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  • Role of carotenoids and retinoids during heart development
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-22
    Ioan Ovidiu Sirbu; Aimée Rodica Chiş; Alexander Radu Moise

    The nutritional requirements of the developing embryo are complex. In the case of dietary vitamin A (retinol, retinyl esters and provitamin A carotenoids), maternal derived nutrients serve as precursors to signaling molecules such as retinoic acid, which is required for embryonic patterning and organogenesis. Despite variations in the composition and levels of maternal vitamin A, embryonic tissues need to generate a precise amount of retinoic acid to avoid congenital malformations. Here, we summarize recent findings regarding the role and metabolism of vitamin A during heart development and we survey the association of genes known to affect retinoid metabolism or signaling with various inherited disorders. A better understanding of the roles of vitamin A in the heart and of the factors that affect retinoid metabolism and signaling can help design strategies to meet nutritional needs and to prevent birth defects and disorders associated with altered retinoid metabolism. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2020-01-22
  • Lipidomic characterization of exosomes isolated from human plasma using various mass spectrometry techniques
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-21
    Ondřej Peterka; Robert Jirásko; Michaela Chocholoušková; Ladislav Kuchař; Denise Wolrab; Roman Hájek; David Vrána; Ondřej Strouhal; Bohuslav Melichar; Michal Holčapek
    更新日期:2020-01-22
  • The role of β-carotene and vitamin A in atherogenesis: Evidences from pre-clinical and clinical studies
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-21
    Anthony P. Miller; Johana Coronel; Jaume Amengual

    Atherosclerotic cardiovascular disease (ASCVD) is the principal contributor to myocardial infarction, the leading cause of death worldwide. Epidemiological and mechanistic studies indicate that β-carotene and its vitamin A derivatives stimulate lipid catabolism in several tissues to reduce the incidence of obesity, but their roles within ASCVD are elusive. Herein, we review the mechanisms by which β-carotene and vitamin A modulate ASCVD. First, we summarize the current knowledge linking these nutrients with epidemiological studies and lipoprotein metabolism as one of the initiating factors of ASCVD. Next, we focus on different aspects of vitamin A metabolism in immune cells such as the mechanisms of carotenoid uptake and conversion to the vitamin A metabolite, retinoic acid. Lastly, we review the effects of retinoic acid on immuno-metabolism, differentiation, and function of macrophages and T cells, the two pillars of the innate and adaptive immune response in ASCVD, respectively. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2020-01-22
  • Molecular and cellular insights into the role of SND1 in lipid metabolism
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-21
    Hiart Navarro-Imaz; Begoña Ochoa; Itsaso García-Arcos; María José Martínez; Yolanda Chico; Olatz Fresnedo; Yuri Rueda

    Staphylococcal nuclease and Tudor domain containing 1 (SND1) is an evolutionarily conserved protein present in eukaryotic cells from protozoa to mammals. SND1 has gained importance because it is overexpressed in aggressive cancer cells and diverse primary tumors. Indeed, it is regarded as a marker of cancer malignity. A broad range of molecular functions and the participation in many cellular processes have been attributed to SND1, mostly related to the regulation of gene expression. An increasing body of evidence points to a relevant relationship between SND1 and lipid metabolism. In this review, we summarize the knowledge about SND1 and its molecular and functional relationship with lipid metabolism. We highlight that SND1 plays a direct role in the regulation of cholesterol metabolism by affecting the activation of sterol response element-binding protein 2 (SREBP2) and we propose that that might have implications in the response of lipid homeostasis to stress situations.

    更新日期:2020-01-22
  • Novel signaling aspects of ceramide 1-phosphate
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-17
    Natalia Presa; Ana Gomez-Larrauri; Asier Dominguez-Herrera; Miguel Trueba; Antonio Gomez-Muñoz

    The bioactive sphingolipid ceramide 1-phosphate (C1P) regulates key physiologic cell functions and is implicated in a number of metabolic alterations and pathological processes. Initial studies using different types of fibroblasts and monocytes/macrophages revealed that C1P was mitogenic and that it promoted cell survival through inhibition of apoptosis. Subsequent studies implicated C1P in inflammatory responses with a specific role as pro-inflammatory agent. Specifically, C1P potently stimulated cytosolic phospholipase A2 (cPLA2) resulting in elevation of arachidonic acid and pro-inflammatory eicosanoid levels. However, increasing experimental evidence suggests that C1P can also exert anti-inflammatory actions in some cell types and tissues. Specifically, it has been demonstrated that C1P inhibits the release of pro-inflammatory cytokines and blocks activation of the pro-inflammatory transcription factor NF-κB in some cell types. Moreover, C1P was shown to increase the release of anti-inflammatory interleukin-10 in macrophages, and to overcome airway inflammation and reduce lung emphysema in vivo. Noteworthy, C1P stimulated cell migration, an action that is associated with diverse physiological cell functions, as well as with inflammatory responses and tumor dissemination. More recently, ceramide kinase (CerK), the enzyme that produces C1P in mammalian cells, has been shown to be upregulated during differentiation of pre-adipocytes into mature adipocytes, and that exogenous C1P, acting through a putative Gi protein-coupled receptor, negatively regulates adipogenesis. Although the latter actions seem to be contradictory, it is plausible that exogenous C1P may balance the adipogenic effects of intracellularly generated (CerK-derived) C1P in adipose tissue. The present review highlights novel signaling aspects of C1P and its impact in the regulation of cell growth and survival, inflammation and tumor dissemination.

    更新日期:2020-01-17
  • The regulation of p53, p38 MAPK, JNK and XBP-1s by sphingosine kinases in human embryonic kidney cells
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-15
    Mariam Alsanafi; Samuel L. Kelly; Melissa McNaughton; Alfred H. Merrill; Nigel J. Pyne; Susan Pyne

    Since inhibitors of sphingosine kinases (SK1, SK2) have been shown to induce p53-mediated cell death, we have further investigated their role in regulating p53, stress activated protein kinases and XBP-1s in HEK293T cells. Treatment of these cells with the sphingosine kinase inhibitor, SKi, which fails to induce apoptosis, promoted the conversion of p53 into two proteins with molecular masses of 63 and 90 kDa, and which was enhanced by over-expression of ubiquitin. The SKi induced conversion of p53 to p63/p90 was also enhanced by siRNA knockdown of SK1, but not SK2 or dihydroceramide desaturase (Degs1), suggesting that SK1 is a negative regulator of this process. In contrast, another sphingosine kinase inhibitor, ABC294640 only very weakly stimulated formation of p63/p90 and induced apoptosis of HEK293T cells. We have previously shown that SKi promotes the polyubiquitination of Degs1, and these forms positively regulate p38 MAPK/JNK pathways to promote HEK293T cell survival/growth. siRNA knockdown of SK1 enhanced the activation of p38 MAPK/JNK pathways in response to SKi, suggesting that SK1 functions to oppose these pro-survival pathways in HEK293T cells. SKi also enhanced the stimulatory effect of the proteasome inhibitor, MG132 on the expression of the pro-survival protein XBP-1s and this was reduced by siRNA knockdown of SK2 and increased by knockdown of p53. These findings suggest that SK1 and SK2 have opposing roles in regulating p53-dependent function in HEK293T cells.

    更新日期:2020-01-15
  • Circulating cord blood HDL-S1P complex preserves the integrity of the feto-placental vasculature
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-15
    Ilaria Del Gaudio; Ivana Sreckovic; Pablo Zardoya-Laguardia; Eva Bernhart; Christina Christoffersen; Saša Frank; Gunther Marsche; Sebastian E. Illanes; Christian Wadsack

    Perinatal and long-term offspring morbidities are strongly dependent on the preservation of placental vascular homeostasis during pregnancy. In adults, the HDL-apoM-S1P complex protects the endothelium and maintains vascular integrity. However, the metabolism and biology of cord blood-derived HDLs (referred to as neonatal HDL, nHDL) strikingly differ from those in adults. Here, we investigate the role of neonatal HDLs in the regulation of placental vascular function. We show that nHDL is a major carrier of sphingosine-1-phosphate (S1P), which is anchored to the particle through apoM (rs = 0.90, p < 0.0001) in the fetal circulation. Furthermore, this complex interacts with S1P receptors on the feto-placental endothelium and activates specifically extracellular signal-regulated protein kinases 1 and 2 (ERK) and phospholipase C (PLC) downstream signaling, promotes endothelial cell proliferation and calcium flux. Notably, the nHDL-S1P complex triggers actin filaments reorganization, leading to an enhancement of placental endothelial barrier function. Additionally, nHDL induces vasorelaxation of isolated placental chorionic arteries. Taken together, these results suggest that circulating nHDL exerts vasoprotective effects on the feto-placental endothelial barrier mainly via S1P signaling.

    更新日期:2020-01-15
  • Effects of peptidoglycan on the development of steatohepatitis
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-14
    Meiling Jin; Yihong Lai; Peili Zhao; Qian Shen; Wen Su; Yue Yin; Weizhen Zhang

    Elevating evidences suggested roles of peptidoglycan (PGN) for the insulin resistance, metabolic inflammation and liver disorders. But, whether PGN affects the occurrence of steatohepatitis remains unclear. Here, we reported that subcutaneous infusion of purified PGN for 4 weeks significantly increased hepatic levels of triglyceride, inflammation and fibrosis in mice fed normal chow. These alterations were associated with raise in circulating triglyceride, cholesterol, insulin content and inflammatory cytokines. PGN significantly increased triglyceride contents as well as lipogenesis related genes in primary hepatocytes or LO2 cells, either in basal or oleic acid treated conditions. Administration of PGN stimulated the expression of NOD2, as well as phosphorylation of p65 and IκBα, leading to subsequent nuclear translocation of p65. Over-expression of NOD2 significantly enhanced the phosphorylation of p65, levels of nuclear PPARγ and SREBP1, followed by increase in triglyceride contents in LO2 cells treated with or without oleic acid. Further, over-expression of NOD2 significantly augmented the up-regulation of PPARγ induced by rosiglitazone. Inhibition of NFκB blocked the effect of NOD2 on the upregulation of PPARγ. Our study demonstrates that PGN stimulates hepatic lipogenesis by NOD2-NFκB-PPARγ signaling. PGN from intestinal microbiota is thus sufficient to induce the progression of steatohepatitis.

    更新日期:2020-01-14
  • Carotenoids and their role in cancer prevention
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-11
    Joe L. Rowles; John W. Erdman

    Approximately two of every five people will develop cancer in their lifetime. Dietary modifications are one of the most promising lifestyle changes that can adjust the risk of developing cancer by nearly 40%. Carotenoids are a diverse group of natural pigments and are present in many fruits and vegetables. The data surrounding carotenoids and their potential roles in carcinogenesis have been rapidly growing over the past two decades. This review summarizes the literature surrounding the associations between the most six common carotenoids in the diet and ten of the most commonly diagnosed cancers. In this study, preclinical, epidemiological, and toxicology data were reviewed. Data from these studies suggest that several carotenoids might provide a beneficial impact on reducing carcinogenesis. Further studies are needed to determine the causal relationships between individual carotenoids and cancer incidence and progression. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2020-01-13
  • The macular carotenoids: A biochemical overview
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-10
    Ranganathan Arunkumar; Aruna Gorusupudi; Paul S. Bernstein
    更新日期:2020-01-10
  • Health benefits of fucoxanthin in the prevention of chronic diseases
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-10
    Minkyung Bae; Mi-Bo Kim; Young-Ki Park; Ji-Young Lee

    Fucoxanthin is a xanthophyll carotenoid abundant in macroalgae, such as brown seaweeds. When fucoxanthin is consumed, it can be esterified or hydrolyzed to fucoxanthinol in the gastrointestinal tract and further converted into amarouciaxanthin A in the liver. It has a unique chemical structure that confers its biological effects. Fucoxanthin has a strong antioxidant capacity by scavenging singlet molecular oxygen and free radicals. Also, it exerts an anti-inflammatory effect. Studies have demonstrated potential health benefits of fucoxanthin for the prevention of chronic diseases, such as cancer, obesity, diabetes mellitus, and liver disease. Animal studies have shown that fucoxanthin supplementation has no adverse effects. However, investigation of the safety of fucoxanthin consumption in humans is lacking. Clinical trials are required to assess the safety of fucoxanthin in conjunction with the study of mechanisms by which fucoxanthin exhibits its health benefits. This review focuses on current knowledge of metabolism and functions of fucoxanthin with its potential health benefits. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2020-01-10
  • The mitochondrial PKCδ/retinol signal complex exerts real-time control on energy homeostasis
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-10
    Youn-Kyung Kim; Ulrich Hammerling

    The review focuses on the role of vitamin A (retinol) in the control of energy homeostasis, and on the manner in which certain retinoids subvert this process, leading potentially to disease. In eukaryotic cells, the pyruvate dehydrogenase complex (PDHC) is negatively regulated by four pyruvate dehydrogenase kinases (PDKs) and two antagonistically acting pyruvate dehydrogenase phosphatases (PDPs). The second isoform, PDK2, is regulated by an autonomous mitochondrial signal cascade that is anchored on protein kinase Cδ (PKCδ), where retinoids play an indispensible co-factor role. Along with its companion proteins p66Shc, cytochrome c, and vitamin A, the PKCδ/retinol complex is located in the intermembrane space of mitochondria. At this site, and in contrast to cytosolic locations, PKCδ is activated by the site-specific oxidation of its cysteine-rich activation domain (CRD) that is configured into a complex RING-finger. Oxidation involves the transfer of electrons from cysteine moieties to oxidized cytochrome c, a step catalyzed by vitamin A. The PKCδ/retinol signalosome monitors the internal cytochrome c redox state that reflects the workload of the respiratory chain. Upon sensing demands for energy PKCδ signals the PDHC to increase glucose-derived fuel flux entering the KREBS cycle. Conversely, if excessive fuel flux surpasses the capacity of the respiratory chain, threatening the release of damaging reactive oxygen species (ROS), the polarity of the cytochrome c redox system is reversed, resulting in the chemical reduction of the PKCδ CRD, restoration of the RING-finger, refolding of PKCδ into the inactive, globular form, and curtailment of PDHC output, thereby constraining the respiratory capacity within safe margins. Several retinoids, notably anhydroretinol and fenretinide, capable of displacing retinol from binding sites on PKCδ, can co-activate PKCδ signaling but, owing to their extended system of conjugated double bonds, are unable to silence PKCδ in a timely manner. Left in the ON position, PKCδ causes chronic overload of the respiratory chain leading to mitochondrial dysfunction. This review explores how defects in the PKCδ signal machinery potentially contribute to metabolic and degenerative diseases.

    更新日期:2020-01-10
  • X-box binding protein 1 (XBP1): A key protein for renal osmotic adaptation. Its role in lipogenic program regulation
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-09
    Cecilia Casali; Ricardo Malvicini; Luciana Erjavec; Leandro Parra; Ayelen Artuch; María C. Fernández Tome

    In renal cells, hyperosmolarity can induce cellular stress or differentiation. Both processes require active endoplasmic reticulum (ER)-associated protein synthesis. Lipid biosynthesis also occurs at ER surface. We showed that hyperosmolarity upregulates glycerophospholipid (GP) and triacylglycerol (GL-TG) de novo synthesis. Considering that massive synthesis of proteins and/or lipids may drive to ER stress, herein we evaluated whether hyperosmolar environment induces ER stress and the participation of inositol-requiring enzyme 1α (IRE1α)-XBP1 in hyperosmotic-induced lipid synthesis. Treatment of Madin-Darby canine kidney (MDCK) cells with hyperosmolar medium triggered ER stress-associated unfolded protein response (UPR). Hyperosmolarity significantly increased xbp1 mRNA and protein as function of time; 24 h of treatment raised the spliced form of XBP1 protein (XBP1s) and induced its translocation to nuclear compartment where it can act as a transcription factor. XBP1 silencing or IRE1α ribonuclease (RNAse) inhibition impeded the expression of lipin1, lipin2 and diacylglycerol acyl transferase-1 (DGAT1) enzymes which yielded decreased GL-TG synthesis. The lack of XBP1s also decreased sterol regulatory element binding protein (SREBP) 1 and 2. Together our data demonstrate that hyperosmolarity induces IRE1α → XBP1s activation; XBP1s drives the expression of SREBP1 and SREBP2 which in turn regulates the expression of the lipogenic enzymes lipin1 (LPIN1) and 2 (LPIN2) and DGAT1. We also demonstrated for the first time that tonicity-responsive enhancer binding protein (TonEBP), the master regulator of osmoprotective response, regulates XBP1 expression. Thus, XBP1 acts as an osmoprotective protein since it is activated by high osmolarity and upregulates lipid metabolism, membranes generation and the restoration of ER homeostasis

    更新日期:2020-01-09
  • Sustained maternal smoking-associated changes in the physico-chemical properties of fetal RBC membranes might serve as early markers for vascular comorbidities
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-08
    Gábor Balogh; Payal Chakraborty; Krisztina N. Dugmonits; Mária Péter; Attila G. Végh; László Vígh; Edit Hermesz

    Maternal smoking-induced congenital heart and microvascular defects are closely associated with the impaired functioning of the in-utero feto-placental circulation system. Current groundbreaking facts revealed intimate crosstalk between circulating red blood cells (RBCs) and the vascular endothelium. Thus, RBCs have become the protagonists under varied pathological and adverse pro-oxidative cellular stress conditions. We isolated and screened fetal RBCs from the arterial cord blood of neonates, born to non-smoking (RBC-NS) and smoking mothers (RBC-S), assuming that parameters of fetal RBCs are blueprints of conditions experienced in-utero. Using atomic force microscopy and mass spectrometry-based shotgun lipidomics in the RBC-S population we revealed induced membrane stiffness, loss in intrinsic plastic activities and several abnormalities in their membrane-lipid composition, that could consequently result in perturbed hemodynamic flow movements. Altogether, these features are indicative of the outcome of neonatal microvascular complications and suggest unavailability for the potential rescue mechanism in cases of vascular endothelium impairment due to altered membrane integrity and rheological properties.

    更新日期:2020-01-09
  • Endothelial lipase increases eNOS activating capacity of high-density lipoprotein
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-07
    Snježana Radulović; Benjamin Gottschalk; Gerd Hörl; Pablo Zardoya-Laguardia; Irene Schilcher; Seth Hallström; Nemanja Vujić; Kurt Schmidt; Markus Trieb; Wolfgang F. Graier; Roland Malli; Dagmar Kratky; Gunther Marsche; Saša Frank

    Endothelial lipase (EL) changes structural and functional properties of high-density lipoprotein (HDL). HDL is a relevant modulator of endothelial nitric oxide synthase (eNOS) activity, but the effect of EL on HDL induced eNOS-activation has not yet been investigated. Here, we examined the impact of EL-modified HDL (EL-HDL) on eNOS activity, subcellular trafficking, and eNOS- dependent vasorelaxation. EL-HDL and empty virus (EV)-HDL as control were isolated from human serum incubated with EL-overexpressing or EV infected HepG2 cells. EL-HDL exhibited higher capacity to induce eNOS phosphorylation at Ser1177 and eNOS activity in EA.hy 926 cells, as well as eNOS-dependent vasorelaxation of mouse aortic rings compared to control HDL. As revealed by confocal and structured illumination-microscopy EL-HDL-driven induction of eNOS was accompanied by an increased eNOS-GFP targeting to the plasma membrane and a lower eNOS-GFP colocalization with Golgi and mitochondria. Widefield microscopy of filipin stained cells revealed that EL-HDL lowered cellular free cholesterol (FC) and as found by thin-layer chromatography increased cellular cholesterol ester (CE) content. Additionally, cholesterol efflux capacity, acyl-coenzyme A: cholesterol acyltransferase activity, and HDL particle uptake were comparable between EL-HDL and control HDL. In conclusion, EL increases eNOS activating capacity of HDL, a phenomenon accompanied by an enrichment of the plasma membrane eNOS pool, a decreased cell membrane FC and increased cellular CE content.

    更新日期:2020-01-07
  • Stable reduction of STARD4 alters cholesterol regulation and lipid homeostasis
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-07
    David B. Iaea; Zachary R. Spahr; Rajesh K. Singh; Robin B. Chan; Bowen Zhou; Rohan Bareja; Olivier Elemento; Gilbert Di Paolo; Xiaoxue Zhang; Frederick R. Maxfield

    STARD4, a member of the evolutionarily conserved START gene family, is a soluble sterol transport protein implicated in cholesterol sensing and maintenance of cellular homeostasis. STARD4 is widely expressed and has been shown to transfer sterol between liposomes as well as organelles in cells. However, STARD4 knockout mice lack an obvious phenotype, so the overall role of STARD4 is unclear. To model long term depletion of STARD4 in cells, we use short hairpin RNA technology to stably decrease STARD4 expression in human U2OS osteosarcoma cells (STARD4-KD). We show that STARD4-KD cells display increased total cholesterol, slower cholesterol trafficking between the plasma membrane and the endocytic recycling compartment, and increased plasma membrane fluidity. These effects can all be rescued by transient expression of a short hairpin RNA-resistant STARD4 construct. Some of the cholesterol increase was due to excess storage in late endosomes or lysosomes. To understand the effects of reduced STARD4, we carried out transcriptional and lipidomic profiling of control and STARD4-KD cells. Reduction of STARD4 activates compensatory mechanisms that alter membrane composition and lipid homeostasis. Based on these observations, we propose that STARD4 functions as a critical sterol transport protein involved in sterol sensing and maintaining lipid homeostasis.

    更新日期:2020-01-07
  • Eosinophils synthesize trihydroxyoctadecenoic acids (TriHOMEs) via a 15-lipoxygenase dependent process
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-07
    David Fuchs; Xiao Tang; Anna-Karin Johnsson; Sven-Erik Dahlén; Mats Hamberg; Craig E. Wheelock

    Trihydroxyoctadecenoic acids (TriHOMEs) are linoleic acid-derived lipid mediators reported to be dysregulated in obstructive lung disease. In contrast to many other oxylipins, TriHOME biosynthesis in humans is still poorly understood. The association of TriHOMEs with inflammation prompted the current investigation into the ability of human granulocytes to synthesize the 16 different 9,10,13-TriHOME and 9,12,13-TriHOME isomers and of the TriHOME biosynthetic pathway. Following incubation with linoleic acid, eosinophils and (to a lesser extent) the mast cell line LAD2, but not neutrophils, formed TriHOMEs. Stereochemical analysis revealed that TriHOMEs produced by eosinophils predominantly evidenced the 13(S) configuration, suggesting 15-lipoxygenase (15-LOX)-mediated synthesis. TriHOME formation was blocked following incubation with the 15-LOX inhibitor BXL-3887 and was shown to be largely independent of soluble epoxide hydrolase and cytochrome P450 activities. TriHOME synthesis was abolished when linoleic acid was replaced with 13-HODE, but increased in incubations with 13-HpODE, indicating the intermediary role of epoxy alcohols in TriHOME formation. In contrast to eosinophils, LAD2 cells formed TriHOMEs having predominantly the 13(R) configuration, demonstrating that there are multiple synthetic routes for TriHOME formation. These findings provide for the first-time insight into the synthetic route of TriHOMEs in humans and expand our understanding of their formation in inflammatory diseases.

    更新日期:2020-01-07
  • Changes in redox and endoplasmic reticulum homeostasis are related to congenital generalized lipodystrophy type 2
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-07
    Aquiles Sales Craveiro Sarmento; Josivan Gomes Lima; Ana Rafaela de Souza Timoteo; Marcela Abbott Galvão Ururahy; Aurigena Antunes de Araújo; Roseane Carvalho Vasconcelos; Verônica Kristina Cândido Dantas; Lucymara Fassarella Agnez-Lima; Julliane Tamara Araújo de Melo Campos
    更新日期:2020-01-07
  • Carotenoids and fatty liver disease: Current knowledge and research gaps
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-02
    Robin D. Clugston

    Carotenoids form an important part of the human diet, consumption of which has been associated with many health benefits. With the growing global burden of liver disease, increasing attention has been paid on the possible beneficial role that carotenoids may play in the liver. This review focuses on carotenoid actions in non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Indeed, many human studies have suggested an association between decreased circulating levels of carotenoids and increased incidence of NAFLD and ALD. The literature describing supplementation of individual carotenoids in rodent models of NAFLD and ALD is reviewed, with particular attention paid to β-carotene and lycopene, but also including β-cryptoxanthin, lutein, zeaxanthin, and astaxanthin. The effect of beta-carotene oxygenase 1 and 2 knock-out mice on hepatic lipid metabolism is also discussed. In general, there is evidence to suggest that carotenoids have beneficial effects in animal models of both NAFLD and ALD. Mechanistically, these benefits may occur via three possible modes of action: 1) improved hepatic antioxidative status broadly attributed to carotenoids in general, 2) the generation of vitamin A from β-carotene and β-cryptoxanthin, leading to improved hepatic retinoid signaling, and 3) the generation of apocarotenoid metabolites from β-carotene and lycopene, that may regulate hepatic signaling pathways. Gaps in our knowledge regarding carotenoid mechanisms of action in the liver are highlighted throughout, and the review ends by emphasizing the importance of dose effects, mode of delivery, and mechanism of action as important areas for further study. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2020-01-02
  • Inhibition of class I HDACs imprints adipogenesis toward oxidative and brown-like phenotype
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-02
    Alessandra Ferrari; Raffaella Longo; Carolina Peri; Lara Coppi; Donatella Caruso; Antonello Mai; Nico Mitro; Emma De Fabiani; Maurizio Crestani
    更新日期:2020-01-02
  • Diacylglycerol kinase δ destabilizes serotonin transporter protein through the ubiquitin-proteasome system
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-28
    Qiang Lu; Chiaki Murakami; Fumi Hoshino; Yuki Murakami; Fumio Sakane
    更新日期:2019-12-29
  • Proliferation of C6 glioma cells requires the phospholipid remodeling enzyme tafazzin independent of cardiolipin composition
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-26
    Lorenz Schild; Mona Döring; Steffen Jansing; Daniela Peter; Gayatri Jagirdar; Carmen Wolke; Andreas Gardemann; Uwe Lendeckel

    The mitochondrial phospholipid (CL) has been linked to mitochondrial and cellular functions. It has been postulated that the composition of CL is of impact for mitochondrial energy metabolism and cell proliferation. Although a correlation between CL composition and proliferation could be demonstrated for several cell types, evidence for a causal relationship remains obscure. Here, we applied two independent approaches, i) supplementation of fatty acids and ii) knock-out of the phospholipid remodeling enzyme tafazzin, to manipulate CL composition and analyzed the response on proliferation of C6 glioma cells. Both strategies caused substantial changes in the distribution of cellular fatty acids as well as in the distribution of fatty acids incorporated in CL that were accompanied by changes of the composition of molecular CL species. These changes did not correlate with cell proliferation. However, knock-out of tafazzin caused dramatic reduction in proliferation of C6 glioma cells independent of CL composition. The mechanism of tafazzin-dependent restriction of proliferation remains unclear. Among the various fatty acids administered only palmitic acid restricted cell proliferation by induction of cell death.

    更新日期:2019-12-27
  • Structural and mechanistic aspects of carotenoid cleavage dioxygenases (CCDs)
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-23
    Anahita Daruwalla; Philip D. Kiser

    Carotenoid cleavage dioxygenases (CCDs) comprise a superfamily of mononuclear non-heme iron proteins that catalyze the oxygenolytic fission of alkene bonds in carotenoids to generate apocarotenoid products. Some of these enzymes exhibit additional activities such as carbon skeleton rearrangement and trans-cis isomerization. The group also includes a subfamily of enzymes that split the interphenyl alkene bond in molecules such as resveratrol and lignostilbene. CCDs are involved in numerous biological processes ranging from production of light-sensing chromophores to degradation of lignin derivatives in pulping waste sludge. These enzymes exhibit unique features that distinguish them from other families of non-heme iron enzymes. The distinctive properties and biological importance of CCDs have stimulated interest in their modes of catalysis. Recent structural, spectroscopic, and computational studies have helped clarify mechanistic aspects of CCD catalysis. Here, we review these findings emphasizing common and unique properties of CCDs that enable their variable substrate specificity and regioselectivity. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2019-12-23
  • Interplay between β-carotene and lipoprotein metabolism at the maternal-fetal barrier
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-19
    Loredana Quadro; Elena Giordano; Brianna K. Costabile; Titli Nargis; Jahangir Iqbal; Younkyung Kim; Lesley Wassef; M. Mahmood Hussain

    Vitamin A is an essential nutrient, critical for proper embryonic development in mammals. Both embryonic vitamin A-deficiency or -excess lead to congenital malformations or lethality in mammals, including humans. This is due to the defective transcriptional action of retinoic acid, the active form of vitamin A, that regulates in a spatial- and temporal-dependent manner the expression of genes essential for organogenesis. Thus, an adequate supply of vitamin A from the maternal circulation is vital for normal mammalian fetal development. Provitamin A carotenoids circulate in the maternal bloodstream and are available to the embryo. Of all the dietary carotenoids, β-carotene is the main vitamin A precursor, contributing at least 30% of the vitamin A intake in the industrialized countries and often constituting the sole source of retinoids (vitamin A and its derivatives) in the developing world. In humans, up to 40% of the absorbed dietary β-carotene is incorporated in its intact form in chylomicrons for distribution to other organs within the body, including the developing tissues. Here, it can serve as a source of vitamin A upon conversion into apocarotenoids by its cleavage enzymes. Given that β-carotene is carried in the bloodstream by lipoproteins, and that the placenta acquires, assembles and secretes lipoproteins, it is becoming evident that the maternal-fetal transfer of β-carotene relies on lipoprotein metabolism. Here, we will explore the current knowledge about this important biological process, the cross-talk between carotenoid and lipid metabolism in the context of the maternal-fetal transfer of this provitamin A precursor, and the mechanisms whereby β-carotene is metabolized by the developing tissues. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2019-12-19
  • Hyperalphalipoproteinemic scavenger receptor BI knockout mice exhibit a disrupted epidermal lipid barrier
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-19
    Renata Martins Cardoso; Eline Creemers; Samira Absalah; Menno Hoekstra; Gert S. Gooris; Joke A. Bouwstra; Miranda Van Eck

    Scavenger receptor class B type I (SR-BI) mediates the selective uptake of cholesteryl esters (CE) from high-density lipoproteins (HDL). An impaired SR-BI function leads to hyperalphalipoproteinemia with elevated levels of cholesterol transported in the HDL fraction. Accumulation of cholesterol in apolipoprotein B (apoB)-containing lipoproteins has been shown to alter skin lipid composition and barrier function in mice. To investigate whether these hypercholesterolemic effects on the skin also occur in hyperalphalipoproteinemia, we compared skins of wild-type and SR-BI knockout (SR-BI−/−) mice. SR-BI deficiency did not affect the epidermal cholesterol content and induced only minor changes in the ceramide subclasses. The epidermal free fatty acid (FFA) pool was, however, enriched in short and unsaturated chains. Plasma CE levels strongly correlated with epidermal FFA C18:1 content. The increase in epidermal FFA coincided with downregulation of cholesterol and FFA synthesis genes, suggesting a compensatory response to increased flux of plasma cholesterol and FFAs into the skin. Importantly, the SR-BI−/− epidermal lipid barrier showed increased permeability to ethyl-paraminobenzoic acid, indicating an impairment of the barrier function. In conclusion, increased HDL-cholesterol levels in SR-BI−/− can alter the epidermal lipid composition and lipid barrier function similarly as observed in hypercholesterolemia due to elevated levels of apoB-containing lipoproteins.

    更新日期:2019-12-19
  • Structural and functional basis for increased HDL-cholesterol levels due to the naturally occurring V19L mutation in human apolipoprotein A-I
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-18
    Christina Gkolfinopoulou; Angeliki Bourtsala; Angeliki Chroni

    Several hereditary point mutations in human apolipoprotein A-I (apoA-I) have been associated with low HDL-cholesterol levels and/or increased coronary artery disease (CAD) risk. However, one apoA-I mutation, the V19L, recently identified in Icelanders, has been associated with increased HDL-cholesterol levels and decreased CAD risk. In an effort to gain mechanistic insight linking the presence of this mutation in apoA-I with the increase of HDL-cholesterol levels we evaluated the effect of V19L mutation on the conformational integrity and functional properties of apoA-I in lipid-free and lipidated form. ApoA-I[V19L] was found to be thermodynamically destabilized in lipid-free form and displays an increased capacity to associate with phospholipids compared to WT apoA-I. When associated to reconstituted HDL (rHDL), apoA-I[V19L] was more thermodynamically stabilized than WT apoA-I. ApoA-I[V19L] displayed normal capacity to promote ABCA1-mediated cholesterol efflux and to activate the enzyme LCAT, in lipid-free and rHDL-associated forms, respectively. Additionally, rHDL-associated apoA-I[V19L] showed normal capacity to promote ABCG1-mediated cholesterol efflux, but 45% increased capacity to promote SR-BI-mediated cholesterol efflux, while the SR-BI-mediated HDL-lipid uptake was normal. Overall, our findings show that the apoA-I V19L mutation does not affect the first steps of HDL biogenesis pathway. However, the increased capacity of apoA-I[V19L] to associate with phospholipids, in combination with the enhanced thermodynamic stability of lipoprotein-associated apoA-I[V19L] and increased capacity of apoA-I[V19L]-containing lipoprotein particles to accept additional cholesterol by SR-BI could account for the increased HDL-cholesterol levels observed in human carriers of the mutation.

    更新日期:2019-12-19
  • Carotenoids in human skin
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-12
    Sarah Zerres; Wilhelm Stahl

    The skin is shielding our organism from exogenous threats including solar radiation. Carotenoids which are ingested with the diet accumulate in the skin with the highest levels occurring in skin of the forehead and in the palms of the hands. Blood and skin levels of carotenoids increase during supplementation and due to their antioxidant properties and UV-absorbing effects carotenoids are used as photoprotective agents. Systemic photoprotection with carotenoids after supplementation or ingestion of a carotenoid rich diet has been demonstrated in several human intervention studies. Although protection is only moderate it may contribute to UV protection in combination with other measures. Beyond photoprotection, ingestion of carotenoids has been postulated to be of additional benefit for cutaneous tissue and influences moisture and texture or elasticity of the skin. However, only a limited number of studies is available yet to substantiate such a claim.

    更新日期:2019-12-13
  • Cytological and functional characteristics of fascia adipocytes in rats: A unique population of adipocytes
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-06
    Yanfei Zhang, Xueying Su, Yingyue Dong, Tongsheng Chen, Yuanyuan Zhang, Bihan Wu, Hanxiao Li, Xiaozhe Sun, Lisha Xia, Dandan Zhang, Huamin Wang, Guoheng Xu

    The dermal adipocytes, superficial fascia and subcutaneous adipose tissue (SAT) exist in the interspaces between the dermis and muscular fascia. They are adjacent to each other and traditionally recognized as one SAT. Recently, the dermal adipocyte was redefined as a unique population independent from the SAT. Also, we identified a novel type of adipogenic progenitors in rat superficial fascia. This study aimed to examine cytological and functional characteristics of fascial adipocytes in rats. Superficial fascia had no adipocytes in neonatal rats but gradually appeared numbers of adipocytes in growing rats. Adipogenic progenitors were found to reside in fascia and had strong ability in spontaneous and induced adipogenic differentiation in vitro. Differentiated fascial adipocytes versus subcutaneous or visceral adipocytes expressed increased adipose triglyceride lipase but decreased beta-adrenoreceptor, perilipin-1 and hormone-sensitive lipase (HSL), thus having high basal lipolysis but low lipolysis response to catecholamines. Phosphorylation of perilipin-1 and HSL and translocation of HSL to lipid droplets were attenuated in response to catecholamines rather than post-adrenoreceptoral lipolytic stimulators. The results suggested that superficial fascia was an origin of adipocytes with distinct developmental, cytological and functional characteristics. We proposed that fascial adipocytes could be considered as a unique population of adipocytes in the body. The fascia origin of adipocytes as an adipogenic model might logically explain fat neogenesis occurred at anatomical locations where originally exist no adipose tissues and thereby no adipose-derived stromal precursors. Also, the special histoanatomical relations and overlaps between the dermis, superficial fascia, SAT, and their adipocytes were discussed.

    更新日期:2019-12-07
  • Identification of a hormone response element that mediates suppression of APOF by LXR and PPARα agonists
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-06
    Yan Liu, Lahoucine Izem, Richard E. Morton

    Apolipoprotein F (ApoF) regulates cholesteryl ester transfer protein activity. We previously observed that hepatic APOF mRNA levels are decreased by high fat, cholesterol-enriched diets. Here we show in human liver C3A cells that APOF mRNA levels are reduced by agonists of LXR and PPARα nuclear receptors. This negative regulation requires co-incubation with the RXR agonist, retinoic acid. Bioinformatic analysis of the ~2 kb sequence upstream of the APOF promoter identified one potential LXR and 4 potential PPARα binding sites clustered between nucleotides −2007 and −1961. ChIP analysis confirmed agonist-dependent binding of LXRα, PPARα, and RXRα to this hormone response element complex (HREc). A luciferase reporter containing the 2 kb 5′ APOF sequence was negatively regulated by LXR and PPARα ligands as seen in cells. This regulation was maintained in constructs lacking the ~1700 nucleotides between the HREc and the APOF proximal promoter. Mutations of the HREc that disrupted LXRα and PPARα binding led to the loss of reporter construct inhibition by agonists of these nuclear receptors. siRNA knockdown studies showed that APOF gene regulation by LXRα or PPARα agonists did not require an interaction between these two nuclear receptors. Thus, APOF is subject to negative regulation by agonist-activated LXR or PPARα nuclear receptors binding to a regulatory element ~1900 bases 5′ to the APOF promoter. High fat, cholesterol-enriched diets likely reduce APOF gene expression via these receptors interacting at this regulatory site.

    更新日期:2019-12-06
  • Aquaporin-9 is involved in the lipid-lowering activity of the nutraceutical silybin on hepatocytes through modulation of autophagy and lipid droplets composition
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-06
    Francesca Baldini, Piero Portincasa, Elena Grasselli, Gianluca Damonte, Annalisa Salis, Michela Bonomo, Marilina Florio, Nadia Serale, Adriana Voci, Patrizia Gena, Laura Vergani, Giuseppe Calamita
    更新日期:2019-12-06
  • A high-fat diet enriched in medium chain triglycerides triggers hepatic thermogenesis and improves metabolic health in lean and obese mice
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-12-05
    Sabri Ahmed Rial, Antoine Jutras-Carignan, Karl-Frédérik Bergeron, Catherine Mounier
    更新日期:2019-12-05
  • Carotenoid metabolism at the intestinal barrier
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-30
    Johannes von Lintig, Jean Moon, Joan Lee, Srinivasagan Ramkumar
    更新日期:2019-11-30
  • Shotgun lipidomics-based characterization of the landscape of lipid metabolism in colorectal cancer
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-30
    Yuting Wang, Sebastian Hinz, Ortrud Uckermann, Pia Hönscheid, Witigo von Schönfels, Greta Burmeister, Alexander Hendricks, Jacobo Miranda Ackerman, Gustavo B. Baretton, Jochen Hampe, Mario Brosch, Clemens Schafmayer, Andrej Shevchenko, Sebastian Zeissig

    Solid tumors are characterized by global metabolic alterations which contribute to their growth and progression. Altered gene expression profiles and plasma lipid composition suggested a role for metabolic reprogramming in colorectal cancer (CRC) development. However, a conclusive picture of CRC-associated lipidome alterations in the tumor tissue has not emerged. Here, we determined molar abundances of 342 species from 20 lipid classes in matched biopsies of CRC and adjacent normal mucosa. We demonstrate that in contrast to previous reports, CRC shows a largely preserved lipidome composition that resembles that of normal colonic mucosa. Important exceptions include increased levels of lyso-phosphatidylinositols in CRC and reduced abundance of ether phospholipids in advanced stages of CRC. As such, our observations challenge the concept of widespread alterations in lipid metabolism in CRC and rather suggest changes in the cellular lipid profile that are limited to selected lipids involved in signaling and the scavenging of reactive oxygen species.

    更新日期:2019-11-30
  • Conserved mechanism of phospholipid substrate recognition by the P4-ATPase Neo1 from Saccharomyces cerevisiae
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-28
    Yannan Huang, Mehmet Takar, Jordan T. Best, Todd R. Graham

    The type IV P-type ATPases (P4-ATPases) thus far characterized are lipid flippases that transport specific substrates, such as phosphatidylserine (PS) and phosphatidylethanolamine (PE), from the exofacial leaflet to the cytofacial leaflet of membranes. This transport activity generates compositional asymmetry between the two leaflets important for signal transduction, cytokinesis, vesicular transport, and host-pathogen interactions. Most P4-ATPases function as a heterodimer with a β-subunit from the Cdc50 protein family, but Neo1 from Saccharomyces cerevisiae and its metazoan orthologs lack a β-subunit requirement and it is unclear how these proteins transport substrate. Here we tested if residues linked to lipid substrate recognition in other P4-ATPases also contribute to Neo1 function in budding yeast. Point mutations altering entry gate residues in the first (Q209A) and fourth (S457Q) transmembrane segments of Neo1, where phospholipid substrate would initially be selected, disrupt PS and PE membrane asymmetry, but do not perturb growth of cells. Mutation of both entry gate residues inactivates Neo1, and cells expressing this variant are inviable. We also identified a gain-of-function mutation in the second transmembrane segment of Neo1 (Neo1[Y222S]), predicted to help form the entry gate, that substantially enhances Neo1's ability to replace the function of a well characterized phospholipid flippase, Drs2, in establishing PS and PE asymmetry. These results suggest a common mechanism for substrate recognition in widely divergent P4-ATPases.

    更新日期:2019-11-29
  • Altered arachidonic acid-derived inflammatory eicosanoids brain levels in a rodent model of anorexia nervosa
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-26
    R. Collu, J.M. Post, M. Scherma, E. Giunti, W. Fratta, B. Lutz, P. Fadda, L. Bindila

    Increasing evidence underline the role of inflammation in the behavioral, emotional and cognitive dysregulations displayed in anorexia nervosa (AN). Among the inflammatory mediators acting at both, peripheral and central levels, growing attention receives a class of lipids derived from arachidonic acid (AA), called eicosanoids (eiCs), which exert a complex, multifaceted role in a wide range of neuroinflammatory processes, peripheral inflammation, and generally in immune system function. To date, little is known about their possible involvement in the neurobiological underpinnings of AN. The present study evaluated whether the activity-based model of AN (ABA) may alter AA-metabolic pathways by changing the levels of AA-derived eiCs in specific brain areas implicated in the development of the typical anorexic-like phenotype, i.e. in prefrontal cortex, cerebral cortex, nucleus accumbens, caudate putamen, amygdala, hippocampus, hypothalamus and cerebellum. Our results point to brain region-specific alterations of the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 epoxygenase (CYP) metabolic pathways rendering altered levels of AA-derived eiCs (i.e. prostaglandins, thromboxanes and hydroxyeicosatetraenoic acids) in response to induction of and recovery from the ABA condition. These changes, supported by altered mRNA levels of genes coding for enzymes involved in eiCs-related methabolic pathways (i.e., PLA2, COX-2, 5-LOX and 15-LOX), underlie a widespread brain dysregulation of pro- and anti-inflammatory eiC-mediated processes in the ABA model of AN. These data suggest the importance of eiCs signaling within corticolimbic areas in regulating key neurobehavioral functions and highlight eiCs as biomarker candidates for monitoring the onset and development of AN, and/or possible targets for pharmacological management.

    更新日期:2019-11-26
  • The molecular aspects of absorption and metabolism of carotenoids and retinoids in vertebrates
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-23
    Made Airanthi K. Widjaja-Adhi, Marcin Golczak

    Vitamin A is an essential nutrient necessary for numerous basic physiological functions, including reproduction and development, immune cell differentiation and communication, as well as the perception of light. To evade the dire consequences of vitamin A deficiency, vertebrates have evolved specialized metabolic pathways that enable the absorption, transport, and storage of vitamin A acquired from dietary sources as preformed retinoids or provitamin A carotenoids. This evolutionary advantage requires a complex interplay between numerous specialized retinoid-transport proteins, receptors, and enzymes. Recent advances in molecular and structural biology resulted in a rapid expansion of our understanding of these processes at the molecular level. This progress opened new avenues for the therapeutic manipulation of retinoid homeostasis. In this review, we summarize current research related to the biochemistry of carotenoid and retinoid-processing proteins with special emphasis on the structural aspects of their physiological actions. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

    更新日期:2019-11-26
  • Derepression of bkd by the FadR loss dictates elevated production of BCFAs and isoleucine starvation
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-21
    Yijuan Sun, Qiu Meng, Yongting Zhang, Haichun Gao

    In many γ-proteobacteria, FadR is recognized as a global transcriptional regulator: in addition to being the most prominent regulator for FA biosynthesis and degradation, the protein also mediates expression of many genes in diverse biological processes. In Shewanella oneidensis, a bacterium renowned for its respiratory versatility, FadR directly controls only a few genes. However, the FadR loss substantially increases BCFA contents and impairs growth. In this study, we showed that FadR is required to activate a number of important FA biosynthesis genes, including fabA, fabB, and fabH1. Although most of these genes are controlled by FadR in a direct manner, they are not critically responsible for the phenotypes resulting from the FadR depletion. Subsequent investigations identified BKD encoded by the bkd operon as the critical factor for enhanced BCFA production. In the absence of FadR, the bkd operon is derepressed, resulting in elevated conversion of 3MOP to 3-methylbutanoyl-CoA, one of the direct substrates for BCFA synthesis. We further showed that the growth defect of the fadR mutant is due to BCAA shortage, a scenario also attributable to excessive BKD: 3MOP, the common substrate for both BCFA and BCAA, is disproportionately used for BCFA synthesis, leading to reduced production of BCAA. Collectively, our findings reveal that the S. oneidensis FadR regulon is surely larger than previously proposed and a new mechanism by which FadR impacts bacterial physiology.

    更新日期:2019-11-21
  • GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-21
    Sofia Cárdenas, Cecilia Colombero, Laura Panelo, Rambabu Dakarapu, R. Falck John, A. Costas Monica, Susana Nowicki
    更新日期:2019-11-21
  • Fatty acid desaturase 2 (FADS2) but not FADS1 desaturates branched chain and odd chain saturated fatty acids
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-18
    Zhen Wang, Hui Gyu Park, Dong Hao Wang, Riki Kitano, Kumar S.D. Kothapalli, J. Thomas Brenna

    Branched chain fatty acids (BCFA) and linear chain/normal odd chain fatty acids (n-OCFA) are major fatty acids in human skin lipids, especially sebaceous gland (SG) wax esters. Skin lipids contain variable amounts of monounsaturated BCFA and n-OCFA, in some reports exceeding over 20% of total fatty acids. Fatty acid desaturase 2 (FADS2) codes for a multifunctional enzyme that catalyzes Δ4-, Δ6- and Δ8-desaturation towards ten polyunsaturated fatty acids but only one saturate, palmitic acid, converting it to 16:1n-10; FADS2 is not active towards 14:0 or 18:0. Here we test the hypothesis that FADS2 also operates on BCFA and n-OCFA. MCF-7 cancer cells stably expressing FADS1 or FADS2 along with empty vector control cells were incubated with anteiso-15:0, iso-16:0, iso-17:0, anteiso-17:0, iso-18:0, or n-17:0. BCFA were Δ6-desaturated by FADS2 as follows: iso-16:0 → iso-6Z-16:1, iso-17:0 → iso-6Z-17:1, anteiso-17:0 → anteiso-6Z-17:1 and iso-18:0 → iso-6Z-18:1. anteiso-15:0 was not desaturated in either FADS1 or FADS2 cells. n-17:0 was converted to both n-6Z-17:1 by FADS2 Δ6-desaturation and n-9Z-17:1 by SCD Δ9-desaturation. We thus establish novel FADS2-coded enzymatic activity towards BCFA and n-OCFA, expanding the number of known FADS2 saturated fatty acid substrates from one to six. Because of the importance of FADS2 in human skin, our results imply that dysfunction in activity of sebaceous FADS2 may play a role in skin abnormalities associated with skin lipids.

    更新日期:2019-11-19
  • Isoform and tissue dependent impact of apolipoprotein E on adipose tissue metabolic activation: The role of apolipoprotein A1
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Christina Kalogeropoulou, Aikaterini Hatziri, Eva Xepapadaki, Odysseia Savvoulidou, Eleni A. Karavia, Evangelia Zvintzou, Caterina Constantinou, Kyriakos E. Kypreos

    Adipose organ is made of white (WAT) and brown (BAT) adipose tissue which are primarily responsible for lipid storage and energy production (heat and ATP) respectively. Metabolic activation of WAT may ascribe to this tissue characteristics of BAT, namely non-shivering thermogenesis and ATP production. Recent data indicate that apolipoproteins E (APOE) and A1 (APOA1) regulate WAT mitochondrial metabolic activation. Here, we investigated the functional cross-talk between natural human APOE2 and APOE4 isoforms with APOA1 in this process, using Apoe2knock-in and Apoe4knock-in mice. At baseline when Apoe2knock-in and Apoe4knock-in mice express both APOE and Apoa1, the Apoe2knock-in strain appears to have higher mitochondrial oxidative phosphorylation levels and non-shivering thermogenesis in WAT compared to Apoe4knock-in mice. When mice were switched to a high-fat diet for 18 weeks, circulating levels of endogenous Apoa1 in Apoe2knock-in mice became barely detectable though significant levels of APOE2 were still present. This change was accompanied by a significant reduction in WAT mitochondrial Ucp1 expression while BAT Ucp1 was unaffected. Ectopic APOA1 expression in Apoe2knock-in animals potently stimulated WAT but not BAT mitochondrial Ucp1 expression providing further evidence that APOA1 potently stimulates WAT non-shivering thermogenesis in the presence of APOE2. Ectopic expression of APOA1 in Apoe4knock-in mice stimulated BAT but no WAT mitochondrial Ucp1 levels, suggesting that in the presence of APOE4, APOA1 is a trigger of BAT non-shivering thermogenesis. Overall, our data identified a tissue-specific role of the natural human APOE2 and APOE4 isoforms in WAT- and BAT-metabolic activation respectively, that appears dependent on circulating APOA1 levels.

    更新日期:2019-11-18
  • Adipose tissue as a target for second-generation (atypical) antipsychotics: A molecular view
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-29
    Vitor Ferreira, Diana Grajales, Ángela M. Valverde

    Schizophrenia is a neuropsychiatric disorder that chronically affects 21 million people worldwide. Second-generation antipsychotics (SGAs) are the cornerstone in the management of schizophrenia. However, despite their efficacy in counteracting both positive and negative symptomatology of schizophrenia, recent clinical observations have described an increase in the prevalence of metabolic disturbances in patients treated with SGAs, including abnormal weight gain, hyperglycemia and dyslipidemia. While the molecular mechanisms responsible for these side-effects remain poorly understood, increasing evidence points to a link between SGAs and adipose tissue depots of white, brown and beige adipocytes. In this review, we survey the present knowledge in this area, with a particular focus on the molecular aspects of adipocyte biology including differentiation, lipid metabolism, thermogenic function and the browning/beiging process.

    更新日期:2019-11-18
  • Pho85 and PI(4,5)P2 regulate different lipid metabolic pathways in response to cold
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Jose A. Prieto, Francisco Estruch, Isaac Córcoles-Sáez, Maurizio Del Poeta, Robert Rieger, Irene Stenzel, Francisca Randez-Gil
    更新日期:2019-11-18
  • Lipid accumulation and mitochondrial abnormalities are associated with fiber atrophy in skeletal muscle of rats with collagen-induced arthritis
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-17
    Gaelle Vial, Cécile Coudy-Gandelon, Alexandre Pinel, Fabien Wauquier, C. Chevenet, Daniel Bechet, Yohan Wittrant, Veronique Coxam, Martin Soubrier, Anne Tournadre, Frederic Capel

    Rheumatoid arthritis (RA) has a negative impact on muscle mass, and reduces patient's mobility and autonomy. Furthermore, RA is associated with metabolic comorbidities, notably in lipid homeostasis by unknown mechanisms. To understand the links between the loss in muscle mass and the metabolic abnormalities, arthritis was induced in male Sprague Dawley rats (n = 11) using the collagen-induced arthritis model. Rats immunized with bovine type II collagen were compared to a control group of animals (n = 11) injected with acetic acid and complete Freund's adjuvant. The clinical severity of the ensuing arthritis was evaluated weekly by a semi-quantitative score. Skeletal muscles from the hind limb were used for the histological analysis and exploration of mitochondrial activity, lipid accumulation, metabolism and regenerative capacities A significant atrophy in tibialis anterior muscle fibers was observed in rats with arthritis despite a non-significant decrease in the weight of the muscles. Despite moderate inflammation, accumulation of triglycerides (P < 0.05), reduced mitochondrial DNA copy number (P < 0.05) and non-significant dysfunction in mitochondrial cytochrome c oxidase activity were found in the gastrocnemius muscle. Concomitantly, our results suggested an activation of the muscle specific E3 ubiquitin ligases MuRF-1 and MAFbx. Finally, the adipose tissue from the arthritic rats exhibited decreased PPARγ mRNA suggesting reduced adipogenic capacities. In conclusion, the reduced adipose tissue adipogenic capacity and skeletal muscle mitochondrial capacity are probably involved in the activation of protein catabolism, inhibition of myogenesis, accumulation of lipids and fiber atrophy in skeletal muscle during RA.

    更新日期:2019-11-18
  • Identification of PtdIns(3,4)P2 effectors in human platelets using quantitative proteomics
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-16
    Tom N. Durrant, Samantha F. Moore, Asha L. Bayliss, Yiliang Jiang, Elizabeth W. Aitken, Marieangela C. Wilson, Kate J. Heesom, Ingeborg Hers

    After decades in PtdIns(3,4,5)P3's shadow, PtdIns(3,4)P2 has now emerged as a bona fide regulator of important cellular events, including endocytosis and cell migration. New understanding of PtdIns(3,4)P2's cellular roles has been possible via novel approaches to observe and quantify cellular PtdIns(3,4)P2 dynamics, alongside methods to target the kinases and phosphatases governing phosphoinositide turnover. Despite this, the mechanisms by which PtdIns(3,4)P2 orchestrates its cellular roles remain more poorly understood, most notably because, to date, few PtdIns(3,4)P2 effectors have been identified. Here, we develop and apply an affinity-proteomics strategy to conduct a global screen for PtdIns(3,4)P2 interactors in human platelets; a primary cell type with striking PtdIns(3,4)P2 accumulation. Through an integrated approach, coupling affinity capture of PtdIns(3,4)P2-binding proteins to both label-free and isobaric tag-based quantitative proteomics, we identify a diverse PtdIns(3,4)P2 interactome. Included are long-established PtdIns(3,4)P2-binding proteins such as PLEKHA1, PLEKHA2, AKT and DAPP1, and a host of potentially novel effectors, including MTMR5, PNKD, RASA3 and GAB3. The PtdIns(3,4)P2 interactome shows an enrichment of pleckstrin homology (PH) domain-containing proteins, and through bioinformatics and array analyses we characterise the PH domain of MTMR5 and define its phosphoinositide selectivity. The interactome is also diverse in function, including several proteins known to support protein trafficking and cytoskeletal mobilisation. Such proteins have the ability to drive key platelet events, and to fulfil recently-defined roles for PtdIns(3,4)P2 in a wider range of cell types. Moreover, this study will serve as a valuable resource for the future characterisation of effector-driven PtdIns(3,4)P2 function.

    更新日期:2019-11-18
  • Exercise training induces insulin-sensitizing PAHSAs in adipose tissue of elderly women
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-11-16
    Marie Brezinova, Tomas Cajka, Marina Oseeva, Marek Stepan, Klara Dadova, Lenka Rossmeislova, Milos Matous, Michaela Siklova, Martin Rossmeisl, Ondrej Kuda
    更新日期:2019-11-18
  • Specialized ER membrane domains for lipid metabolism and transport
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-07-23
    Taki Nishimura, Christopher J. Stefan

    The endoplasmic reticulum (ER) is a highly organized organelle that performs vital functions including de novo membrane lipid synthesis and transport. Accordingly, numerous lipid biosynthesis enzymes are localized in the ER membrane. However, it is now evident that lipid metabolism is sub-compartmentalized within the ER and that lipid biosynthetic enzymes engage with lipid transfer proteins (LTPs) to rapidly shuttle newly synthesized lipids from the ER to other organelles. As such, intimate relationships between lipid metabolism and lipid transfer pathways exist within the ER network. Notably, certain LTPs enhance the activities of lipid metabolizing enzymes; likewise, lipid metabolism can ensure the specificity of LTP transfer/exchange reactions. Yet, our understanding of these mutual relationships is still emerging. Here, we highlight past and recent key findings on specialized ER membrane domains involved in efficient lipid metabolism and transport and consider unresolved issues in the field.

    更新日期:2019-11-11
  • Substrate channeling in the glycerol-3-phosphate pathway regulates the synthesis, storage and secretion of glycerolipids
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-04-05
    Jonghwa Lee, Neale D. Ridgway

    The successive acylation of glycerol-3-phosphate (G3P) by glycerol-3-phosphate acyltransferases and acylglycerol-3-phosphate acyltransferases produces phosphatidic acid (PA), a precursor for CDP-diacylglycerol-dependent phospholipid synthesis. PA is further dephosphorylated by LIPINs to produce diacylglycerol (DG), a substrate for the synthesis of triglyceride (TG) by DG acyltransferases and a precursor for phospholipid synthesis via the CDP-choline and CDP–ethanolamine (Kennedy) pathways. The channeling of fatty acids into TG for storage in lipid droplets and secretion in lipoproteins or phospholipids for membrane biogenesis is dependent on isoform expression, activity and localization of G3P pathway enzymes, as well as dietary and hormonal and tissue-specific factors. Here, we review the mechanisms that control partitioning of substrates into lipid products of the G3P pathway.

    更新日期:2019-11-11
  • Lithium chloride promotes lipid accumulation through increased reactive oxygen species generation
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Yunkyoung Lee, Sang-Min Kim, Eun-Hye Jung, Jiwon Park, Ju Won Lee, Inn-Oc Han

    LiCl is widely prescribed for bipolar disorder but adversely associated with a higher incidence of increased body weight. Here, we investigated effects and underlying mechanisms of LiCl on lipid accumulation. LiCl induced dose-dependent lipid accumulation in HepG2 and RAW264.7 cells under normal as well as high glucose conditions. LiCl exposure additionally promoted lipid accumulation in livers of zebrafish. SB216763, a specific GSK-3β inhibitor, did not affect lipid accumulation in HepG2 cells. Expression of key lipogenic enzymes, such as FAS and aP2, as well as SR-B1 were increased in RAW264.7 cells. LiCl enhanced FAS, ACC and SCD-1 mRNA levels while suppressing CPT-1 in HepG2 cells. LiCl stimulated DNA binding activities of SREBP-1c and ChREBP. LiCl activated AMPK phosphorylation but the AMPK inhibitor, AICAR, did not suppress LiCl-induced lipid accumulation in RAW264.7. LiCl, but not SB216763, induced a significant increase in ROS in RAW264.7 and HepG2 cells. NOX activity was dose-dependently enhanced by LiCl. Furthermore, NOX-1, NOX-2 and DUOX-1 mRNA levels were upregulated at an early stage of LiCl stimulation. LiCl-induced lipid accumulation was suppressed by the antioxidant, NAC, and inhibitors of NOX, DPI and APO. Phosphorylation and transcriptional activity of CREB were enhanced by LiCl. The cell-permeable cAMP analog, di-butyryl cAMP, not only promoted lipid accumulation itself but also LiCl-induced lipid accumulation in RAW264.7 cells. H-89, a PKA inhibitor, suppressed CREB activation, lipid accumulation and NOX activity in RAW264.7 cells. Our results indicate that LiCl stimulates lipid accumulation in hepatocyte and macrophage cells potentially through increased PKA-dependent ROS production.

    更新日期:2019-11-01
  • The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Richard W.J. Helder, Walter A. Boiten, Rianne van Dijk, Gerrit S. Gooris, Abdoelwaheb El Ghalbzouri, Joke A. Bouwstra
    更新日期:2019-11-01
  • Scavenger receptor class B, type 1 facilitates cellular fatty acid uptake
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Wei Wang, Zhe Yan, Jie Hu, Wen-Jun Shen, Salman Azhar, Fredric B. Kraemer

    SR-B1 belongs to the class B scavenger receptor, or CD36 super family. SR-B1 and CD36 share an affinity for a wide array of ligands. Although they exhibit similar ligand binding specificity, SR-B1 and CD36 have some very specific lipid transport functions. Whereas SR-B1 primarily facilitates the selective delivery of cholesteryl esters (CEs) and cholesterol from HDL particles to the liver and non-placental steroidogenic tissues, as well as participating in cholesterol efflux from cells, CD36 primarily mediates the uptake of long-chain fatty acids in high fatty acid-requiring organs such as the heart, skeletal muscle and adipose tissue. However, CD36 also mediates cholesterol efflux and facilitates selective lipoprotein-CE delivery, although less efficiently than SR-B1. Interestingly, the ability or efficiency of SR-B1 to mediate fatty acid uptake has not been reported. In this paper, using overexpression and siRNA-mediated knockdown of SR-B1, we show that SR-B1 possesses the ability to facilitate fatty acid uptake. Moreover, this function is not blocked by BLT-1, a specific chemical inhibitor of HDL-CE uptake activity of SR-B1, nor by sulfo-N-succinimidyl oleate, which inhibits fatty acid uptake by CD36. Attenuated fatty acid uptake was also observed in primary adipocytes isolated from SR-B1 knockout mice. In conclusion, facilitation of fatty acid uptake is an additional function that is mediated by SR-B1.

    更新日期:2019-11-01
  • Maternal diet, rather than obesity itself, has a main influence on milk triacylglycerol profile in dietary obese rats
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    C.A. Pomar, O. Kuda, J. Kopecky, M. Rombaldova, H. Castro, C. Picó, J. Sánchez, A. Palou
    更新日期:2019-11-01
  • Trichothecin inhibits invasion and metastasis of colon carcinoma associating with SCD-1-mediated metabolite alteration
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Chaoliang Liao, Min Li, Xiang Li, Namei Li, Xu Zhao, Xiaoyi Wang, Yawen Song, Jing Quan, Can Cheng, Jikai Liu, Ann M. Bode, Ya Cao, Xiangjian Luo

    Lipid metabolic abnormalities have received intensified concerns and increased de novo synthesis of lipids is recognized as a common feature of many human cancers. Nevertheless, the role of lipid metabolism that confers aggressive properties on human cancers still remains to be revealed. Natural compounds represent an abundant pool of agents for the discovery of novel lead compounds. Trichothecin (TCN) is a sesquiterpenoid originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Here, we assess the association of stearoyl-CoA desaturase 1 (SCD-1) over-expression with malignant progression of colorectal cancer (CRC). Based on this association, the effect of TCN on migration and invasion of colon carcinoma cells closely related to the inhibition of SCD-1 is evaluated. We further demonstrate that reduced production of unsaturated fatty acids (FAs) by blocking SCD-1 activity is beneficial for the anti-invasion effect of TCN. The aim of this study was to clarify the mechanistic connection between metabolite alterations induced by metabolic rewiring and the aggressive tumor phenotype and further develop novel pharmacological tools for the intervention of tumor invasion associated with SCD-1-mediated metabolite alterations.

    更新日期:2019-11-01
  • Fenretinide favorably affects mucins (MUC5AC/MUC5B) and fatty acid imbalance in a manner mimicking CFTR-induced correction
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Dušan Garić, Juan B. De Sanctis, Daciana Catalina Dumut, Juhi Shah, Maria Johanna Peña, Mina Youssef, Basil J. Petrof, Francisek Kopriva, John W. Hanrahan, Marian Hajduch, Danuta Radzioch
    更新日期:2019-11-01
  • ER morphology and endo-lysosomal crosstalk: Functions and disease implications
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Crystal A. Lee, Craig Blackstone

    The endoplasmic reticulum (ER) is a continuous endomembrane system comprising the nuclear envelope, ribosome-studded sheets, dense peripheral matrices, and an extensive polygonal network of interconnected tubules. In addition to performing numerous critical cellular functions, the ER makes extensive contacts with other organelles, including endosomes and lysosomes. The molecular and functional characterization of these contacts has advanced significantly over the past several years. These contacts participate in key functions such as cholesterol transfer, endosome tubule fission, and Ca2+ exchange. Disruption of key proteins at the contact sites can result in often severe diseases, particularly those affecting the nervous system.

    更新日期:2019-11-01
  • Angiopoietin-1 aggravates atherosclerosis by inhibiting cholesterol efflux and promoting inflammatory response
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Xiang Ou, Jia-Hui Gao, Lin-Hao He, Xiao-Hua Yu, Gang Wang, Jin Zou, Zhen-Wang Zhao, Da-Wei Zhang, Zhi-jiao Zhou, Chao-Ke Tang

    Objective Angiopoietin-1 (Ang-1), a secreted protein, mainly regulates angiogenesis. Ang-1 has been shown to promote the development of atherosclerosis, whereas little is known about its effects on lipid metabolism and inflammation in this process. Method Ang-1 was transfected into ApoE−/− mice via lentiviral vector or incubated with THP-1 derived macrophages. Oil red O and HE staining were performed to measure the size of atherosclerotic plaques in ApoE−/− mice. Immunofluorescence was employed to show the expression of target proteins in aorta. [3H] labeled cholesterol was performed to examine the efficiency of cholesterol efflux and reverse cholesterol transport (RCT) both in vivo and vitro. Western blot and qPCR were used to quantify target proteins both in vivo and vitro. ELISA detected the levels of pro-inflammatory cytokines in mouse peritoneal macrophage. Results Our data showed that Ang-1 augmented atherosclerotic plaques formation and inhibited cholesterol efflux. The binding of Ang-1 to Tie2 resulted in downregulation of LXRα, ABCA1 and ABCG1 expression via inhibiting the translocation of TFE3 into nucleus. In addition, Ang-1 decreased serum HDL-C levels and reduced reverse cholesterol transport (RCT) in ApoE−/− mice. Furthermore, Ang-1 induced lipid accumulation followed by increasing TNF-α, IL-6, IL-1β,and MCP-1 produced by MPMs, as well as inducing M1 phenotype macrophage marker iNOS and CD86 expression in aorta of ApoE−/− mice. Conclusion Ang-1 has an adverse effect on cholesterol efflux by decreasing the expression of ABCA1 and ABCG1 via Tie2/TFE3/LXRα pathway, thereby promoting inflammation and accelerating atherosclerosis progression.

    更新日期:2019-11-01
  • Wnt5a/Ror2 pathway contributes to the regulation of cholesterol homeostasis and inflammatory response in atherosclerosis
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Chan-Juan Zhang, Neng Zhu, Zheng Liu, Zhe Shi, Jia Long, Xu-Yu Zu, Zhen-Wang Tang, Zhe-Yu Hu, Duan-Fang Liao, Li Qin
    更新日期:2019-11-01
  • Sphingomyelin synthase activity affects TRIF-dependent signaling of Toll-like receptor 4 in cells stimulated with lipopolysaccharide
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-31
    Kamila Prymas, Anna Świątkowska, Gabriela Traczyk, Ewelina Ziemlińska, Anna Dziewulska, Anna Ciesielska, Katarzyna Kwiatkowska
    更新日期:2019-11-01
  • PPARA/RXRA signalling regulates the fate of hepatic non-esterified fatty acids in a sheep model of maternal undernutrition
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-30
    Yanfeng Xue, Changzheng Guo, Fan Hu, Weiyun Zhu, Shengyong Mao
    更新日期:2019-11-01
  • Interleukin 10 promotes macrophage uptake of HDL and LDL by stimulating fluid-phase endocytosis
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-30
    Diego Lucero, Promotto Islam, Lita A. Freeman, Xueting Jin, Milton Pryor, Jingrong Tang, Howard S. Kruth, Alan T. Remaley

    Objective Highly elevated plasma levels of interleukin-10 (IL-10) are causally associated with “Disappearing HDL Syndrome” and low plasma LDL-cholesterol, but the underlying mechanism is poorly understood. Fluid-phase endocytosis, a process highly dependent on actin dynamics, enables cells to internalize relatively high amounts of extracellular fluids and solutes. We sought to investigate whether IL-10 induces lipoprotein uptake by fluid-phase endocytosis in macrophages. Methods and results Macrophages (RAW264.7, Kupffer and human) were incubated with vehicle (PBS) or IL-10 (20 ng/ml) for 7 days. Uptake of HDL, LDL, and/or fluid-phase endocytosis probes (albumin-Alexa680®, 70 kDa FITC-Dextran and Lucifer Yellow, LY) was evaluated by FACS. Intracellular cofilin and phosphorylated cofilin (p-cofilin) levels were determined by immunoblotting. Macrophage uptake of lipoproteins and probes was non-saturable and increased after IL-10 incubation (p < 0.0001). Furthermore, pre-incubation with fluid-phase endocytosis inhibitors (LY294002, Latrunculin A, and Amiloride) significantly reduced uptake (p < 0.05). IL-10 increased the cofilin/p-cofilin ratio (p = 0.021), signifying increased cofilin activation and hence filamentous actin. Consistently, phalloidin staining revealed increased filamentous actin in macrophages after IL-10 treatment (p = 0.0018). Finally, RNA-seq analysis demonstrated enrichment of gene sets related to actin filament dynamics, membrane ruffle formation and endocytosis in IL-10-treated macrophages (p < 0.05). IL-10 did not alter mRNA levels of Ldlr, Vldlr, Scarb1, Cd36 or Lrp1. In primary human monocyte-derived macrophages and murine Kupffer cells, IL-10 incubation also increased uptake of lipoproteins, albumin and LY (p < 0.01). Conclusions Interleukin-10 induces the uptake of HDL and LDL by fluid-phase endocytosis by increasing actin-filament rearrangement in macrophages, thus providing a plausible mechanism contributing to “Disappearing HDL Syndrome”.

    更新日期:2019-11-01
  • Lipase-like 5 enzyme controls mitochondrial activity in response to starvation in Caenorhabditis elegans
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2019-10-30
    Felipe Macedo, Gabriel Loureiro Martins, Luis A. Luévano-Martínez, Gustavo Monteiro Viana, Karin A. Riske, Alex Inague, Marcos Y. Yoshinaga, Hugo Aguilaniu, Sayuri Miyamoto, Isaias Glezer, Fernanda Marques da Cunha

    The C. elegans lipase-like 5 (lipl-5) gene is predicted to code for a lipase homologous to the human gastric acid lipase. Its expression was previously shown to be modulated by nutritional or immune cues, but nothing is known about its impact on the lipid landscape and ensuing functional consequences. In the present work, we used mutants lacking LIPL-5 protein and found that lipl-5 is important for normal lipidome composition as well as its remodeling in response to food deprivation. Particularly, lipids with signaling functions such as ceramides and mitochondrial lipids were affected by lipl-5 silencing. In comparison with wild type worms, animals lacking LIPL-5 were enriched in cardiolipins linked to polyunsaturated C20 fatty acids and coenzyme Q-9. Differences in mitochondrial lipid composition were accompanied by differences in mitochondrial activity as mitochondria from well-fed lipl-5 mutants were significantly more able to oxidize respiratory substrates when compared with mitochondria from well-fed wild type worms. Strikingly, starvation elicited important changes in mitochondrial activity in wild type worms, but not in lipl-5 worms. This indicates that this lipase is a determinant of mitochondrial functional remodeling in response to food withdrawal.

    更新日期:2019-11-01
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