fatty acid metabolic dysfunction in the liver, indicating that the liver is the direct target organ of GDF15.²⁴ However, the post-translational regulation of GDF15, such as the maturation of pro-GDF15, and the downstream molecular mechanisms of GDF15 in hepatocytes, remain to be investigated.

The results from the current study demonstrate that ARRB1 expression is diminished in liver samples from patients with NASH and in murine NASH models. Arrb1 deficiency accelerates the development of steatohepatitis in mice fed either a high-fat diet (HFD) or methionine/choline-deficient diet (MCDD) and upregulates lipogenic genes and downregulates β-oxidative genes. Functionally, ARRB1 interacts with GDF15 and facilitates the transportation of pro-GDF15 to the Golgi apparatus for cleavage and maturation, thereby promoting fatty acid β-oxidation and inhibiting de novo lipogenesis. Thus, our results collectively indicate that ARRB1 is a crucial regulator linking GDF15 maturation to the development of NASH.

Section snippets

Human liver samples

Liver samples with NASH were obtained from patients with NAFLD who were undergoing bariatric surgery (n = 40). Three experienced pathologists, blinded to clinical data, evaluated independently all the liver specimens according to the NAFLD activity score (NAS), defined as the sum of steatosis, inflammation, and hepatocyte ballooning. Patients with a NAS score ≥5 were considered likely to have NASH. The exclusion criteria were the presence of other causes of liver disease, including alcohol

Patients with NASH and mouse models of NASH have low hepatic levels of ARRB1

To investigate the involvement of ARRB1 in NASH, we first analyzed the expression of ARRB1 in liver samples from 40 patients without NASH and 40 patients pathologically diagnosed with NASH. Both hepatic ARRB1 mRNA and protein levels were significantly lower in patients with NASH than in those without NASH (Fig. 1A–C). Moreover, Arrb1 expression was lower at both the mRNA and protein levels in the liver of WT mice fed an HFD compared with those fed a LFD for 26 weeks, or in the liver of mice fed

Discussion

This study demonstrates that ARRB1 has an important role in the pathogenesis of NASH. The expression of ARRB1 was diminished in livers from patients or mice with NASH. Moreover, deletion of Arrb1 significantly exacerbated hepatic steatosis, fibrosis, and inflammation in both HFD- and MCDD-fed mouse models. Mechanistically, ARRB1 interacts with pro-GDF15 and promotes its localization to the Golgi apparatus where it undergoes cleavage and/or maturation.

ARRB1 was originally identified and

Financial support

This work was supported by grants from the National Key Research and Development Program of China (Grant number 2016YFC0905900 to B.S.), State Key Program of the National Natural Science Foundation (Grant numbers 81430062 and 81930086 to B.S.), National Natural Science Youth Foundation (Grant number 81600487 to W.T.), and Innovative Research Groups of the National Natural Science Foundation (Grant number 81521004 to B.S.). B.S. is Distinguished Professor Yangtze River Scholar.

Authors’ contributions

Z.Z., X.X., W.T., and R.J. drafted the manuscript; Z.Z., X.X., R.J., Y.L., Q.S., R.F., Q.H., J.W., Y.L., and H.Y. conducted the experiments; Z.Z., X.X., R.J., W.T., and B.S. participated in research design; W.T. and B.S. contributed to the writing of the manuscript, discussed data, and supervised the study; all authors performed data analysis and interpretation, and read and approved the final manuscript.

Conflict of interest

The authors declare no conflict of interest that pertains to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

References (48)

C. Estes et al.
Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030
J Hepatol
(2018)
J. Font-Burgada et al.
Obesity and cancer: the oil that feeds the flame
Cell Metab
(2016)
M. Eslam et al.
Genetics and epigenetics of NAFLD and NASH: clinical impact
J Hepatol
(2018)
M.V. Machado et al.
Pathogenesis of nonalcoholic steatohepatitis
Gastroenterology
(2016)
J.S. Smith et al.
The beta-arrestins: multifunctional regulators of G protein-coupled receptors
J Biol Chem
(2016)
S. Tan et al.
beta-Arrestin-1 protects against endoplasmic reticulum stress/p53-upregulated modulator of apoptosis-mediated apoptosis via repressing p-p65/inducible nitric oxide synthase in portal hypertensive gastropathy
Free Radic Biol Med
(2015)
L.N. Zhuang et al.
Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma)
J Biol Chem
(2011)
M. Zhang et al.
Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid beta-oxidation and ketogenesis via activating XBP1 signaling in liver
Redox Biol
(2018)
V.W.W. Tsai et al.
The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases
Cell Metab
(2018)
L.N. Zhuang et al.
Beta-arrestin-1 protein represses diet-induced obesity
J Biol Chem
(2011)

D. Son et al.

miR-374a-5p promotes tumor progression by targeting ARRB1 in triple negative breast cancer

Cancer Lett

(2019)

X. Zhang et al.

CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy

J Hepatol

(2016)

S.J. Baek et al.

Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia

Gastroenterology

(2006)

Z. Younossi et al.

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Nat Rev Gastroenterol Hepatol

(2018)

S.L. Friedman et al.

Mechanisms of NAFLD development and therapeutic strategies

Nat Med

(2018)

D. Greco et al.

Gene expression in human NAFLD

Am J Physiol Gastrointest Liver Physiol

(2008)

S.S. Choi et al.

Hepatic triglyceride synthesis and nonalcoholic fatty liver disease

Curr Opin Lipidol

(2008)

T. Hardy et al.

Nonalcoholic fatty liver disease: pathogenesis and disease spectrum

Annu Rev Pathol

(2016)

S.M. DeWire et al.

Beta-arrestins and cell signaling

Annu Rev Physiol

(2007)

Y. Shi et al.

Critical regulation of CD4+ T cell survival and autoimmunity by beta-arrestin 1

Nat Immunol

(2007)

Y. Yang et al.

beta-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

Nat Commun

(2015)

L. Tao et al.

beta-Arrestin1 alleviates acute pancreatitis via repression of NF-kappaBp65 activation

J Gastroenterol Hepatol

(2019)

Y. Yin et al.

CD97 promotes tumor aggressiveness through the traditional G protein-coupled receptor-Mediated signaling in hepatocellular carcinoma

Hepatology

(2018)

J.Y. Hsu et al.

Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15

Nature

(2017)

Cited by (36)

GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
2024, Metabolism: Clinical and Experimental
The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL.
To examine how GDF15 regulates AMPK.
Wild-type and Gdf15^−/− mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used.
Gdf15^−/− mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-β1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15^−/− mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-β1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15^−/− mice.
Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-β1/SMAD3 pathway.
Integrative multi-omics deciphers the spatial characteristics of host-gut microbiota interactions in Crohn's disease
2023, Cell Reports Medicine
Dysregulated host-microbial interactions play critical roles in initiation and perpetuation of gut inflammation in Crohn’s disease (CD). However, the spatial distribution and interaction network across the intestine and its accessory tissues are still elusive. Here, we profile the host proteins and tissue microbes in 540 samples from the intestinal mucosa, submucosa-muscularis-serosa, mesenteric adipose tissues, mesentery, and mesenteric lymph nodes of 30 CD patients and spatially decipher the host-microbial interactions. We observe aberrant antimicrobial immunity and metabolic processes across multi-tissues during CD and determine bacterial transmission along with altered microbial communities and ecological patterns. Moreover, we identify several candidate interaction pairs between host proteins and microbes associated with perpetuation of gut inflammation and bacterial transmigration across multi-tissues in CD. Signature alterations in host proteins (e.g., SAA2 and GOLM1) and microbes (e.g., Alistipes and Streptococcus) are further imprinted in serum and fecal samples as potential diagnostic biomarkers, thus providing a rationale for precision diagnosis.
Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis
2022, Journal of Hepatology
Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation, though the underlying mechanisms remain unclear. We aimed to investigate the role of X-box binding protein-1 (XBP1) in the progression of NASH.
Human liver tissues obtained from patients with NASH and controls were used to assess XBP1 expression. NASH models were developed in hepatocyte-specific Xbp1 knockout (Xbp1^ΔHep), macrophage-specific Xbp1 knockout (Xbp1^ΔMf), macrophage-specific Nlrp3 knockout, and wild-type (Xbp1^FL/FL or Nlrp3^FL/FL) mice fed with a high-fat diet for 26 weeks or a methionine/choline-deficient diet for 6 weeks.
The expression of XBP1 was significantly upregulated in liver samples from patients with NASH. Hepatocyte-specific Xbp1 deficiency inhibited the development of steatohepatitis in mice fed the high-fat or methionine/choline-deficient diets. Meanwhile, macrophage-specific Xbp1 knockout mice developed less severe steatohepatitis and fibrosis than wild-type Xbp1^FL/FL mice in response to the high-fat or methionine/choline-deficient diets. Macrophage-specific Xbp1 knockout mice showed M2 anti-inflammatory polarization. Xbp1-deleted macrophages reduced steatohepatitis by decreasing the expression of NLRP3 and secretion of pro-inflammatory cytokines, which mediate M2 macrophage polarization in macrophage-specific Xbp1 knockout mice. Steatohepatitis was less severe in macrophage-specific Nlrp3 knockout mice than in wild-type Nlrp3^FL/FL mice. Xbp1-deleted macrophages prevented hepatic stellate cell activation by decreasing expression of TGF-β1. Less fibrotic changes were observed in macrophage-specific Xbp1 knockout mice than in wild-type Xbp1^FL/FL mice. Inhibition of XBP1 suppressed the development of NASH.
XBP1 regulates the development of NASH. XBP1 inhibitors protect against steatohepatitis. Thus, XBP1 is a potential target for the treatment of NASH.
XBP1 is a transcription factor that is upregulated in liver tissues of patients with non-alcoholic steatohepatitis (NASH). Conditional knockout of Xbp1 in hepatocytes resulted in decreased lipid accumulation in mice, while genetic deletion of Xbp1 in macrophages ameliorated nutritional steatohepatitis and fibrosis in mice. Pharmacological inhibition of XBP1 protects against steatohepatitis and fibrosis, highlighting a promising therapeutic strategy for NASH.
Corydalis saxicola Bunting Total Alkaloids ameliorate diet-induced non-alcoholic steatohepatitis by regulating hepatic PI3K/Akt and TLR4/NF-κB pathways in mice
2022, Biomedicine and Pharmacotherapy
Corydalis saxicola Bunting (Yanhuanglian), distributed in Southwest China, is mainly used for treatment of hepatitis, oral mucosal erosion, conjunctivitis, dysentery, acute abdominal pain and hemorrhoids in the folk. Corydalis saxicola Bunting Total Alkaloids (CSBTA) are the active ingredients extracted from the root of C. saxicola bunting. Non-alcoholic steatohepatitis (NASH) is the hinge between steatosis and cirrhosis in the spectrum of Non-alcoholic fatty liver disease (NAFLD), which has become one of the most common chronic liver diseases in the world. CSBTA can reduce tumors and brain diseases through anti-inflammatory and antioxidant pathways. Our study was designed to clarify the effects of CSBTA on the HFHC (High fat and high carbohydrate drinking) diet induced mice. In our research, A HFHC diet induced NASH mice model was applied to investigate the effects of CSBTA in vivo and obeticholic acid (OA) was set as positive control. Moreover, the underlying mechanisms were explored by palmitic acid (PA) and lipopolysaccharide (LPS) stimulated HepG2 cells in vitro. The in vivo study illustrated that CSBTA could alleviate mice away from the onset of NASH, and reduce intrahepatocellular lipid accumulation and hepatocyte inflammation under high fat condition. Further in vitro analysis confirmed that CSBTA attenuated inflammation and hepatic lipid accumulation by improving hepatic PI3K/Akt and suppressing hepatic TLR4/NF-κB pathways. In summary, this study demonstrated that CSBTA might be a promising compound for the treatment of NAFLD.
Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation
2022, Redox Biology
Citation Excerpt :
Liver-specific deletion of NAG-1/GDF15 via adenovirus injection has been reported to increase hepatic lipid and TG accumulation, and to inhibit fatty acid β-oxidation in the liver of fasting mice, accompanied by reduced gene expression of PPARa, ACOX1, and CPT1a [35]. A recent study reported that overexpression of NAG-1/GDF15 through adenovirus transfection in mice or using recombinant protein in hepatic cells inhibited lipid accumulation and the progression of NASH [36]. Together with our study, the current evidence suggests that NAG-1/GDF15 could be a promising target for the prevention or treatment of steatosis and NAFLD-related metabolic deterioration via regulating fatty acids metabolism.
Mitochondrial dysfunction and oxidative stress-mediated inflammasome activation play critical roles in the pathogenesis of the non-alcoholic fatty liver disease (NAFLD). Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1), or growth differentiation factor-15 (GDF15), is associated with many biological processes and diseases, including NAFLD. However, the role of NAG-1/GDF15 in regulating oxidative stress and whether this process is associated with absent in melanoma 2 (AIM2) inflammasome activation in NAFLD are unknown. In this study, we revealed that NAG-1/GDF15 is significantly downregulated in liver tissues of patients with steatosis compared to normal livers using the Gene Expression Omnibus (GEO) database, and in free fatty acids (FFA, oleic acid/palmitic acid, 2:1)-induced HepG2 and Huh-7 cellular steatosis models. Overexpression of NAG-1/GDF15 in transgenic (Tg) mice significantly alleviated HFD-induced obesity and hepatic steatosis, improved lipid homeostasis, enhanced fatty acid β-oxidation and lipolysis, inhibited fatty acid synthesis and uptake, and inhibited AIM2 inflammasome activation and the secretion of IL-18 and IL-1β, as compared to their wild-type (WT) littermates without reducing food intake. Furthermore, NAG-1/GDF15 overexpression attenuated FFA-induced triglyceride (TG) accumulation, lipid metabolism deregulation, and AIM2 inflammasome activation in hepatic steatotic cells, while knockdown of NAG-1/GDF15 demonstrated opposite effects. Moreover, NAG-1/GDF15 overexpression inhibited HFD- and FFA-induced oxidative stress and mitochondrial damage which in turn reduced double-strand DNA (dsDNA) release into the cytosol, while NAG-1/GDF15 siRNA showed opposite effects. The reduced ROS production and dsDNA release may be responsible for attenuated AIM2 activation by NAG-1/GDF15 upon fatty acid overload. In conclusion, our results provide evidence that other than regulating lipid homeostasis, NAG-1/GDF15 protects against hepatic steatosis through a novel mechanism via suppressing oxidative stress, mitochondrial damage, dsDNA release, and AIM2 inflammasome activation.
GDF15, an emerging key player in human aging
2022, Ageing Research Reviews
Citation Excerpt :
Moreover, very recently it has been observed that also β-arrestin 1 (ARRB1) plays a fundamental role in the maturation of GDF15 (Zhang et al., 2020; Wang et al., 2021). In particular, in hepatocytes ARRB1 binds the pro-GDF15 and facilitates its transport to the Golgi apparatus to promote the subsequent GDF15 cleavage and maturation through PCSK enzymes (Zhang et al., 2020; Wang et al., 2021). However, to date it is not yet clear what kind of stimuli (physiological or pathological) activate PCSK enzymes to regulate the maturation of GDF15 and their specific biological function in the aging process.
Growth differentiation factor 15 (GDF15) is recently emerging not only as a stress-related mitokine, but also as a key player in the aging process, being one of the most up-regulated protein with age and associated with a variety of age-related diseases (ARDs). Many data indicate that GDF15 has protective roles in several tissues during different stress and aging, thus playing a beneficial role in apparent contrast with the observed association with many ARDs. A possible detrimental role for this protein is then hypothesized to emerge with age. Therefore, GDF15 can be considered as a pleiotropic factor with beneficial activities that can turn detrimental in old age possibly when it is chronically elevated. In this review, we summarize the current knowledge on the biology of GDF15 during aging. We also propose GDF15 as a part of a dormancy program, where it may play a role as a mediator of defense processes aimed to protect from inflammatory damage and other stresses, according to the life history theory.

View all citing articles on Scopus

: Author names in bold designate shared co-first authorship

^†: These authors contributed equally as joint first co-authors.

View full text

Research ArticleARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation

Highlights

Background & Aims

Methods

Results

Conclusion

Lay summary

Graphical abstract

Introduction

Section snippets

Human liver samples

Patients with NASH and mouse models of NASH have low hepatic levels of ARRB1

Discussion

Financial support

Authors’ contributions

Conflict of interest

J Hepatol

Cell Metab

J Hepatol

Gastroenterology

J Biol Chem

Free Radic Biol Med

J Biol Chem

Redox Biol

Cell Metab

J Biol Chem

Cancer Lett

J Hepatol

Gastroenterology

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Nat Rev Gastroenterol Hepatol

Mechanisms of NAFLD development and therapeutic strategies

Nat Med

Gene expression in human NAFLD

Am J Physiol Gastrointest Liver Physiol

Hepatic triglyceride synthesis and nonalcoholic fatty liver disease

Curr Opin Lipidol

Nonalcoholic fatty liver disease: pathogenesis and disease spectrum

Annu Rev Pathol

Beta-arrestins and cell signaling

Annu Rev Physiol

Critical regulation of CD4+ T cell survival and autoimmunity by beta-arrestin 1

Nat Immunol

beta-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

Nat Commun

beta-Arrestin1 alleviates acute pancreatitis via repression of NF-kappaBp65 activation

J Gastroenterol Hepatol

CD97 promotes tumor aggressiveness through the traditional G protein-coupled receptor-Mediated signaling in hepatocellular carcinoma

Hepatology

Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15

Nature

Research Article
ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation