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Dixon ED, Claudel T, Nardo AD, Riva A, Fuchs CD, Mlitz V, Busslinger G, Scharnagl H, Stojakovic T, Senéca J, Hinteregger H, Grabner GF, Kratky D, Verkade H, Zimmermann R, Haemmerle G, Trauner M. Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice. J Hepatol 2025; 82:658-675. [PMID: 39357546 DOI: 10.1016/j.jhep.2024.09.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND & AIMS Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice. METHODS Streptozotocin-injected male mice were fed a high-fat diet to induce MASH. Mice receiving the ATGL inhibitor atglistatin (ATGLi) were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated the benefits of ATGLi on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model. RESULTS ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic triacylglycerol species containing polyunsaturated fatty acids, like linoleic acid, as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signalling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors. CONCLUSIONS Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BA composition, interfering with dietary lipid absorption, and improving metabolic disturbances. Validation with NG-497 opens a new therapeutic perspective for MASLD. IMPACT AND IMPLICATIONS Despite the recent approval of drugs novel mechanistic insights and pathophysiology-oriented therapeutic options for MASLD (metabolic dysfunction-associated steatotic liver disease) are still urgently needed. Herein, we show that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, using atglistatin (ATGLi), improves MASH (metabolic dysfunction-associated steatohepatitis), fibrosis, and key features of metabolic dysfunction in mouse models of MASH and liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings reveal a possible new avenue for MASLD treatment.
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Affiliation(s)
- Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Alexander Daniel Nardo
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Alessandra Riva
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Claudia Daniela Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Veronika Mlitz
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Georg Busslinger
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
| | - Tatjana Stojakovic
- Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Austria
| | - Joana Senéca
- Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna, Vienna, Austria; Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Helga Hinteregger
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Gernot F Grabner
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Dagmar Kratky
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Henkjan Verkade
- Department of Paediatrics, University Medical Centre Groningen, Groningen, Netherlands
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
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Banerjee A, Farci P. Fibrosis and Hepatocarcinogenesis: Role of Gene-Environment Interactions in Liver Disease Progression. Int J Mol Sci 2024; 25:8641. [PMID: 39201329 PMCID: PMC11354981 DOI: 10.3390/ijms25168641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
The liver is a complex organ that performs vital functions in the body. Despite its extraordinary regenerative capacity compared to other organs, exposure to chemical, infectious, metabolic and immunologic insults and toxins renders the liver vulnerable to inflammation, degeneration and fibrosis. Abnormal wound healing response mediated by aberrant signaling pathways causes chronic activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM), leading to hepatic fibrosis and cirrhosis. Fibrosis plays a key role in liver carcinogenesis. Once thought to be irreversible, recent clinical studies show that hepatic fibrosis can be reversed, even in the advanced stage. Experimental evidence shows that removal of the insult or injury can inactivate HSCs and reduce the inflammatory response, eventually leading to activation of fibrolysis and degradation of ECM. Thus, it is critical to understand the role of gene-environment interactions in the context of liver fibrosis progression and regression in order to identify specific therapeutic targets for optimized treatment to induce fibrosis regression, prevent HCC development and, ultimately, improve the clinical outcome.
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Affiliation(s)
- Anindita Banerjee
- Department of Transfusion Transmitted Diseases, ICMR-National Institute of Immunohaematology, Mumbai 400012, Maharashtra, India;
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Singh S, Kumar A, Gupta S, Agrawal R. Curative role of natural PPARγ agonist in non-alcoholic fatty liver disease (NAFLD). Tissue Barriers 2024; 12:2289830. [PMID: 38050958 PMCID: PMC11262216 DOI: 10.1080/21688370.2023.2289830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/15/2023] [Indexed: 12/07/2023] Open
Abstract
NAFLD is a condition that develops when the liver accumulates excess fat without alcohol consumption. This chronic liver ailment progresses along with insulin resistant and is typically not diagnosed until the patients have cirrhosis. Nuclear hormone receptor superfamily PPARs are essential for metabolism of fatty acids and glucose. In liver, lipid metabolism is regulated by nuclear receptors and PPARα, and PPARβ/δ encourages fatty acid β-oxidation. PPAR-γ, an energy-balanced receptor is a crucial regulator in NAFLD. The partial activation of PPAR-γ could lead to increased level of adiponectin and insulin sensitivity, thus improved NAFLD. Because of less side effects, natural compounds are emerged as potential therapeutic agents for NAFLD by PPARγ agonists. Although the results from preclinical studies are promising, further research is needed to determine the potential dosing and efficacy of mentioned compounds in human subjects. In this review, we summarize the effect of natural PPARγ agonist in the NAFLD.
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Affiliation(s)
- Swati Singh
- College of Pharmacy, JSS Academy of Technical Sciences, Noida, Uttar Pradesh, India
| | - Anit Kumar
- Department of Pharmacology, Divine College of Pharmacy, Bihar, India
| | - Suruchi Gupta
- School of Pharmacy, YBN University, Ranchi, Jharkhand, India
| | - Rohini Agrawal
- College of Pharmacy, JSS Academy of Technical Sciences, Noida, Uttar Pradesh, India
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4
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Yun YR, Lee JE. Kimchi attenuates endoplasmic reticulum stress-induced hepatic steatosis in HepG2 cells and C57BL/6N mice. Nutr Res 2024; 124:43-54. [PMID: 38367426 DOI: 10.1016/j.nutres.2024.01.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/25/2024] [Accepted: 01/25/2024] [Indexed: 02/19/2024]
Abstract
Kimchi is a traditional fermented food that contains abundant nutrients and functional ingredients with various health benefits. We previously reported that kimchi active components suppress hepatic steatosis caused by endoplasmic reticulum (ER) stress in vitro and in vivo. Therefore, we assessed the effect of kimchi on the inhibition of hepatic steatosis caused by ER stress in HepG2 cells and C57BL/6N mice to verify the hypothesis that kimchi may potentially inhibit nonalcoholic fatty liver disease. We investigated the effect of kimchi on cell viability and triglyceride concentrations in cells and on lipid profile, lipid accumulation, and expression of related genes in cells and mice with hepatic steatosis. A mechanistic study was also performed using the liver X receptor α agonist T0901317 and the AMP-activated protein kinase agonist AICAR. Kimchi was noncytotoxic and effectively reduced triglyceride concentrations and suppressed hepatic steatosis-related gene expression in cells and mice. Additionally, kimchi recovered weight loss, lowered the serum and liver tissue lipid profiles, suppressed lipid accumulation, and reduced the effects of T0901317 and AICAR on lipogenic gene expression in tunicamycin-treated mice. Our results highlight that kimchi could prevent hepatic steatosis caused by ER stress in cells and mice.
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Affiliation(s)
- Ye-Rang Yun
- World Institute of Kimchi, Nam-Gu, Gwangju 61755, Republic of Korea.
| | - Ji-Eun Lee
- World Institute of Kimchi, Nam-Gu, Gwangju 61755, Republic of Korea
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Pantoja MHDA, Novais FJD, Mourão GB, Mateescu RG, Poleti MD, Beline M, Monteiro CP, Fukumasu H, Titto CG. Exploring candidate genes for heat tolerance in ovine through liver gene expression. Heliyon 2024; 10:e25692. [PMID: 38370230 PMCID: PMC10869868 DOI: 10.1016/j.heliyon.2024.e25692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/24/2024] [Accepted: 01/31/2024] [Indexed: 02/20/2024] Open
Abstract
Thermotolerance has become an essential factor in the prevention of the adverse effects of heat stress, but it varies among animals. Identifying genes related to heat adaptability traits is important for improving thermotolerance and for selecting more productive animals in hot environments. The primary objective of this research was to find candidate genes in the liver that play a crucial role in the heat stress response of Santa Ines sheep, which exhibit varying levels of heat tolerance. To achieve this goal, 80 sheep were selected based on their thermotolerance and placed in a climate chamber for 10 days, during which the average temperature was maintained at 36 °C from 10 a.m. to 4 p.m. and 28 °C from 4 p.m. to 10 a.m. A subset of 14 extreme animals, with seven thermotolerant and seven non-thermotolerant animals based on heat loss (rectal temperature), were selected for liver sampling. RNA sequencing and differential gene expression analysis were performed. Thermotolerant sheep showed higher expression of genes GPx3, RGS6, GPAT3, VLDLR, LOC101108817, and EVC. These genes were mainly related to the Hedgehog signaling pathway, glutathione metabolism, glycerolipid metabolism, and thyroid hormone synthesis. These enhanced pathways in thermotolerant animals could potentially mitigate the negative effects of heat stress, conferring greater heat resistance.
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Affiliation(s)
- Messy Hannear de Andrade Pantoja
- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP, 13635-900, Brazil
| | - Francisco José de Novais
- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP, 13635-900, Brazil
| | - Gerson Barreto Mourão
- Escola Superior de Agricultura Luiz de Queiroz, Universidade São Paulo, Av. Pádua Dias, 11, Piracicaba, SP, 13418-900, Brazil
| | - Raluca G. Mateescu
- Department of Animal Science, University of Florida, Gainesville, FL, United States
| | - Mirele Daiana Poleti
- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP, 13635-900, Brazil
| | - Mariane Beline
- Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061-0002, United States
| | - Camylla Pedrosa Monteiro
- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP, 13635-900, Brazil
| | - Heidge Fukumasu
- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP, 13635-900, Brazil
| | - Cristiane Gonçalves Titto
- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP, 13635-900, Brazil
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Hofer P, Grabner GF, König M, Xie H, Bulfon D, Ludwig AE, Wolinski H, Zimmermann R, Zechner R, Heier C. Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL. J Lipid Res 2023; 64:100457. [PMID: 37832604 PMCID: PMC10665947 DOI: 10.1016/j.jlr.2023.100457] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/01/2023] [Accepted: 10/04/2023] [Indexed: 10/15/2023] Open
Abstract
Intracellular lipolysis-the enzymatic breakdown of lipid droplet-associated triacylglycerol (TAG)-depends on the cooperative action of several hydrolytic enzymes and regulatory proteins, together designated as lipolysome. Adipose triglyceride lipase (ATGL) acts as a major cellular TAG hydrolase and core effector of the lipolysome in many peripheral tissues. Neurons initiate lipolysis independently of ATGL via DDHD domain-containing 2 (DDHD2), a multifunctional lipid hydrolase whose dysfunction causes neuronal TAG deposition and hereditary spastic paraplegia. Whether and how DDHD2 cooperates with other lipolytic enzymes is currently unknown. In this study, we further investigated the enzymatic properties and functions of DDHD2 in neuroblastoma cells and primary neurons. We found that DDHD2 hydrolyzes multiple acylglycerols in vitro and substantially contributes to neutral lipid hydrolase activities of neuroblastoma cells and brain tissue. Substrate promiscuity of DDHD2 allowed its engagement at different steps of the lipolytic cascade: In neuroblastoma cells, DDHD2 functioned exclusively downstream of ATGL in the hydrolysis of sn-1,3-diacylglycerol (DAG) isomers but was dispensable for TAG hydrolysis and lipid droplet homeostasis. In primary cortical neurons, DDHD2 exhibited lipolytic control over both, DAG and TAG, and complemented ATGL-dependent TAG hydrolysis. We conclude that neuronal cells use noncanonical configurations of the lipolysome and engage DDHD2 as dual TAG/DAG hydrolase in cooperation with ATGL.
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Affiliation(s)
- Peter Hofer
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Gernot F Grabner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Mario König
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Hao Xie
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Dominik Bulfon
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Anton E Ludwig
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Heimo Wolinski
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Christoph Heier
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
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7
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Li X, Wang J, Li Y, He W, Cheng QJ, Liu X, Xu DL, Jiang ZG, Xiao X, He YH. The gp130/STAT3-endoplasmic reticulum stress axis regulates hepatocyte necroptosis in acute liver injury. Croat Med J 2023; 64:149-163. [PMID: 37391912 PMCID: PMC10332293 DOI: 10.3325/cmj.2023.64.149] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 05/25/2023] [Indexed: 08/30/2023] Open
Abstract
AIM To investigate the effect of the gp130/STAT3-endoplasmic reticulum (ER) stress axis on hepatocyte necroptosis during acute liver injury. METHODS ER stress and liver injury in LO2 cells were induced with thapsigargin, and in BALB/c mice with tunicamycin and carbon tetrachloride (CCl4). Glycoprotein 130 (gp130) expression, the degrees of ER stress, and hepatocyte necroptosis were assessed. RESULTS ER stress significantly upregulated gp130 expression in LO2 cells and mouse livers. The silencing of activating transcription factor 6 (ATF6), but not of ATF4, increased hepatocyte necroptosis and mitigated gp130 expression in LO2 cells and mice. Gp130 silencing reduced the phosphorylation of CCl4-induced signal transducer and activator of transcription 3 (STAT3), and aggravated ER stress, necroptosis, and liver injury in mice. CONCLUSION ATF6/gp130/STAT3 signaling attenuates necroptosis in hepatocytes through the negative regulation of ER stress during liver injury. Hepatocyte ATF6/gp130/STAT3 signaling may be used as a therapeutic target in acute liver injury.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Yi-Huai He
- Yi-Huai He, Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China,
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8
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Krauss RM, Lu JT, Higgins JJ, Clary CM, Tabibiazar R. VLDL receptor gene therapy for reducing atherogenic lipoproteins. Mol Metab 2023; 69:101685. [PMID: 36739970 PMCID: PMC9950951 DOI: 10.1016/j.molmet.2023.101685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/16/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Over the past 40 years, there has been considerable research into the management and treatment of atherogenic lipid disorders. Although the majority of treatments and management strategies for cardiovascular disease (CVD) center around targeting low-density lipoprotein cholesterol (LDL-C), there is mounting evidence for the residual CVD risk attributed to high triglyceride (TG) and lipoprotein(a) (Lp(a)) levels despite the presence of lowered LDL-C levels. Among the biological mechanisms for clearing TG-rich lipoproteins, the VLDL receptor (VLDLR) plays a key role in the trafficking and metabolism of lipoprotein particles in multiple tissues, but it is not ordinarily expressed in the liver. Since VLDLR is capable of binding and internalizing apoE-containing TG-rich lipoproteins as well as Lp(a), hepatic VLDLR expression has the potential for promoting clearance of these atherogenic particles from the circulation and managing the residual CVD risk not addressed by current lipid lowering therapies. This review provides an overview of VLDLR function and the potential for developing a genetic medicine based on liver-targeted VLDLR gene expression.
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Affiliation(s)
- Ronald M. Krauss
- University of California, San Francisco, 5700 Martin Luther King, Jr. Way, Oakland CA 94609, USA,Corresponding author.
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Fernandes HJR, Kent JP, Bruntraeger M, Bassett AR, Koulman A, Metzakopian E, Snowden SG. Mitochondrial and Endoplasmic Reticulum Stress Trigger Triglyceride Accumulation in Models of Parkinson's Disease Independent of Mutations in MAPT. Metabolites 2023; 13:112. [PMID: 36677037 PMCID: PMC9861589 DOI: 10.3390/metabo13010112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/11/2022] [Accepted: 12/14/2022] [Indexed: 01/10/2023] Open
Abstract
The metabolic basis of Parkinson's disease pathology is poorly understood. However, the involvement of mitochondrial and endoplasmic reticulum stress in dopamine neurons in disease aetiology is well established. We looked at the effect of rotenone- and tunicamycin-induced mitochondrial and ER stress on the metabolism of wild type and microtubule-associated protein tau mutant dopamine neurons. Dopamine neurons derived from human isolated iPSCs were subjected to mitochondrial and ER stress using RT and TM, respectively. Comprehensive metabolite profiles were generated using a split phase extraction analysed by reversed phase lipidomics whilst the aqueous phase was measured using HILIC metabolomics. Mitochondrial and ER stress were both shown to cause significant dysregulation of metabolism with RT-induced stress producing a larger shift in the metabolic profile of both wild type and MAPT neurons. Detailed analysis showed that accumulation of triglycerides was a significant driver of metabolic dysregulation in response to both stresses in both genotypes. Whilst the consequence is similar, the mechanisms by which triglyceride accumulation occurs in dopamine neurons in response to mitochondrial and ER stress are very different. Thus, improving our understanding of how these mechanisms drive the observed triglyceride accumulation can potentially open up new therapeutic avenues.
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Affiliation(s)
- Hugo J. R. Fernandes
- Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK
| | - Josh P. Kent
- Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK
- Core Metabolomics and Lipidomics Laboratory, Institute of Metabolic Science, University of Cambridge, Level 4 Pathology, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | | | - Andrew R. Bassett
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | - Albert Koulman
- Core Metabolomics and Lipidomics Laboratory, Institute of Metabolic Science, University of Cambridge, Level 4 Pathology, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - Emmanouil Metzakopian
- Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK
| | - Stuart G. Snowden
- Department of Biological Sciences, Royal Holloway University of London, Egham, London TW20 0EX, UK
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Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis and Natural Products for Prevention and Treatment. Int J Mol Sci 2022; 23:ijms232415489. [PMID: 36555127 PMCID: PMC9779435 DOI: 10.3390/ijms232415489] [Citation(s) in RCA: 166] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage factors. Recent studies have shown that the development of NAFLD is associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. A range of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the pathogenesis of NAFLD and some natural products that have been shown to have therapeutic effects on NAFLD. Our work shows that natural products can be a potential therapeutic option for NAFLD.
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Qin ZL, Yao QF, Ren H, Zhao P, Qi ZT. Lipid Droplets and Their Participation in Zika Virus Infection. Int J Mol Sci 2022; 23:ijms232012584. [PMID: 36293437 PMCID: PMC9604050 DOI: 10.3390/ijms232012584] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/11/2022] [Accepted: 10/14/2022] [Indexed: 11/23/2022] Open
Abstract
Lipid droplets (LDs) are highly conserved and dynamic intracellular organelles. Their functions are not limited to serving as neutral lipid reservoirs; they also participate in non-energy storage functions, such as cell lipid metabolism, protection from cell stresses, maintaining protein homeostasis, and regulating nuclear function. During a Zika virus (ZIKV) infection, the viruses hijack the LDs to provide energy and lipid sources for viral replication. The co-localization of ZIKV capsid (C) protein with LDs supports its role as a virus replication platform and a key compartment for promoting the generation of progeny virus particles. However, in view of the multiple functions of LDs, their role in ZIKV infection needs further elucidation. Here, we review the basic mechanism of LD biogenesis and biological functions and discuss how ZIKV infection utilizes these effects of LDs to facilitate virus replication, along with the future application strategy of developing new antiviral drugs based on the interaction of ZIKV with LDs.
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12
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Kołakowski A, Dziemitko S, Chmielecka A, Żywno H, Bzdęga W, Charytoniuk T, Chabowski A, Konstantynowicz-Nowicka K. Molecular Advances in MAFLD—A Link between Sphingolipids and Extracellular Matrix in Development and Progression to Fibrosis. Int J Mol Sci 2022; 23:ijms231911380. [PMID: 36232681 PMCID: PMC9569877 DOI: 10.3390/ijms231911380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/18/2022] [Accepted: 09/23/2022] [Indexed: 11/25/2022] Open
Abstract
Metabolic-Associated Fatty Liver Disease (MAFLD) is a major cause of liver diseases globally and its prevalence is expected to grow in the coming decades. The main cause of MAFLD development is changed in the composition of the extracellular matrix (ECM). Increased production of matrix molecules and inflammatory processes lead to progressive fibrosis, cirrhosis, and ultimately liver failure. In addition, increased accumulation of sphingolipids accompanied by increased expression of pro-inflammatory cytokines in the ECM is closely related to lipogenesis, MAFLD development, and its progression to fibrosis. In our work, we will summarize all information regarding the role of sphingolipids e.g., ceramide and S1P in MAFLD development. These sphingolipids seem to have the most significant effect on macrophages and, consequently, HSCs which trigger the entire cascade of overproduction matrix molecules, especially type I and III collagen, proteoglycans, elastin, and also tissue inhibitors of metalloproteinases, which as a result cause the development of liver fibrosis.
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Affiliation(s)
- Adrian Kołakowski
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Sylwia Dziemitko
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | | | - Hubert Żywno
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Wiktor Bzdęga
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Tomasz Charytoniuk
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
- Department of Ophthalmology, Antoni Jurasz University Hospital No. 1, 85-094 Bydgoszcz, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland
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Xuan Y, Gao P, Shen Y, Wang S, Gu X, Tang D, Wang X, Zhu F, Lu L, Chen L. Association of hypertriglyceridemic waist phenotype with non-alcoholic fatty liver disease: a cross-sectional study in a Chinese population. Hormones (Athens) 2022; 21:437-446. [PMID: 35597838 DOI: 10.1007/s42000-022-00374-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 04/29/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND The aim of this study was to determine the association between hypertriglyceridemic waist (HTGW) phenotype and non-alcoholic fatty liver disease (NAFLD) in a middle- to older-aged Chinese population. METHODS In this cross-sectional study, a total of 9015 participants (age 40-79 years) were recruited and grouped into four phenotypes, as follows: NWNT: normal waist-normal triglyceride; NWET: normal waist-elevated triglycerides; EWNT: elevated waist-normal triglycerides; and hypertriglyceridemic waist (HTGW). Logistic regression analysis was carried out to assess the associations between HTGW phenotype and NAFLD. Receiver-operating characteristic (ROC) curves were drawn to evaluate the utility of waist circumference-triglyceride index (WTI) as a reference factor for screening for NAFLD. RESULTS HTGW phenotype had a higher prevalence of NAFLD (53.3%), diabetes (19.6%), and hypertension (79.8%) than the other three subgroups. After adjusting for age, sex, and BMI, HTGW phenotype was associated with NAFLD (odds ratio (OR) 6.12; 95% confidence interval (CI) 5.11-7.32). Further adjusted for potential confounders, the HTGW phenotype was still significantly associated with NAFLD (adjusted OR 5.18; 95% CI 4.30-6.23) regardless of gender. The subgroup analyses generally revealed similar associations across all subgroups. ROC curve analysis showed that when the maximum area under the curve was 0.748, the WTI was 90.1, and the corresponding sensitivity and specificity were 90.6 and 59.5%, respectively. CONCLUSIONS HTGW phenotype is strongly associated with NAFLD and can be used as a reference factor for NAFLD screening.
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Affiliation(s)
- Yan Xuan
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Gao
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Shen
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sujie Wang
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Gu
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dou Tang
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xun Wang
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - FanFan Zhu
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Leiqun Lu
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ling Chen
- Institute and Department of Endocrinology, Shanghai Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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14
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Yun YR, Lee JE. Alliin, capsaicin, and gingerol attenuate endoplasmic reticulum stress-induced hepatic steatosis in HepG2 cells and C57BL/6N mice. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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15
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Branković M, Jovanović I, Dukić M, Radonjić T, Oprić S, Klašnja S, Zdravković M. Lipotoxicity as the Leading Cause of Non-Alcoholic Steatohepatitis. Int J Mol Sci 2022; 23:ijms23095146. [PMID: 35563534 PMCID: PMC9105530 DOI: 10.3390/ijms23095146] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 04/30/2022] [Accepted: 04/30/2022] [Indexed: 12/11/2022] Open
Abstract
The emerging issues nowadays are non-alcoholic fatty liver disease (NAFLD) and its advanced stage non-alcoholic steatohepatitis (NASH), which further can be a predisposing factor for chronic liver complications, such as cirrhosis and/or development of hepatocellular carcinoma (HCC). Liver lipotoxicity can influence the accumulation of reactive oxygen species (ROS), so oxidative stress is also crucial for the progression of NASH. Moreover, NASH is in strong connection with metabolic disorders, and supporting evidence shows that insulin resistance (IR) is in a close relation to NAFLD, as it is involved in the progression to NASH and further progression to hepatic fibrosis. The major issue is that, at the moment, NASH treatment is based on lifestyle changes only due to the fact that no approved therapeutic options are available. The development of new therapeutic strategies should be conducted towards the potential NAFLD and NASH treatment by the modulation of IR but also by dietary antioxidants. As it seems, NASH is going to be the leading indication for liver transplantation as a consequence of increased disease prevalence and the lack of approved treatment; thus, an effective solution is needed as soon as possible.
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Affiliation(s)
- Marija Branković
- University Hospital Medical Center Bežanijska kosa, Dr Žorža Matea bb, 11000 Belgrade, Serbia; (I.J.); (M.D.); (T.R.); (S.O.); (S.K.); (M.Z.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Correspondence:
| | - Igor Jovanović
- University Hospital Medical Center Bežanijska kosa, Dr Žorža Matea bb, 11000 Belgrade, Serbia; (I.J.); (M.D.); (T.R.); (S.O.); (S.K.); (M.Z.)
| | - Marija Dukić
- University Hospital Medical Center Bežanijska kosa, Dr Žorža Matea bb, 11000 Belgrade, Serbia; (I.J.); (M.D.); (T.R.); (S.O.); (S.K.); (M.Z.)
| | - Tijana Radonjić
- University Hospital Medical Center Bežanijska kosa, Dr Žorža Matea bb, 11000 Belgrade, Serbia; (I.J.); (M.D.); (T.R.); (S.O.); (S.K.); (M.Z.)
| | - Svetlana Oprić
- University Hospital Medical Center Bežanijska kosa, Dr Žorža Matea bb, 11000 Belgrade, Serbia; (I.J.); (M.D.); (T.R.); (S.O.); (S.K.); (M.Z.)
| | - Slobodan Klašnja
- University Hospital Medical Center Bežanijska kosa, Dr Žorža Matea bb, 11000 Belgrade, Serbia; (I.J.); (M.D.); (T.R.); (S.O.); (S.K.); (M.Z.)
| | - Marija Zdravković
- University Hospital Medical Center Bežanijska kosa, Dr Žorža Matea bb, 11000 Belgrade, Serbia; (I.J.); (M.D.); (T.R.); (S.O.); (S.K.); (M.Z.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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16
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Aragón-Herrera A, Otero-Santiago M, Anido-Varela L, Moraña-Fernández S, Campos-Toimil M, García-Caballero T, Barral L, Tarazón E, Roselló-Lletí E, Portolés M, Gualillo O, Moscoso I, Lage R, González-Juanatey JR, Feijóo-Bandín S, Lago F. The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile. Front Pharmacol 2022; 13:827033. [PMID: 35185578 PMCID: PMC8847595 DOI: 10.3389/fphar.2022.827033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/04/2022] [Indexed: 12/22/2022] Open
Abstract
The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.
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Affiliation(s)
- Alana Aragón-Herrera
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Manuel Otero-Santiago
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Laura Anido-Varela
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Sandra Moraña-Fernández
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Manuel Campos-Toimil
- Group of Pharmacology of Chronic Diseases (CD Pharma), Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Tomás García-Caballero
- Department of Morphological Sciences, University of Santiago de Compostela and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Luis Barral
- Group of Polymers, Department of Physics and Earth Sciences, University of La Coruña, La Coruña, Spain
| | - Estefanía Tarazón
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain.,Cardiocirculatory Unit, Health Research Institute of La Fe University Hospital, Valencia, Spain
| | - Esther Roselló-Lletí
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain.,Cardiocirculatory Unit, Health Research Institute of La Fe University Hospital, Valencia, Spain
| | - Manuel Portolés
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain.,Cardiocirculatory Unit, Health Research Institute of La Fe University Hospital, Valencia, Spain
| | - Oreste Gualillo
- Laboratory of Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Isabel Moscoso
- Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Institute of Biomedical Research of Santiago de Compostela (IDIS-SERGAS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Ricardo Lage
- Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Institute of Biomedical Research of Santiago de Compostela (IDIS-SERGAS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - José Ramón González-Juanatey
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Sandra Feijóo-Bandín
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Francisca Lago
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
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17
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Fuchs CD, Radun R, Dixon ED, Mlitz V, Timelthaler G, Halilbasic E, Herac M, Jonker JW, Ronda OAHO, Tardelli M, Haemmerle G, Zimmermann R, Scharnagl H, Stojakovic T, Verkade HJ, Trauner M. Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice. Hepatology 2022; 75:125-139. [PMID: 34387896 DOI: 10.1002/hep.32112] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/29/2021] [Accepted: 08/11/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Increased fatty acid (FA) flux from adipose tissue to the liver contributes to the development of NAFLD. Because free FAs are key lipotoxic triggers accelerating disease progression, inhibiting adipose triglyceride lipase (ATGL)/patatin-like phospholipase domain containing 2 (PNPLA2), the main enzyme driving lipolysis, may attenuate steatohepatitis. APPROACH AND RESULTS Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with methionine-choline-deficient (MCD) or high-fat high-carbohydrate (HFHC) diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis, and endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator-activated receptor (PPAR) α and PPARδ was measured. After short hairpin RNA-mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid:palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild-type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary-challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC-2 and myeloperoxidase-positive cells and low mRNA expression levels of inflammatory markers (such as IL-1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. Accordingly, pretreatment of LPS-treated HepG2 cells with the PPARδ agonist GW0742 suppressed mRNA expression of inflammatory markers. Additionally, ATGL knockdown in HepG2 cells attenuated LPS/OP21-induced expression of proinflammatory cytokines and chemokines such as chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand (Ccl) 2, and Ccl5. CONCLUSIONS Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.
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Affiliation(s)
- Claudia D Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Richard Radun
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emmanuel D Dixon
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Veronika Mlitz
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Gerald Timelthaler
- Institute for Cancer Research, Internal Medicine I, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Merima Herac
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - Johan W Jonker
- Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Onne A H O Ronda
- Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Matteo Tardelli
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Guenter Haemmerle
- BioTechMed-Graz, Graz, Austria.,Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Robert Zimmermann
- BioTechMed-Graz, Graz, Austria.,Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Henkjan J Verkade
- Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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18
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Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology. Biomolecules 2021; 12:biom12010057. [PMID: 35053204 PMCID: PMC8773762 DOI: 10.3390/biom12010057] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/25/2022] Open
Abstract
The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme that catalyzes the first step of TG breakdown to glycerol and fatty acids. Although its role in controlling lipid homeostasis has been relatively well-studied in the adipose tissue, heart, and skeletal muscle, it remains largely unknown how and to what extent ATGL is regulated in the liver, responds to stimuli and regulators, and mediates disease progression. Therefore, in this review, we describe the current understanding of the structure–function relationship of ATGL, the molecular mechanisms of ATGL regulation at translational and post-translational levels, and—most importantly—its role in lipid and glucose homeostasis in health and disease with a focus on the liver. Advances in understanding the molecular mechanisms underlying hepatic lipid accumulation are crucial to the development of targeted therapies for treating hepatic metabolic disorders.
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19
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Rady B, Nishio T, Dhar D, Liu X, Erion M, Kisseleva T, Brenner DA, Pocai A. PNPLA3 downregulation exacerbates the fibrotic response in human hepatic stellate cells. PLoS One 2021; 16:e0260721. [PMID: 34879108 PMCID: PMC8654208 DOI: 10.1371/journal.pone.0260721] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/16/2021] [Indexed: 11/20/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) results, in part, from the interaction of metabolic derangements with predisposing genetic variants, leading to liver-related complications and mortality. The strongest genetic determinant is a highly prevalent missense variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3 p.I148M). In human liver hepatocytes PNPLA3 localizes to the surface of lipid droplets where the mutant form is believed to enhance lipid accumulation and release of pro-inflammatory cytokines. Less is known about the role of PNPLA3 in hepatic stellate cells (HSCs). Here we characterized HSC obtained from patients carrying the wild type (n = 8 C/C) and the heterozygous (n = 6, C/G) or homozygous (n = 6, G/G) PNPLA3 I148M and investigated the effect of genotype and PNPLA3 downregulation on baseline and TGF-β-stimulated fibrotic gene expression. HSCs from all genotypes showed comparable baseline levels of PNPLA3 and expression of the fibrotic genes α-SMA, COL1A1, TIMP1 and SMAD7. Treatment with TGF-β increased PNPLA3 expression in all 3 genotypes (~2-fold) and resulted in similar stimulation of the expression of several fibrogenic genes. In primary human HSCs carrying wild-type (WT) PNPLA3, siRNA treatment reduced PNPLA3 mRNA by 79% resulting in increased expression of α-SMA, Col1a1, TIMP1, and SMAD7 in cells stimulated with TGF-β. Similarly, knock-down of PNPLA3 in HSCs carrying either C/G or G/G genotypes resulted in potentiation of TGF-β induced expression of fibrotic genes. Knockdown of PNPLA3 did not impact fibrotic gene expression in the absence of TGF-β treatment. Together, these data indicate that the presence of the I148M PNPLA3 mutation in HSC has no effect on baseline activation and that downregulation of PNPLA3 exacerbates the fibrotic response irrespective of the genotype.
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Affiliation(s)
- Brian Rady
- Cardiovascular & Metabolism, Janssen Pharmaceuticals, Spring House, PA, United States of America
| | - Takahiro Nishio
- Department of Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - Debanjan Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - Xiao Liu
- Department of Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - Mark Erion
- Cardiovascular & Metabolism, Janssen Pharmaceuticals, Spring House, PA, United States of America
| | - Tatiana Kisseleva
- Department of Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - David A. Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - Alessandro Pocai
- Cardiovascular & Metabolism, Janssen Pharmaceuticals, Spring House, PA, United States of America
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20
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Hubel E, Fishman S, Holopainen M, Käkelä R, Shaffer O, Houri I, Zvibel I, Shibolet O. Repetitive amiodarone administration causes liver damage via adipose tissue ER stress-dependent lipolysis, leading to hepatotoxic free fatty acid accumulation. Am J Physiol Gastrointest Liver Physiol 2021; 321:G298-G307. [PMID: 34259586 DOI: 10.1152/ajpgi.00458.2020] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Drug-induced liver injury is an emerging form of acute and chronic liver disease that may manifest as fatty liver. Amiodarone (AMD), a widely used antiarrhythmic drug, can cause hepatic injury and steatosis by a variety of mechanisms, not all completely understood. We hypothesized that repetitive AMD administration may induce hepatic lipotoxicity not only via effects on the liver but also via effects on adipose tissue. Indeed, repetitive AMD administration induced endoplasmic reticulum (ER) stress in both liver and adipose tissue. In adipose tissue, AMD reduced lipogenesis and increased lipolysis. Moreover, AMD treatment induced ER stress and ER stress-dependent lipolysis in 3T3L1 adipocytes in vitro. In the liver, AMD caused increased expression of genes encoding proteins involved in fatty acid (FA) uptake and transfer (Cd36, Fabp1, and Fabp4), and resulted in increased hepatic accumulation of free FAs, but not of triacylglycerols. In line with this, there was increased expression of hepatic de novo FA synthesis genes. However, AMD significantly reduced the expression of the desaturase Scd1 and elongase Elovl6, detected at mRNA and protein levels. Accordingly, the FA profile of hepatic total lipids revealed increased accumulation of palmitate, an SCD1 and ELOVL6 substrate, and reduced levels of palmitoleate and cis-vaccenate, products of the enzymes. In addition, AMD-treated mice displayed increased hepatic apoptosis. The studies show that repetitive AMD induces ER stress and aggravates lipolysis in adipose tissue while inducing a lipotoxic hepatic lipid environment, suggesting that AMD-induced liver damage is due to compound insult to liver and adipose tissue.NEW & NOTEWORTHY AMD chronic administration induces hepatic lipid accumulation by several mechanisms, including induction of hepatic ER stress, impairment of β-oxidation, and inhibition of triacylglycerol secretion. Our study shows that repetitive AMD treatment induces not only hepatic ER stress but also adipose tissue ER stress and lipolysis and hepatic accumulation of free fatty acids and enrichment of palmitate in the total lipids. Understanding the toxicity mechanisms of AMD would help devise ways to limit liver damage.
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Affiliation(s)
- Einav Hubel
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sigal Fishman
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Minna Holopainen
- Helsinki University Lipidomics Unit, Helsinki Institute for Life Science and Biocenter Finland, Helsinki, Finland.,Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Reijo Käkelä
- Helsinki University Lipidomics Unit, Helsinki Institute for Life Science and Biocenter Finland, Helsinki, Finland.,Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Ortal Shaffer
- Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Inbal Houri
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Isabel Zvibel
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oren Shibolet
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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21
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Dixon ED, Nardo AD, Claudel T, Trauner M. The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD. Genes (Basel) 2021; 12:genes12050645. [PMID: 33926085 PMCID: PMC8145571 DOI: 10.3390/genes12050645] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 12/11/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD.
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Affiliation(s)
| | | | | | - Michael Trauner
- Correspondence: ; Tel.: +43-140-4004-7410; Fax: +43-14-0400-4735
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Placental mobilization of free fatty acids contributes to altered materno-fetal transfer in obesity. Int J Obes (Lond) 2021; 45:1114-1123. [PMID: 33637949 PMCID: PMC8081658 DOI: 10.1038/s41366-021-00781-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 01/08/2021] [Accepted: 02/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Metabolic changes in obese pregnant women, such as changes of plasma lipids beyond physiological levels, may subsequently affect fetal development in utero. These metabolic derangements may remain in the offspring and continue throughout life. The placenta mediates bidirectional exchange of nutrients between mother and fetus. The impact of prepregnancy obesity on placental transfer of lipids is still unknown. OBJECTIVE We aimed to examine materno-to-fetal free fatty acid (FFA) transfer by a combined experimental and modeling approach. Flux of 13C-labeled FFA was evaluated by ex vivo perfusion of human placentae as a function of prepregnancy obesity. Mathematical modeling complemented ex vivo results by providing FFA kinetic parameters. RESULTS Obesity was strongly associated with elevated materno-to-fetal transfer of applied 13C-FFA. Clearance of polyunsaturated 13C-docosahexaenoic acid (DHA) was most prominently affected. The use of the mathematical model revealed a lower tissue storage capacity for DHA in obese compared with lean placentae. CONCLUSION Besides direct materno-to-fetal FFA transfer, placental mobilization accounts for the fetal FA supply. Together, with metabolic changes in the mother and an elevated materno-fetal FFA transfer shown in obesity, these changes suggest that they may be transmitted to the fetus, with yet unknown consequences.
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23
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Tardelli M, Bruschi FV, Trauner M. The Role of Metabolic Lipases in the Pathogenesis and Management of Liver Disease. Hepatology 2020; 72:1117-1126. [PMID: 32236963 PMCID: PMC7590081 DOI: 10.1002/hep.31250] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/02/2020] [Accepted: 03/18/2020] [Indexed: 12/20/2022]
Abstract
Intracellular lipolysis is an enzymatic pathway responsible for the catabolism of triglycerides (TGs) that is complemented by lipophagy as the autophagic breakdown of lipid droplets. The hydrolytic cleavage of TGs generates free fatty acids (FFAs), which can serve as energy substrates, precursors for lipid synthesis, and mediators in cell signaling. Despite the fundamental and physiological importance of FFAs, an oversupply can trigger lipotoxicity with impaired membrane function, endoplasmic reticulum stress, mitochondrial dysfunction, cell death, and inflammation. Conversely, impaired release of FFAs and other lipid mediators can also disrupt key cellular signaling functions that regulate metabolism and inflammatory processes. This review will focus on specific functions of intracellular lipases in lipid partitioning, covering basic and translational findings in the context of liver disease. In addition, the clinical relevance of genetic mutations in human disease and potential therapeutic opportunities will be discussed.
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Affiliation(s)
- Matteo Tardelli
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria,Division of Gastroenterology and HepatologyJoan and Sanford I. Weill Cornell Department of MedicineWeill Cornell Medical CollegeNew YorkNY
| | - Francesca Virginia Bruschi
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
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24
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Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature. Nat Cell Biol 2020; 22:828-841. [PMID: 32541879 DOI: 10.1038/s41556-020-0526-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 04/22/2020] [Indexed: 12/13/2022]
Abstract
Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex-Mof, Kansl2 or Kansl3-unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work establishes that neurovascular function is determined by the neural metabolic environment.
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25
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Xu C, Song D, Holck AL, Zhou Y, Liu R. Identifying Lipid Metabolites Influenced by Oleic Acid Administration Using High-Performance Liquid Chromatography-Mass Spectrometry-Based Lipidomics. ACS OMEGA 2020; 5:11314-11323. [PMID: 32478219 PMCID: PMC7254503 DOI: 10.1021/acsomega.9b04402] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 04/14/2020] [Indexed: 05/09/2023]
Abstract
Oleic acid (OA), one of the most important monounsaturated fatty acids, possesses protective properties against chronic liver disease (CLD) development, but the underlying metabolic metabolism remains unknown. HPLC-MS-based lipidomics was utilized to identify and quantify the endogenously altered lipid metabolites when hepatocytes were exposed to OA administration. The identified lipids could be grouped into 22 lipid classes; of which, 10 classes were significantly influenced by the OA treatment: lysophosphatidylcholine (LPC), phosphatidylglycerol (PG), ceramides (Cer), hexosylceramides (Hex1Cer), dihexosylceramides (Hex2Cer), cholesterol ester (ChE), and coenzyme (Co) were decreased, while diglyceride (DG), triglyceride (TG), and acyl carnitine (AcCa) were increased. In addition, as the variable importance in projection (VIP) list (VIP > 1.0 and P < 0.05) showed, 478 lipid species showed significant difference with OA administration, and these molecules could be potential biomarkers in conjunction with OA administration. In summary, our results provided a novel perspective to understand the influences of OA administration by investigating endogenous altered levels of lipid metabolites via lipidomics.
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Affiliation(s)
- Chao Xu
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
| | - Dan Song
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
| | - Askild L. Holck
- NOFIMA
- Norwegian Institute of Food, Fisheries and Aquaculture Research, P.O. Box 210, N-1431 Aas, Norway
| | - Youyou Zhou
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
| | - Rong Liu
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
- National
Center for International Research on Animal Gut Nutrition, Nanjing 210095, China
- Jiangsu
Collaborative Innovation Center of Meat Production and Processing, Nanjing 210095, China
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26
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Laitakari A, Tapio J, Mäkelä KA, Herzig KH, Dengler F, Gylling H, Walkinshaw G, Myllyharju J, Dimova EY, Serpi R, Koivunen P. HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD. J Mol Med (Berl) 2020; 98:719-731. [PMID: 32296880 PMCID: PMC7220983 DOI: 10.1007/s00109-020-01903-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/06/2020] [Accepted: 03/24/2020] [Indexed: 02/07/2023]
Abstract
Abstract Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2gt/gt) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2gt/gt mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2gt/gt tissues, including the liver, was 15–35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2gt/gt small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2gt/gt mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. Key messages • HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. • HIF-P4H-2 inhibition downregulates hepatic lipogenesis. • Induced browning of WAT and increased thermogenesis can also mediate protection. • HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD. Electronic supplementary material The online version of this article (10.1007/s00109-020-01903-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Anna Laitakari
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, FIN-90014, Oulu, Finland
| | - Joona Tapio
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, FIN-90014, Oulu, Finland
| | - Kari A Mäkelä
- Research Unit of Biomedicine, Biocenter Oulu, Medical Research Center and University Hospital, Oulu, Finland
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine, Biocenter Oulu, Medical Research Center and University Hospital, Oulu, Finland
- Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Helena Gylling
- Internal Medicine, University of Helsinki and Helsinki University Hospital, 00029 HUS, Helsinki, Finland
| | | | - Johanna Myllyharju
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, FIN-90014, Oulu, Finland
| | - Elitsa Y Dimova
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, FIN-90014, Oulu, Finland
| | - Raisa Serpi
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, FIN-90014, Oulu, Finland
| | - Peppi Koivunen
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, FIN-90014, Oulu, Finland.
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27
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Svegliati-Baroni G, Pierantonelli I, Torquato P, Marinelli R, Ferreri C, Chatgilialoglu C, Bartolini D, Galli F. Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease. Free Radic Biol Med 2019; 144:293-309. [PMID: 31152791 DOI: 10.1016/j.freeradbiomed.2019.05.029] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 05/13/2019] [Accepted: 05/27/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide (about 25% of the general population) and 3-5% of patients develop non-alcoholic steatohepatitis (NASH), characterized by hepatocytes damage, inflammation and fibrosis, which increase the risk of developing liver failure, cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD, particularly the mechanisms whereby a minority of patients develop a more severe phenotype, is still incompletely understood. In this review we examine the available literature on initial mechanisms of hepatocellular damage and inflammation, deriving from toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in the liver cells is not the main determinant of lipotoxicity and that specific lipid classes act as damaging agents. These lipotoxic species affect the cell behavior via multiple mechanisms, including activation of death receptors, endoplasmic reticulum stress, modification of mitochondrial function and oxidative stress. The gut microbiota, which provides signals through the intestine to the liver, is also reported to play a key role in lipotoxicity. Finally, we summarize the most recent lipidomic strategies utilized to explore the liver lipidome and its modifications in the course of NALFD. These include measures of lipid profiles in blood plasma and erythrocyte membranes that can surrogate to some extent lipid investigation in the liver.
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Affiliation(s)
- Gianluca Svegliati-Baroni
- Department of Gastroenterology, Università Politecnica Delle Marche, Ancona, Italy; Obesity Center, Università Politecnica Delle Marche, Ancona, Italy.
| | - Irene Pierantonelli
- Department of Gastroenterology, Università Politecnica Delle Marche, Ancona, Italy; Department of Gastroenterology, Senigallia Hospital, Senigallia, Italy
| | | | - Rita Marinelli
- Department of Pharmaceutical Sciences, University of Perugia, Italy
| | - Carla Ferreri
- ISOF, Consiglio Nazionale Delle Ricerche, Via P. Gobetti 101, 40129, Bologna, Italy
| | | | | | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, Italy
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28
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Jarc E, Petan T. Lipid Droplets and the Management of Cellular Stress. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2019; 92:435-452. [PMID: 31543707 PMCID: PMC6747940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Lipid droplets are cytosolic fat storage organelles present in most eukaryotic cells. Long regarded merely as inert fat reservoirs, they are now emerging as major regulators of cellular metabolism. They act as hubs that coordinate the pathways of lipid uptake, distribution, storage, and use in the cell. Recent studies have revealed that they are also essential components of the cellular stress response. One of the hallmark characteristics of lipid droplets is their capacity to buffer excess lipids and to finely tune their subsequent release based on specific cellular requirements. This simple feature of lipid droplet biology, buffering and delayed release of lipids, forms the basis for their pleiotropic roles in the cellular stress response. In stressed cells, lipid droplets maintain energy and redox homeostasis and protect against lipotoxicity by sequestering toxic lipids into their neutral lipid core. Their mobility and dynamic interactions with mitochondria enable an efficient delivery of fatty acids for optimal energy production. Lipid droplets are also involved in the maintenance of membrane and organelle homeostasis by regulating membrane composition, preventing lipid peroxidation and removing damaged proteins and lipids. Finally, they also engage in a symbiotic relationship with autophagy and act as reservoirs of bioactive lipids that regulate inflammation and immunity. Thus, lipid droplets are central managers of lipid metabolism that function as safeguards against various types of cellular stress.
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Affiliation(s)
- Eva Jarc
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia,Jožef Stefan International Postgraduate School, Ljubljana, Slovenia
| | - Toni Petan
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia,To whom all correspondence should be addressed: Toni Petan, Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia; Tel: +386 1 477 3713, Fax: +386 1 477 3984,
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29
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Haemmerle G, Lass A. Genetically modified mouse models to study hepatic neutral lipid mobilization. Biochim Biophys Acta Mol Basis Dis 2019; 1865:879-894. [PMID: 29883718 PMCID: PMC6887554 DOI: 10.1016/j.bbadis.2018.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/25/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
Abstract
Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals. From the disease etiology it is obvious that a tight regulation between lipid uptake, triacylglycerol synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent triacylglycerol deposition in the liver. In addition to triacylglycerol, also a tight control of other neutral lipid ester classes, i.e. cholesteryl esters and retinyl esters, is crucial for the maintenance of a healthy liver. Excessive cholesteryl ester accumulation is a hallmark of cholesteryl ester storage disease or Wolman disease, which is associated with premature death. The loss of hepatic vitamin A stores (retinyl ester stores of hepatic stellate cells) is incidental to the onset of liver fibrosis. Importantly, this more advanced stage of liver disease usually does not resolve but progresses to life threatening stages, i.e. liver cirrhosis and cancer. Therefore, understanding the enzymes and pathways that mobilize hepatic neutral lipid esters is crucial for the development of strategies and therapies to ameliorate pathophysiological conditions associated with derangements of hepatic neutral lipid ester stores, including liver steatosis, steatohepatitis, and fibrosis. This review highlights the physiological roles of enzymes governing the mobilization of neutral lipid esters at different sites in liver cells, including cytosolic lipid droplets, endoplasmic reticulum, and lysosomes. This article is part of a Special Issue entitled Molecular Basis of Disease: Animal models in liver disease.
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Affiliation(s)
- Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria.
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria; BioTechMed-Graz, Austria.
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30
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Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH. Transplantation 2019; 103:e1-e13. [DOI: 10.1097/tp.0000000000002480] [Citation(s) in RCA: 326] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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31
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Subramanian P, Becerra SP. Role of the PNPLA2 Gene in the Regulation of Oxidative Stress Damage of RPE. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1185:377-382. [PMID: 31884641 DOI: 10.1007/978-3-030-27378-1_62] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Oxidative stress-mediated injury of the retinal pigment epithelium (RPE) can precede progressive retinal degeneration and ultimately lead to blindness (e.g., age-related macular degeneration (AMD)). The RPE expresses the PNPLA2 gene and produces its protein product PEDF-R that exhibits lipase activity. We have shown that transient PNPLA2 overexpression decreases dead-cell proteolytic activity and that synthetic peptides derived from a central region of PEDF-R efficiently protect ARPE-19 and pig primary RPE cells from oxidative stress. This study aims to evaluate the effect of loss of PNPLA2 in RPE cells undergoing oxidative stress. Loss of PNPLA2 conferred increased resistance to cells when subjected to oxidative stress.
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Affiliation(s)
- Preeti Subramanian
- Section of Protein Structure and Function, Laboratory of Retinal Cell and Molecular Biology, NEI, National Institutes of Health, Bethesda, MD, USA
| | - S Patricia Becerra
- Section of Protein Structure and Function, Laboratory of Retinal Cell and Molecular Biology, NEI, National Institutes of Health, Bethesda, MD, USA.
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32
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Of mice and men: The physiological role of adipose triglyceride lipase (ATGL). Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1864:880-899. [PMID: 30367950 PMCID: PMC6439276 DOI: 10.1016/j.bbalip.2018.10.008] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/18/2018] [Accepted: 10/19/2018] [Indexed: 12/12/2022]
Abstract
Adipose triglyceride lipase (ATGL) has been discovered 14 years ago and revised our view on intracellular triglyceride (TG) mobilization – a process termed lipolysis. ATGL initiates the hydrolysis of TGs to release fatty acids (FAs) that are crucial energy substrates, precursors for the synthesis of membrane lipids, and ligands of nuclear receptors. Thus, ATGL is a key enzyme in whole-body energy homeostasis. In this review, we give an update on how ATGL is regulated on the transcriptional and post-transcriptional level and how this affects the enzymes' activity in the context of neutral lipid catabolism. In depth, we highlight and discuss the numerous physiological functions of ATGL in lipid and energy metabolism. Over more than a decade, different genetic mouse models lacking or overexpressing ATGL in a cell- or tissue-specific manner have been generated and characterized. Moreover, pharmacological studies became available due to the development of a specific murine ATGL inhibitor (Atglistatin®). The identification of patients with mutations in the human gene encoding ATGL and their disease spectrum has underpinned the importance of ATGL in humans. Together, mouse models and human data have advanced our understanding of the physiological role of ATGL in lipid and energy metabolism in adipose and non-adipose tissues, and of the pathophysiological consequences of ATGL dysfunction in mice and men.
Summary of mouse models with genetic or pharmacological manipulation of ATGL. Summary of patients with mutations in the human gene encoding ATGL. In depth discussion of the role of ATGL in numerous physiological processes in mice and men.
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Petan T, Jarc E, Jusović M. Lipid Droplets in Cancer: Guardians of Fat in a Stressful World. Molecules 2018; 23:molecules23081941. [PMID: 30081476 PMCID: PMC6222695 DOI: 10.3390/molecules23081941] [Citation(s) in RCA: 258] [Impact Index Per Article: 36.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 07/31/2018] [Accepted: 08/01/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer cells possess remarkable abilities to adapt to adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity to acquire extracellular lipids and the plasticity of their mechanisms for intracellular lipid synthesis, mobilisation, and recycling. Lipid droplets, cytosolic fat storage organelles present in most cells from yeast to men, are emerging as major regulators of lipid metabolism, trafficking, and signalling in various cells and tissues exposed to stress. Their biogenesis is induced by nutrient and oxidative stress and they accumulate in various cancers. Lipid droplets act as switches that coordinate lipid trafficking and consumption for different purposes in the cell, such as energy production, protection against oxidative stress or membrane biogenesis during rapid cell growth. They sequester toxic lipids, such as fatty acids, cholesterol and ceramides, thereby preventing lipotoxic cell damage and engage in a complex relationship with autophagy. Here, we focus on the emerging mechanisms of stress-induced lipid droplet biogenesis; their roles during nutrient, lipotoxic, and oxidative stress; and the relationship between lipid droplets and autophagy. The recently discovered principles of lipid droplet biology can improve our understanding of the mechanisms that govern cancer cell adaptability and resilience to stress.
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Affiliation(s)
- Toni Petan
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana SI-1000, Slovenia.
| | - Eva Jarc
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana SI-1000, Slovenia.
- Jožef Stefan International Postgraduate School, Ljubljana SI-1000, Slovenia.
| | - Maida Jusović
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana SI-1000, Slovenia.
- Jožef Stefan International Postgraduate School, Ljubljana SI-1000, Slovenia.
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Dietary Intake of Curcumin Improves eIF2 Signaling and Reduces Lipid Levels in the White Adipose Tissue of Obese Mice. Sci Rep 2018; 8:9081. [PMID: 29899429 PMCID: PMC5998036 DOI: 10.1038/s41598-018-27105-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/23/2018] [Indexed: 12/13/2022] Open
Abstract
White adipose tissue (eWAT) plays a crucial role in preventing metabolic syndrome. We aimed to investigate WAT distribution and gene expression and lipidomic profiles in epididymal WAT (eWAT) in diet-induced obese mice, reflecting a Western-style diet of humans to elucidate the bioactive properties of the dietary antioxidant curcumin in preventing lifestyle-related diseases. For 16 weeks, we fed C57BL/6J mice with a control diet, a high-fat, high-sucrose and high-cholesterol Western diet or Western diet supplemented with 0.1% (w/w) curcumin. Although the dietary intake of curcumin did not affect eWAT weight or plasma lipid levels, it reduced lipid peroxidation markers’ levels in eWAT. Curcumin accumulated in eWAT and changed gene expressions related to eukaryotic translation initiation factor 2 (eIF2) signalling. Curcumin suppressed eIF2α phosphorylation, which is induced by endoplasmic reticulum (ER) stress, macrophage accumulation and nuclear factor-κB (NF-κB) p65 and leptin expression, whereas it’s anti-inflammatory effect was inadequate to decrease TNF-α and IFN-γ levels. Lipidomic and gene expression analysis revealed that curcumin decreased some diacylglycerols (DAGs) and DAG-derived glycerophospholipids levels by suppressing the glycerol-3-phosphate acyltransferase 1 and adipose triglyceride lipase expression, which are associated with lipogenesis and lipolysis, respectively. Presumably, these intertwined effects contribute to metabolic syndrome prevention by dietary modification.
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35
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Jarc E, Kump A, Malavašič P, Eichmann TO, Zimmermann R, Petan T. Lipid droplets induced by secreted phospholipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:247-265. [DOI: 10.1016/j.bbalip.2017.12.006] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 11/13/2017] [Accepted: 12/07/2017] [Indexed: 12/12/2022]
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Moslehi A, Farahabadi M, Chavoshzadeh SA, Barati A, Ababzadeh S, Mohammadbeigi A. The Effect of Amygdalin on Endoplasmic Reticulum (ER) Stress Induced Hepatic Steatosis in Mice. Malays J Med Sci 2018; 25:16-23. [PMID: 29599631 DOI: 10.21315/mjms2018.25.1.3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 11/18/2017] [Indexed: 12/22/2022] Open
Abstract
Background Endoplasmic reticulum (ER) stress creates abnormalities in the insulin action, inflammatory responses, lipoprotein B100 degradation, and hepatic lipogenesis. Hepatic steatosis leads to a broad spectrum of hepatic disorders such as nonalcoholic fatty liver disease (NAFLD) and NASH. Amygdalin has beneficial effects on asthma, bronchitis, diabetes, and atherosclerosis. We designed this study to evaluate the effect of amygdalin on the ER stress induced hepatic steatosis. Methods Inbred mice received saline, DMSO and amygdalin, as control groups. ER stress was induced by tunicamycin (TM) injection. Amygdalin was administered 1 h before the TM challenge (Amy + TM group). Mice body and liver weights were measured. Hematoxylin and eosin (H&E) and oil red O staining from liver tissue, were performed. Alanin aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride and cholesterol levels were measured. Results Histological evaluation revealed that amygdalin was unable to decrease the TM induced liver steatosis; however, ALT and AST levels decreased [ALT: 35.33(2.15) U/L versus 92.33(6.66) U/L; (57.000, (50.63, 63.36), P < 0.001) and AST: 93(5.09) U/L versus 345(97.3) U/L, (252, (163.37, 340.62), P < 0.001)]. Amygdalin also decreased triglyceride and cholesterol plasma levels in the Amy + TM group [TG: 42.66(2.15) versus 53.33(7.24) mg/dL; (10.67, (3.80, 17.54), P = 0.006) and TC: 9.33(3.55) versus 112.66(4.31) mg/dL, (103.33, (98.25, 108.40) P < 0.001)]. Conclusion Amygdalin improved the ALT, AST, and lipid serum levels after the TM challenge; however, it could not attenuate hepatic steatosis.
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Affiliation(s)
- Azam Moslehi
- Cellular& Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Mohsen Farahabadi
- BSC of Operating Room, Qom University of Medical Sciences, Qom, Iran
| | | | - Akram Barati
- BSC of Nursing, Qom University of Medical Sciences, Qom, Iran
| | - Shima Ababzadeh
- Cellular& Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Abolfazl Mohammadbeigi
- Research Center for Environmental Pollutants, Qom University of Medical Sciences, Qom, Iran
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37
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Röhrl C, Stangl H. Cholesterol metabolism-physiological regulation and pathophysiological deregulation by the endoplasmic reticulum. Wien Med Wochenschr 2018; 168:280-285. [PMID: 29488036 PMCID: PMC6132555 DOI: 10.1007/s10354-018-0626-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 01/30/2018] [Indexed: 12/22/2022]
Abstract
Cholesterol is an essential lipid for mammalian cells and its homeostasis is tightly regulated. Disturbance of cellular cholesterol homeostasis is linked to atherosclerosis and cardiovascular diseases. A central role in the sensing and regulation of cholesterol homeostasis is attributed to the endoplasmic reticulum (ER). This organelle harbours inactive transcription factors, which sense ER cholesterol levels and initiate transcriptional responses after activation and translocation into the nucleus. Thereupon, these responses enable adaption to high or low cellular cholesterol levels. Besides the abovementioned canonical functions, ER stress-induced by metabolic burden-and the resulting unfolded protein response influence cholesterol metabolism relevant to metabolic disorders. This review summarizes basic as well as recent knowledge on the role of the ER in terms of regulation of cholesterol metabolism.
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Affiliation(s)
- Clemens Röhrl
- Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090, Vienna, Austria
| | - Herbert Stangl
- Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090, Vienna, Austria.
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38
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Lemberger UJ, Fuchs CD, Karer M, Haas S, Stojakovic T, Schöfer C, Marschall HU, Wrba F, Taketo MM, Egger G, Trauner M, Österreicher CH. Hepatocyte specific expression of an oncogenic variant of β-catenin results in cholestatic liver disease. Oncotarget 2018; 7:86985-86998. [PMID: 27895309 PMCID: PMC5349966 DOI: 10.18632/oncotarget.13521] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 09/26/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development, tissue homeostasis, wound healing and malignant transformation in different organs including the liver. The consequences of continuous β-catenin signaling in hepatocytes remain elusive. RESULTS Livers of Ctnnb1CA hep mice were characterized by disturbed liver architecture, proliferating cholangiocytes and biliary type of fibrosis. Serum ALT and bile acid levels were significantly increased in Ctnnb1CA hep mice. The primary bile acid synthesis enzyme Cyp7a1 was increased whereas Cyp27 and Cyp8b1 were reduced in Ctnnb1CA hep mice. Expression of compensatory bile acid transporters including Abcb1, Abcb4, Abcc2 and Abcc4 were significantly increased in Ctnnb1CA hep mice while Ntcp was reduced. Accompanying changes of bile acid transporters favoring excretion of bile acids were observed in intestine and kidneys of Ctnnb1CA hep mice. Additionally, disturbed bile acid regulation through the FXR-FGF15-FGFR4 pathway was observed in mice with activated β-catenin. MATERIALS AND METHODS Mice with a loxP-flanked exon 3 of the Ctnnb1 gene were crossed to Albumin-Cre mice to obtain mice with hepatocyte-specific expression of a dominant stable form of β-catenin (Ctnnb1CA hep mice). Ctnnb1CA hep mice were analyzed by histology, serum biochemistry and mRNA profiling. CONCLUSIONS Expression of a dominant stable form of β-catenin in hepatocytes results in severe cholestasis and biliary type fibrosis.
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Affiliation(s)
- Ursula J Lemberger
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.,Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.,Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Claudia D Fuchs
- Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Matthias Karer
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Stefanie Haas
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Christian Schöfer
- Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Fritz Wrba
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Makoto M Taketo
- Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Gerda Egger
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
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Rutkowski DT. Liver function and dysfunction - a unique window into the physiological reach of ER stress and the unfolded protein response. FEBS J 2018; 286:356-378. [PMID: 29360258 DOI: 10.1111/febs.14389] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 01/08/2018] [Accepted: 01/17/2018] [Indexed: 02/06/2023]
Abstract
The unfolded protein response (UPR) improves endoplasmic reticulum (ER) protein folding in order to alleviate stress. Yet it is becoming increasingly clear that the UPR regulates processes well beyond those directly involved in protein folding, in some cases by mechanisms that fall outside the realm of canonical UPR signaling. These pathways are highly specific from one cell type to another, implying that ER stress signaling affects each tissue in a unique way. Perhaps nowhere is this more evident than in the liver, which-beyond being a highly secretory tissue-is a key regulator of peripheral metabolism and a uniquely proliferative organ upon damage. The liver provides a powerful model system for exploring how and why the UPR extends its reach into physiological processes that occur outside the ER, and how ER stress contributes to the many systemic diseases that involve liver dysfunction. This review will highlight the ways in which the study of ER stress in the liver has expanded the view of the UPR to a response that is a key guardian of cellular homeostasis outside of just the narrow realm of ER protein folding.
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Affiliation(s)
- D Thomas Rutkowski
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, IA, USA.,Department of Internal Medicine, University of Iowa Carver College of Medicine, IA, USA
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40
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Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH) and ultimately may lead to cirrhosis. Hepatic steatosis or fatty liver is defined as increased accumulation of lipids in hepatocytes and results from increased production or reduced clearance of hepatic triglycerides or fatty acids. Fatty liver can progress to NASH in a significant proportion of subjects. NASH is a necroinflammatory liver disease governed by multiple pathways that are not completely elucidated. This review describes the main mechanisms that have been reported to contribute to the pathophysiology of NAFLD and NASH.
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41
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Gan L, Liu Z, Luo D, Ren Q, Wu H, Li C, Sun C. Reduced Endoplasmic Reticulum Stress-Mediated Autophagy Is Required for Leptin Alleviating Inflammation in Adipose Tissue. Front Immunol 2017; 8:1507. [PMID: 29250056 PMCID: PMC5715390 DOI: 10.3389/fimmu.2017.01507] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 10/25/2017] [Indexed: 12/15/2022] Open
Abstract
Leptin is an adipocyte-derived hormone and maintains adipose function under challenged conditions. Autophagy is also essential to maintain cellular homeostasis and regulate characteristics of adipose tissue. However, the effects of leptin on autophagy of adipocyte remain elusive. Here, we demonstrated endoplasmic reticulum (ER) stress and leptin were correlated with autophagy and inflammation by transcriptome sequencing of adipose tissue. Leptin-mediated inhibition of autophagy was involved in upstream reduction of ER stress proteins such as Chop, GRP78, and Atf4, since blockage of autophagy using pharmacological approach had no effect on tunicamycin-induced ER stress. Moreover, we determined KLF4, the potential transcriptional factor of Atf4, was required for the leptin-mediated autophagy in the regulation of adipocyte inflammation. Importantly, ATF4 physically interacted with ATG5 and subsequently formed a complex to promote adipocyte autophagy. Further analysis revealed that Atg5, a core component of autophagosome, was the target for leptin-mediate autophagy. In addition, leptin alleviated ER stress-induced inflammation by reducing autophagy-mediated degradation of IκB in adipocytes. Exogenous leptin treatment also ameliorated autophagy and inflammation of white adipose tissue in ob/ob mice. Taken together, our results indicated that leptin inhibited ER stress-mediated autophagy and inflammation through the negatively regulation of Atf4/Atg5 complex in adipocytes. These findings identify a new potential means for intervention of autophagy to prevent or treat obese caused metabolic syndrome of mammals.
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Affiliation(s)
- Lu Gan
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Zhenjiang Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Dan Luo
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Qian Ren
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Hua Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Changxing Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Chao Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
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Moslehi A, Nabavizadeh F, Zekri A, Amiri F. Naltrexone changes the expression of lipid metabolism-related proteins in the endoplasmic reticulum stress induced hepatic steatosis in mice. Clin Exp Pharmacol Physiol 2017; 44:207-212. [PMID: 27813192 DOI: 10.1111/1440-1681.12695] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 10/30/2016] [Accepted: 10/30/2016] [Indexed: 12/11/2022]
Abstract
Endoplasmic reticulum (ER) stress is closely associated with several chronic diseases such as obesity, atherosclerosis, type 2 diabetes, and hepatic steatosis. Steatosis in hepatocytes may also lead to disorders such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), fibrosis, and possibly cirrhosis. Opioid peptides are involved in triglyceride and cholesterol dysregulation. Naltrexone also attenuates ER stress induced hepatic steatosis in mice. In this study, we evaluated the effects of naltrexone on the expression of lipid metabolism-related nuclear factors and enzymes in the ER stress induced hepatic steatosis. C57/BL6 mice received saline, DMSO and naltrexone as control groups. In a fourth group, ER stress was induced by tunicamycin (TM) injection and in the last group, naltrexone was given before TM administration. Histopathological evaluations, real-time RT-PCR and western blot were performed. We found that GRP78, IRE1α, PERK and ATF6 gene expression and steatosis significantly reduced in naltrexone treated animals. Naltrexone alleviated the gene and protein expression of SREBP1c. Expression of ACAT1, apolipoprotein B (ApoB) and PPARα also increased after naltrexone treatment. In conclusion, this study, for the first time, shows that naltrexone has a considerable role in attenuation of ER stress-induced liver injury.
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Affiliation(s)
- Azam Moslehi
- Cellular& Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Fatemeh Nabavizadeh
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Zekri
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Physiology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Fatemeh Amiri
- Physiology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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Welte MA, Gould AP. Lipid droplet functions beyond energy storage. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:1260-1272. [PMID: 28735096 PMCID: PMC5595650 DOI: 10.1016/j.bbalip.2017.07.006] [Citation(s) in RCA: 368] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/17/2017] [Accepted: 07/17/2017] [Indexed: 02/07/2023]
Abstract
Lipid droplets are cytoplasmic organelles that store neutral lipids and are critically important for energy metabolism. Their function in energy storage is firmly established and increasingly well characterized. However, emerging evidence indicates that lipid droplets also play important and diverse roles in the cellular handling of lipids and proteins that may not be directly related to energy homeostasis. Lipid handling roles of droplets include the storage of hydrophobic vitamin and signaling precursors, and the management of endoplasmic reticulum and oxidative stress. Roles of lipid droplets in protein handling encompass functions in the maturation, storage, and turnover of cellular and viral polypeptides. Other potential roles of lipid droplets may be connected with their intracellular motility and, in some cases, their nuclear localization. This diversity highlights that lipid droplets are very adaptable organelles, performing different functions in different biological contexts. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.
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Affiliation(s)
- Michael A Welte
- Department of Biology, University of Rochester, Rochester, NY, United States.
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44
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Zhang J, Zamani M, Thiele C, Taher J, Amir Alipour M, Yao Z, Adeli K. AUP1 (Ancient Ubiquitous Protein 1) Is a Key Determinant of Hepatic Very-Low-Density Lipoprotein Assembly and Secretion. Arterioscler Thromb Vasc Biol 2017; 37:633-642. [PMID: 28183703 DOI: 10.1161/atvbaha.117.309000] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 01/23/2017] [Indexed: 12/14/2022]
Abstract
OBJECTIVE AUP1 (ancient ubiquitous protein 1) is an endoplasmic reticulum-associated protein that also localizes to the surface of lipid droplets (LDs), with dual role in protein quality control and LD regulation. Here, we investigated the role of AUP1 in hepatic lipid mobilization and demonstrate critical roles in intracellular biogenesis of apoB100 (apolipoprotein B-100), LD mobilization, and very-low-density lipoprotein (VLDL) assembly and secretion. APPROACH AND RESULTS: siRNA (short/small interfering RNA) knockdown of AUP1 significantly increased secretion of VLDL-sized apoB100-containing particles from HepG2 cells, correcting a key metabolic defect in these cells that normally do not secrete much VLDL. Secreted particles contained higher levels of metabolically labeled triglyceride, and AUP1-deficient cells displayed a larger average size of LDs, suggesting a role for AUP1 in lipid mobilization. Importantly, AUP1 was also found to directly interact with apoB100, and this interaction was enhanced with proteasomal inhibition. Knockdown of AUP1 reduced apoB100 ubiquitination, decreased intracellular degradation of newly synthesized apoB100, and enhanced extracellular apoB100 secretion. Interestingly, the stimulatory effect of AUP1 knockdown on VLDL assembly was reminiscent of the effect previously observed after MEK-ERK (mitogen-activated protein kinase kinase-extracellular signal-regulated kinase) inhibition; however, further studies indicated that the AUP1 effect was independent of MEK-ERK signaling. CONCLUSIONS In summary, our findings reveal an important role for AUP1 as a regulator of apoB100 stability, hepatic LD metabolism, and intracellular lipidation of VLDL particles. AUP1 may be a crucial factor in apoB100 quality control, determining the rate at which apoB100 is degraded or lipidated to enable VLDL particle assembly and secretion.
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Affiliation(s)
- Jing Zhang
- From the Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (J.Z., M.Z., J.T., K.A.); Department of Biochemistry (M.Z., K.A.) and Department of Laboratory Medicine and Pathobiology (J.T., K.A.), University of Toronto, Ontario, Canada; Biochemistry and Cell Biology of Lipids Unit, LIMES Institute, University of Bonn, Germany (C.T.); and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (M.A.A., Z.Y.)
| | - Mostafa Zamani
- From the Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (J.Z., M.Z., J.T., K.A.); Department of Biochemistry (M.Z., K.A.) and Department of Laboratory Medicine and Pathobiology (J.T., K.A.), University of Toronto, Ontario, Canada; Biochemistry and Cell Biology of Lipids Unit, LIMES Institute, University of Bonn, Germany (C.T.); and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (M.A.A., Z.Y.)
| | - Christoph Thiele
- From the Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (J.Z., M.Z., J.T., K.A.); Department of Biochemistry (M.Z., K.A.) and Department of Laboratory Medicine and Pathobiology (J.T., K.A.), University of Toronto, Ontario, Canada; Biochemistry and Cell Biology of Lipids Unit, LIMES Institute, University of Bonn, Germany (C.T.); and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (M.A.A., Z.Y.)
| | - Jennifer Taher
- From the Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (J.Z., M.Z., J.T., K.A.); Department of Biochemistry (M.Z., K.A.) and Department of Laboratory Medicine and Pathobiology (J.T., K.A.), University of Toronto, Ontario, Canada; Biochemistry and Cell Biology of Lipids Unit, LIMES Institute, University of Bonn, Germany (C.T.); and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (M.A.A., Z.Y.)
| | - Mohsen Amir Alipour
- From the Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (J.Z., M.Z., J.T., K.A.); Department of Biochemistry (M.Z., K.A.) and Department of Laboratory Medicine and Pathobiology (J.T., K.A.), University of Toronto, Ontario, Canada; Biochemistry and Cell Biology of Lipids Unit, LIMES Institute, University of Bonn, Germany (C.T.); and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (M.A.A., Z.Y.)
| | - Zemin Yao
- From the Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (J.Z., M.Z., J.T., K.A.); Department of Biochemistry (M.Z., K.A.) and Department of Laboratory Medicine and Pathobiology (J.T., K.A.), University of Toronto, Ontario, Canada; Biochemistry and Cell Biology of Lipids Unit, LIMES Institute, University of Bonn, Germany (C.T.); and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (M.A.A., Z.Y.)
| | - Khosrow Adeli
- From the Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (J.Z., M.Z., J.T., K.A.); Department of Biochemistry (M.Z., K.A.) and Department of Laboratory Medicine and Pathobiology (J.T., K.A.), University of Toronto, Ontario, Canada; Biochemistry and Cell Biology of Lipids Unit, LIMES Institute, University of Bonn, Germany (C.T.); and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (M.A.A., Z.Y.).
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Perazzolo S, Hirschmugl B, Wadsack C, Desoye G, Lewis RM, Sengers BG. The influence of placental metabolism on fatty acid transfer to the fetus. J Lipid Res 2017; 58:443-454. [PMID: 27913585 PMCID: PMC5282960 DOI: 10.1194/jlr.p072355] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 11/17/2016] [Indexed: 12/15/2022] Open
Abstract
The factors determining fatty acid transfer across the placenta are not fully understood. This study used a combined experimental and computational modeling approach to explore placental transfer of nonesterified fatty acids and identify the rate-determining processes. Isolated perfused human placenta was used to study the uptake and transfer of 13C-fatty acids and the release of endogenous fatty acids. Only 6.2 ± 0.8% of the maternal 13C-fatty acids taken up by the placenta was delivered to the fetal circulation. Of the unlabeled fatty acids released from endogenous lipid pools, 78 ± 5% was recovered in the maternal circulation and 22 ± 5% in the fetal circulation. Computational modeling indicated that fatty acid metabolism was necessary to explain the discrepancy between uptake and delivery of 13C-fatty acids. Without metabolism, the model overpredicts the fetal delivery of 13C-fatty acids 15-fold. Metabolic rate was predicted to be the main determinant of uptake from the maternal circulation. The microvillous membrane had a greater fatty acid transport capacity than the basal membrane. This study suggests that incorporation of fatty acids into placental lipid pools may modulate their transfer to the fetus. Future work needs to focus on the factors regulating fatty acid incorporation into lipid pools.
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Affiliation(s)
- Simone Perazzolo
- Faculty of Engineering and Environment, University of Southampton, SO17 1BJ, UK
- Institute for Life Sciences Southampton, University of Southampton, SO17 1BJ, UK
| | - Birgit Hirschmugl
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria
| | - Christian Wadsack
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria
| | - Gernot Desoye
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria
| | - Rohan M Lewis
- Institute for Life Sciences Southampton, University of Southampton, SO17 1BJ, UK
- Bioengineering Research Group, Faculty of Medicine, University of Southampton, SO17 1BJ, UK
| | - Bram G Sengers
- Faculty of Engineering and Environment, University of Southampton, SO17 1BJ, UK
- Institute for Life Sciences Southampton, University of Southampton, SO17 1BJ, UK
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46
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Yan J, Wang C, Jin Y, Meng Q, Liu Q, Liu Z, Liu K, Sun H. Catalpol prevents alteration of cholesterol homeostasis in non-alcoholic fatty liver disease via attenuating endoplasmic reticulum stress and NOX4 over-expression. RSC Adv 2017. [DOI: 10.1039/c6ra26046b] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Catalpol has protective effects against hepatic lipid accumulation and alteration of cholesterol homeostasis in HFD- and PA-induced NAFLDviainhibiting ER stress and NOX4 over-expression.
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Affiliation(s)
- Jiting Yan
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Changyuan Wang
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Yue Jin
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Qiang Meng
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Qi Liu
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Zhihao Liu
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Kexin Liu
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Huijun Sun
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
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47
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Ochi T, Munekage K, Ono M, Higuchi T, Tsuda M, Hayashi Y, Okamoto N, Toda K, Sakamoto S, Oben JA, Saibara T. Patatin-like phospholipase domain-containing protein 3 is involved in hepatic fatty acid and triglyceride metabolism through X-box binding protein 1 and modulation of endoplasmic reticulum stress in mice. Hepatol Res 2016; 46:584-92. [PMID: 26347999 DOI: 10.1111/hepr.12587] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 09/02/2015] [Accepted: 09/02/2015] [Indexed: 12/13/2022]
Abstract
AIM Non-alcoholic steatohepatitis (NASH) is the major cause of chronic liver disease worldwide. Endoplasmic reticulum (ER) stress is considered to be an important pathological characteristic in NASH. A sequence variation (I148M) in the patatin-like phospholipase domain-containing protein 3/adiponutrin (PNPLA3) gene is known to be associated with the development of NASH. However, PNPLA3 deficiency has been considered to not be associated with fatty liver disease. To clarify, therefore, the role of PNPLA3 in liver, we established PNPLA3 knockout (KO) mice and investigated the phenotypes and involved factors under ER stress. METHODS ER stress was induced by i.p. injection with tunicamycin or with saline at 0 and 24 h in KO and C57BL/6 (wild-type [WT]) mice. At 48 h after the starting of treatment, blood and liver samples were studied. RESULTS Hepatic steatosis and triglyceride content were remarkably increased in WT mice than in KO mice under ER stress. The hepatic palmitate/oleate ratio was significantly higher originally in KO mice than in WT mice. Moreover, the expression of stearoyl-coenzyme A desaturase-1 (SCD1) in KO mice under ER stress was decreased further than that in WT mice. Expression of ER stress markers X-box binding protein 1 (XBP1) and ERdj4 was increased in WT mice but not in KO mice under ER stress. CONCLUSION We first demonstrated the hepatic phenotype of PNPLA3 deficiency under ER stress. Our observations would indicate that PNPLA3 has an important role in hepatic fatty acid metabolism and triglyceride accumulation through XBP1 under ER stress.
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Affiliation(s)
- Tsunehiro Ochi
- Departments of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Kensuke Munekage
- Departments of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Masafumi Ono
- Departments of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Takuma Higuchi
- Laboratory of Molecular Biology, Science Research Center, Kochi Medical School, Kochi, Japan
| | - Masayuki Tsuda
- The Division of Laboratory Animal Science, Science Research Center, Kochi Medical School, Kochi, Japan
| | | | - Nobuto Okamoto
- Departments of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Katsumi Toda
- Department of Biochemistry, Kochi Medical School, Kochi, Japan
| | - Shuji Sakamoto
- Laboratory of Molecular Biology, Science Research Center, Kochi Medical School, Kochi, Japan
| | - Jude A Oben
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London.,Department of Gastroenterology & Hepatology, Guy's and St. Thomas' Hospital, London, UK
| | - Toshiji Saibara
- Departments of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
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48
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Wu JW, Yang H, Mitchell GA. Potential mechanism underlying the PNPLA3(I) (148) (M) -Hepatic steatosis connection. Hepatology 2016; 63:676-7. [PMID: 26096616 DOI: 10.1002/hep.27943] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Jiang Wei Wu
- Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada
| | - Hao Yang
- Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada
| | - Grant A Mitchell
- Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montréal, QC, Canada
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49
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Saponaro C, Gaggini M, Carli F, Gastaldelli A. The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis. Nutrients 2015; 7:9453-74. [PMID: 26580649 PMCID: PMC4663603 DOI: 10.3390/nu7115475] [Citation(s) in RCA: 363] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 10/19/2015] [Accepted: 10/29/2015] [Indexed: 12/17/2022] Open
Abstract
Excessive accumulation of lipids can lead to lipotoxicity, cell dysfunction and alteration in metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. This is now a recognized risk factor for the development of metabolic disorders, such as obesity, diabetes, fatty liver disease (NAFLD), cardiovascular diseases (CVD) and hepatocellular carcinoma (HCC). The causes for lipotoxicity are not only a high fat diet but also excessive lipolysis, adipogenesis and adipose tissue insulin resistance. The aims of this review are to investigate the subtle balances that underlie lipolytic, lipogenic and oxidative pathways, to evaluate critical points and the complexities of these processes and to better understand which are the metabolic derangements resulting from their imbalance, such as type 2 diabetes and non alcoholic fatty liver disease.
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Affiliation(s)
- Chiara Saponaro
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, 53100 Siena, Italy.
| | - Melania Gaggini
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
- Dipartimento di Patologia Chirurgica, Molecolare Medica e di Area Critica, Università di Pisa, 56126 Pisa, Italy.
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
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50
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Zhi H, Qu L, Wu F, Chen L, Tao J. Group IIE secretory phospholipase A2 regulates lipolysis in adipocytes. Obesity (Silver Spring) 2015; 23:760-8. [PMID: 25755141 DOI: 10.1002/oby.21015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 12/10/2014] [Indexed: 11/10/2022]
Abstract
OBJECTIVE To examine the function of group IIE secretory phospholipase A(2) (sPLA(2) -IIE) in adipocytes and to explore the possible signaling mechanism involved. METHODS The expression of sPLA(2) -IIE was demonstrated using real-time PCR and Western blot analysis. Lipid accumulation was evaluated via the measurement of cellular triglycerides (TG). Lipolysis was quantified by measuring the release of free glycerol. The expressions of M-type sPLA(2) receptor (PLA(2) R1) and the genes encoding adipogenic proteins were measured using real-time PCR. The activities of the Janus kinase 2 (JAK2), extracellular regulated protein kinase (ERK), and hormone-sensitive lipase (HSL) were determined using Western blot. RESULTS sPLA(2) -IIE(-/-) mice gained significantly more epididymal fat than wild-type (WT) mice. When treated with adipogenic stimuli ex vivo, stromal vascular cells isolated from the adipose tissue of sPLA(2) -IIE(-/-) mice accumulated significantly more TG than those from WT mice. Conversely, a significant reduction in lipid accumulation and an increase of free glycerol were observed in OP9 cells overexpressing sPLA(2) -IIE and in 3T3-L1 cells treated with sPLA(2) -IIE protein. Moreover, sPLA(2) -IIE significantly induced adipocyte glycerol release and HSL activity, which was inhibited by PD98059, an ERK inhibitor. CONCLUSIONS sPLA(2) -IIE regulates lipolysis in adipocytes, likely through the ERK/HSL signaling pathway.
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Affiliation(s)
- Hui Zhi
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. Correspondence: Ling Chen ; State Key Laboratory of Respiratory Diseases, Institute of Respiratory Diseases, Guangzhou College of Medicine, Guangzhou, China
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