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Li M, Houben T, Bitorina AV, Meesters DM, Israelsen M, Kjærgaard M, Koek GH, Hendrikx T, Verbeek J, Krag A, Thiele M, Shiri-Sverdlov R. Plasma cathepsin D as an early indicator of alcohol-related liver disease. JHEP Rep 2024; 6:101117. [PMID: 39263329 PMCID: PMC11388167 DOI: 10.1016/j.jhepr.2024.101117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 09/13/2024] Open
Abstract
Background & Aims People who drink alcohol excessively are at increased risk of developing metabolic dysfunction and alcohol-related liver disease (MetALD) or the more severe form alcohol-related liver disease (ALD). One of the most significant challenges concerns the early detection of MetALD/ALD. Previously, we have demonstrated that the lysosomal enzyme cathepsin D (CTSD) is an early marker for metabolic dysfunction-associated steatohepatitis (MASH). Here, we hypothesized that plasma CTSD can also serve as an early indicator of MetALD/ALD. Methods We included 303 persistent heavy drinkers classified as having MetALD or ALD (n = 152) and abstinent patients with a history of excessive drinking (n = 151). Plasma CTSD levels of patients with MetALD/ALD without decompensation were compared with 40 healthy controls. Subsequently, the relationship between plasma CTSD levels and hepatic histological scores was established. Receiver-operating characteristic curves were generated to assess the precision of plasma CTSD levels in detecting MetALD/ALD. Lastly, plasma CTSD levels were compared between abstainers and drinkers. Results Plasma CTSD levels were higher in patients with MetALD/ALD compared to healthy controls. While hepatic disease parameters (AST/ALT ratio, liver stiffness measurement) were higher at advanced histopathological stages (assessed by liver biopsy), plasma CTSD levels were already elevated at early histopathological stages. Furthermore, combining plasma CTSD levels with liver stiffness measurement and AST/ALT ratio yielded enhanced diagnostic precision (AUC 0.872) in detecting MetALD/ALD in contrast to the utilization of CTSD alone (AUC 0.804). Plasma CTSD levels remained elevated in abstainers. Conclusion Elevated levels of CTSD in the circulation can serve as an early indicator of MetALD/ALD. Impact and implications Alcohol-related liver disease is the leading cause of liver disease-related morbidity and mortality worldwide. However, the currently available non-invasive methods to diagnose MetALD/ALD are only able to detect advanced stages of MetALD/ALD. Here, we demonstrate that plasma levels of the lysosomal enzyme cathepsin D are already elevated at early stages of MetALD/ALD. Moreover, cathepsin D levels outperformed the currently available non-invasive methods to detect MetALD/ALD. Plasma levels of cathepsin D could therefore be a useful non-invasive marker for detection of MetALD/ALD.
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Affiliation(s)
- Mengying Li
- Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands
| | - Tom Houben
- Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands
| | - Albert V. Bitorina
- Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands
| | - Dennis M. Meesters
- Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands
| | - Mads Israelsen
- Center for Liver Research, Odense University Hospital and University of Southern Denmark, Kloevervaenget 10, entrance 112, DK-5000 Odense, Denmark
| | - Maria Kjærgaard
- Center for Liver Research, Odense University Hospital and University of Southern Denmark, Kloevervaenget 10, entrance 112, DK-5000 Odense, Denmark
| | - Ger H. Koek
- Department of Internal Medicine Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Tim Hendrikx
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Jef Verbeek
- Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, KU Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Aleksander Krag
- Center for Liver Research, Odense University Hospital and University of Southern Denmark, Kloevervaenget 10, entrance 112, DK-5000 Odense, Denmark
| | - Maja Thiele
- Center for Liver Research, Odense University Hospital and University of Southern Denmark, Kloevervaenget 10, entrance 112, DK-5000 Odense, Denmark
| | - Ronit Shiri-Sverdlov
- Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands
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2
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Lucitti JL, Laudermilk LT, Amato GS, Maitra R. The Monoacylglycerol Lipase Inhibitor ABX-1431 Does Not Improve Alcoholic Liver Disease. Cannabis Cannabinoid Res 2024; 9:e1179-e1183. [PMID: 37253145 DOI: 10.1089/can.2023.0003] [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] [Indexed: 06/01/2023] Open
Abstract
Introduction: Excessive alcohol consumption can result in alcoholic liver disease (ALD). There is no FDA-approved drug to specifically treat ALD and current management approaches have limited efficacy. Past studies indicate that monoacylglycerol lipase (MAGL) inhibition can have a positive impact on nonalcoholic fatty liver disease. However, the effect of MAGL inhibition in ALD has not been reported. Materials and Methods: We tested the highly selective and clinically evaluated MAGL inhibitor ABX-1431 in the Lieber-DeCarli liquid alcohol diet-induced model of ALD in C57BL/6 mice. Results: ABX-1431 failed to reduce ALD-associated steatosis and elevated levels of liver enzymes associated with hepatic injury. Furthermore, survival rate declined with increasing doses of ABX-1431 when compared with mice administered vehicle only. Conclusion: These data suggest that MAGL inhibition does not improve ALD and is unlikely to be a good strategy for this condition.
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Affiliation(s)
- Jennifer L Lucitti
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - Lucas T Laudermilk
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - George S Amato
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - Rangan Maitra
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
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3
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Mak KM, Wu C, Cheng CP. Lipid droplets, the Holy Grail of hepatic stellate cells: In health and hepatic fibrosis. Anat Rec (Hoboken) 2022; 306:983-1010. [PMID: 36516055 DOI: 10.1002/ar.25138] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/07/2022] [Accepted: 11/29/2022] [Indexed: 12/15/2022]
Abstract
Lipid droplets (LDs) are distinct morphological markers of hepatic stellate cells (HSCs). They are composed of a core of predominantly retinyl esters and triacylglycerols surrounded by a phospholipid layer; the latter harbors perilipins 2, 3, and 5, which help control LD lipolysis. Electron microscopy distinguishes between Types I and II LDs. Type I LDs are surrounded by acid phosphatase-positive lysosomes, which likely digest LDs. LD count and retinoid concentration are modulated by vitamin A intake. Alcohol consumption depletes hepatic retinoids and HSC LDs, with concomitant transformation of HSCs to fibrogenic myofibroblast-like cells. LD loss and accompanying HSC activation occur in HSC cell culture models. Loss of LDs is a consequence of and not a prerequisite for HSC activation. LDs are endowed with enzymes for synthesizing retinyl esters and triacylglycerols as well as neutral lipases and lysosomal acid lipase for breaking down LDs. HSCs have two distinct metabolic LD pools: an "original" pool in quiescent HSCs and a "new" pool emerging in HSC activation; this two-pool model provides a platform for analyzing LD dynamics in HSC activation. Besides lipolysis, LDs are degraded by lipophagy; however, the coordination between and relative contributions of these two pathways to LD removal are unclear. While induction of autophagy accelerates LD loss in quiescent HSCs and promotes HSC activation, blocking autophagy impairs LD degradation and inhibits HSC activation and fibrosis. This article is a critique of five decades of investigations into the morphology, molecular structure, synthesis, and degradation of LDs associated with HSC activation and fibrosis.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Catherine Wu
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christopher P Cheng
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Osna NA, Rasineni K, Ganesan M, Donohue TM, Kharbanda KK. Pathogenesis of Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1492-1513. [PMID: 36340300 PMCID: PMC9630031 DOI: 10.1016/j.jceh.2022.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
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Key Words
- AA, Arachidonic acid
- ADH, Alcohol dehydrogenase
- AH, Alcoholic hepatitis
- ALD, Alcohol-associated liver disease
- ALDH, Aldehyde dehydrogenase
- ALT, Alanine transaminase
- ASH, Alcohol-associated steatohepatitis
- AST, Aspartate transaminase
- AUD, Alcohol use disorder
- BHMT, Betaine-homocysteine-methyltransferase
- CD, Cluster of differentiation
- COX, Cycloxygenase
- CTLs, Cytotoxic T-lymphocytes
- CYP, Cytochrome P450
- CYP2E1, Cytochrome P450 2E1
- Cu/Zn SOD, Copper/zinc superoxide dismutase
- DAMPs, Damage-associated molecular patterns
- DC, Dendritic cells
- EDN1, Endothelin 1
- ER, Endoplasmic reticulum
- ETOH, Ethanol
- EVs, Extracellular vesicles
- FABP4, Fatty acid-binding protein 4
- FAF2, Fas-associated factor family member 2
- FMT, Fecal microbiota transplant
- Fn14, Fibroblast growth factor-inducible 14
- GHS-R1a, Growth hormone secretagogue receptor type 1a
- GI, GOsteopontinastrointestinal tract
- GSH Px, Glutathione peroxidase
- GSSG Rdx, Glutathione reductase
- GST, Glutathione-S-transferase
- GWAS, Genome-wide association studies
- H2O2, Hydrogen peroxide
- HA, Hyaluronan
- HCC, Hepatocellular carcinoma
- HNE, 4-hydroxynonenal
- HPMA, 3-hydroxypropylmercapturic acid
- HSC, Hepatic stellate cells
- HSD17B13, 17 beta hydroxy steroid dehydrogenase 13
- HSP 90, Heat shock protein 90
- IFN, Interferon
- IL, Interleukin
- IRF3, Interferon regulatory factor 3
- JAK, Janus kinase
- KC, Kupffer cells
- LCN2, Lipocalin 2
- M-D, Mallory–Denk
- MAA, Malondialdehyde-acetaldehyde protein adducts
- MAT, Methionine adenosyltransferase
- MCP, Macrophage chemotactic protein
- MDA, Malondialdehyde
- MIF, Macrophage migration inhibitory factor
- Mn SOD, Manganese superoxide dismutase
- Mt, Mitochondrial
- NK, Natural killer
- NKT, Natural killer T-lymphocytes
- OPN, Osteopontin
- PAMP, Pathogen-associated molecular patterns
- PNPLA3, Patatin-like phospholipase domain containing 3
- PUFA, Polyunsaturated fatty acid
- RIG1, Retinoic acid inducible gene 1
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SCD, Stearoyl-CoA desaturase
- STAT, Signal transduction and activator of transcription
- TIMP1, Tissue inhibitor matrix metalloproteinase 1
- TLR, Toll-like receptor
- TNF, Tumor necrosis factor-α
- alcohol
- alcohol-associated liver disease
- ethanol metabolism
- liver
- miRNA, MicroRNA
- p90RSK, 90 kDa ribosomal S6 kinase
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Affiliation(s)
- Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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Samuvel DJ, Li L, Krishnasamy Y, Gooz M, Takemoto K, Woster PM, Lemasters JJ, Zhong Z. Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice. Autophagy 2022; 18:2671-2685. [PMID: 35293288 PMCID: PMC9629059 DOI: 10.1080/15548627.2022.2046457] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/15/2022] Open
Abstract
Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In Type 2, mitochondrial depolarization (mtDepo) initiates mitophagy to remove the damaged organelles. Previously, we showed that acute ethanol administration produces reversible hepatic mtDepo. Here, we tested the hypothesis that ethanol-induced mtDepo initiates Type 2 mitophagy. GFP-LC3 transgenic mice were gavaged with ethanol (2-6 g/kg) with and without pre-treatment with agents that decrease or increase mtDepo-Alda-1, tacrolimus, or disulfiram. Without ethanol, virtually all hepatocytes contained polarized mitochondria with infrequent autophagic GFP-LC3 puncta visualized by intravital microscopy. At ~4 h after ethanol treatment, mtDepo occurred in an all-or-none fashion within individual hepatocytes, which increased dose dependently. GFP-LC3 puncta increased in parallel, predominantly in hepatocytes with mtDepo. Mitochondrial PINK1 and PRKN/parkin also increased. After covalent labeling of mitochondria with MitoTracker Red (MTR), GFP-LC3 puncta encircled MTR-labeled mitochondria after ethanol treatment, directly demonstrating mitophagy. GFP-LC3 puncta did not associate with fat droplets visualized with BODIPY558/568, indicating that increased autophagy was not due to lipophagy. Before ethanol administration, rhodamine-dextran (RhDex)-labeled lysosomes showed little association with GFP-LC3. After ethanol treatment, TFEB (transcription factor EB) translocated to nuclei, and lysosomal mass increased. Many GFP-LC3 puncta merged with RhDex-labeled lysosomes, showing autophagosomal processing into lysosomes. After ethanol treatment, disulfiram increased, whereas Alda-1 and tacrolimus decreased mtDepo, and mitophagy changed proportionately. In conclusion, mtDepo after acute ethanol treatment induces mitophagic sequestration and subsequent lysosomal processing.Abbreviations : AcAld, acetaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ALD, alcoholic liver disease; Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LMNB1, lamin B1; MAA, malondialdehyde-acetaldehyde adducts; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MPT, mitochondrial permeability transition; mtDAMPS, mitochondrial damage-associated molecular patterns; mtDepo, mitochondrial depolarization; mtDNA, mitochondrial DNA; MTR, MitoTracker Red; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PRKN, parkin; RhDex, rhodamine dextran; TFEB, transcription factor EB; Tg, transgenic; TMRM, tetramethylrhodamine methylester; TOMM20, translocase of outer mitochondrial membrane 20; VDAC, voltage-dependent anion channel.
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Affiliation(s)
- Devadoss J. Samuvel
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Li Li
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Yasodha Krishnasamy
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Monika Gooz
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Kenji Takemoto
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Patrick M. Woster
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - John J. Lemasters
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Zhi Zhong
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
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Arumugam MK, Chava S, Perumal SK, Paal MC, Rasineni K, Ganesan M, Donohue TM, Osna NA, Kharbanda KK. Acute ethanol-induced liver injury is prevented by betaine administration. Front Physiol 2022; 13:940148. [PMID: 36267591 PMCID: PMC9577233 DOI: 10.3389/fphys.2022.940148] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Binge drinking is the most common form of excessive alcohol use. Repeated episodes of binge drinking cause multiple organ injuries, including liver damage. We previously demonstrated that chronic ethanol administration causes a decline in the intrahepatic ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). This decline causes impairments in essential methylation reactions that result in alcohol-induced fatty liver (steatosis) and other features of alcohol-associated liver disease (ALD). Co-treatment with betaine during chronic ethanol feeding, normalizes hepatocellular SAM:SAH ratio and alleviates many features of liver damage including steatosis. Here, we sought to examine whether betaine treatment similarly protects against liver injury in an alcohol binge-drinking model. We hypothesized that ethanol binge with prior or simultaneous betaine administration would prevent or attenuate acute alcohol-induced liver damage. Male C57Bl/6 mice were gavaged twice, 12 h apart, with either 6 g ethanol/kg BW or with an equal volume/kg BW of 0.9% NaCl. Two separate groups of mice (n = 5/group) were gavaged with 4 g betaine/kg BW, either 2 h before or simultaneously with the ethanol or saline gavages. All mice were sacrificed 8 h after the last gavage and serum and liver parameters were quantified. Ethanol binges caused a 50% decrease in hepatic SAM:SAH ratio and a >3-fold rise in liver triglycerides (p ≤ 0.05). These latter changes were accompanied by elevated serum AST and ALT activities and blood alcohol concentrations (BAC) that were ∼three-times higher than the legal limit of intoxication in humans. Mice that were treated with betaine 2 h before or simultaneously with the ethanol binges exhibited similar BAC as in mice given ethanol-alone. Both betaine treatments significantly elevated hepatic SAM levels thereby normalizing the SAM:SAH ratio and attenuating hepatic steatosis and other injury parameters, compared with mice given ethanol alone. Simultaneous betaine co-administration with ethanol was more effective in preventing or attenuating liver injury than betaine given before ethanol gavage. Our findings confirm the potential therapeutic value of betaine administration in preventing liver injury after binge drinking in an animal model.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Srinivas Chava
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Sathish Kumar Perumal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Matthew C. Paal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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7
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Yu LM, Dong X, Li N, Jiang H, Zhao JK, Xu YL, Xu DY, Xue XD, Zhou ZJ, Huang YT, Zhao QS, Wang ZS, Yin ZT, Wang HS. Polydatin attenuates chronic alcohol consumption-induced cardiomyopathy through a SIRT6-dependent mechanism. Food Funct 2022; 13:7302-7319. [PMID: 35726783 DOI: 10.1039/d2fo00966h] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Polydatin has attracted much attention as a potential cardioprotective agent against ischemic heart disease and diabetic cardiomyopathy. However, the effect and mechanism of polydatin supplementation on alcoholic cardiomyopathy (ACM) are still unknown. This study aimed to determine the therapeutic effect of polydatin against ACM and to explore the molecular mechanisms with a focus on SIRT6-AMP-activated protein kinase (AMPK) signaling and mitochondrial function. The ACM model was established by feeding C57/BL6 mice with an ethanol Lieber-DeCarli diet for 12 weeks. The mice received polydatin (20 mg kg-1) or vehicle treatment. We showed that polydatin treatment not only improved cardiac function but also reduced myocardial fibrosis and dynamin-related protein 1 (Drp-1)-mediated mitochondrial fission, and enhanced PTEN-induced putative kinase 1 (PINK1)-Parkin-dependent mitophagy in alcohol-treated myocardium. Importantly, these beneficial effects were mimicked by SIRT6 overexpression but abolished by the infection of recombinant serotype 9 adeno-associated virus (AAV9) carrying SIRT6-specific small hairpin RNA. Mechanistically, alcohol consumption induced a gradual decrease in the myocardial SIRT6 level, while polydatin effectively activated SIRT6-AMPK signaling and modulated mitochondrial dynamics and mitophagy, thus reducing oxidative stress damage and preserving mitochondrial function. In summary, these data present new information regarding the therapeutic actions of polydatin, suggesting that the activation of SIRT6 signaling may represent a new approach for tackling ACM-related cardiac dysfunction.
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Affiliation(s)
- Li-Ming Yu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Xue Dong
- The Third Outpatient Department, General Hospital of Northern Theater Command, 49 Beiling Road, Shenyang, Liaoning 110032, P. R. China
| | - Ning Li
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Hui Jiang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Ji-Kai Zhao
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Yin-Li Xu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Deng-Yue Xu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Xiao-Dong Xue
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Zi-Jun Zhou
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Yu-Ting Huang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Qiu-Sheng Zhao
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Zhi-Shang Wang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Zong-Tao Yin
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
| | - Hui-Shan Wang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
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8
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Guo W, Zhong W, Hao L, Dong H, Sun X, Yue R, Li T, Zhou Z. Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver Disease. Cell Mol Gastroenterol Hepatol 2021; 12:1599-1615. [PMID: 34284164 PMCID: PMC8536789 DOI: 10.1016/j.jcmgh.2021.07.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induces hepatocyte injury, thereby contributing to the development of ALD. METHODS Hepatocyte-specific DGAT1 knockout (DGAT1Δhep) mice and lysosome-associated membrane protein 2 (LAMP2) overexpression mice were generated and subjected to chronic alcohol feeding. Cell studies were conducted to define the causal role and underlying mechanism of FFA-induced hepatocellular injury. RESULTS Hepatocyte-specific DGAT1 deletion exacerbated alcohol-induced liver injury by increasing lipid accumulation and endoplasmic reticulum (ER) stress, reducing LAMP2 protein levels, and impairing autophagy function. Cell studies revealed that FFAs, rather than TG, induced ER stress via ATF4 activation, which, in turn, down-regulated LAMP2, thereby impairing autophagy flux. LAMP2 overexpression in the liver restored autophagy function and ameliorated alcohol-induced liver injury in mice. Reducing hepatic FFAs by peroxisome proliferator-activated receptor α activation attenuated ER stress, restored LAMP2 protein levels, and improved autophagy flux. In addition, suppression of LAMP2 and autophagy function was also detected in the liver of patients with severe alcoholic hepatitis. CONCLUSIONS This study demonstrates that accumulation of hepatic FFAs, rather than TG, plays a crucial role in the pathogenesis of ALD by suppressing LAMP2-autophagy flux pathway through ER stress signaling, which represents an important mechanism of FFA-induced hepatocellular injury in ALD.
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Affiliation(s)
- Wei Guo
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Wei Zhong
- Center for Translational Biomedical Research, Kannapolis, North Carolina,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina
| | - Liuyi Hao
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Haibo Dong
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Xinguo Sun
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Ruichao Yue
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Tianjiao Li
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, Kannapolis, North Carolina,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina,Correspondence Address correspondence to: Zhanxiang Zhou, PhD, Center for Translational Biomedical Research, University of North Carolina at Greensboro, 600 Laureate Way, Suite 2203, Kannapolis, North Carolina 28081.fax: (704) 250-5809.
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9
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Percival BC, Latour YL, Tifft CJ, Grootveld M. Rapid Identification of New Biomarkers for the Classification of GM1 Type 2 Gangliosidosis Using an Unbiased 1H NMR-Linked Metabolomics Strategy. Cells 2021; 10:572. [PMID: 33807817 PMCID: PMC7998791 DOI: 10.3390/cells10030572] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 01/04/2023] Open
Abstract
Biomarkers currently available for the diagnosis, prognosis, and therapeutic monitoring of GM1 gangliosidosis type 2 (GM1T2) disease are mainly limited to those discovered in targeted proteomic-based studies. In order to identify and establish new, predominantly low-molecular-mass biomarkers for this disorder, we employed an untargeted, multi-analyte approach involving high-resolution 1H NMR analysis coupled to a range of multivariate analysis and computational intelligence technique (CIT) strategies to explore biomolecular distinctions between blood plasma samples collected from GM1T2 and healthy control (HC) participants (n = 10 and 28, respectively). The relationship of these differences to metabolic mechanisms underlying the pathogenesis of GM1T2 disorder was also investigated. 1H NMR-linked metabolomics analyses revealed significant GM1T2-mediated dysregulations in ≥13 blood plasma metabolites (corrected p < 0.04), and these included significant upregulations in 7 amino acids, and downregulations in lipoprotein-associated triacylglycerols and alanine. Indeed, results acquired demonstrated a profound distinctiveness between the GM1T2 and HC profiles. Additionally, employment of a genome-scale network model of human metabolism provided evidence that perturbations to propanoate, ethanol, amino-sugar, aspartate, seleno-amino acid, glutathione and alanine metabolism, fatty acid biosynthesis, and most especially branched-chain amino acid degradation (p = 10-12-10-5) were the most important topologically-highlighted dysregulated pathways contributing towards GM1T2 disease pathology. Quantitative metabolite set enrichment analysis revealed that pathological locations associated with these dysfunctions were in the order fibroblasts > Golgi apparatus > mitochondria > spleen ≈ skeletal muscle ≈ muscle in general. In conclusion, results acquired demonstrated marked metabolic imbalances and alterations to energy demand, which are consistent with GM1T2 disease pathogenesis mechanisms.
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Affiliation(s)
- Benita C. Percival
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK;
| | - Yvonne L. Latour
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232-0252, USA;
| | - Cynthia J. Tifft
- Deputy Clinical Director, National Human Genome Research Institute, Director, National Institutes of Health, Bethesda, MD 20892-1205, USA;
| | - Martin Grootveld
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK;
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10
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Le Daré B, Ferron PJ, Gicquel T. The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease? Int J Mol Sci 2021; 22:2139. [PMID: 33670021 PMCID: PMC7926651 DOI: 10.3390/ijms22042139] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 12/24/2022] Open
Abstract
The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases-particularly in the liver. Although these alcoholic liver diseases were initially thought to be caused by the toxicity of ethanol on hepatocytes, the latest research indicates Kupffer cells (the liver macrophages) are at the heart of this "inflammatory shift". Purinergic signaling (notably through P2X7 receptors and the NLRP3 inflammasome) by Kupffer cells appears to be a decisive factor in the pathophysiology of alcoholic liver disease. Hence, the modulation of purinergic signaling might represent a new means of treating alcoholic liver disease. Here, we review current knowledge on the pathophysiology of alcoholic liver diseases and therapeutic perspectives for targeting these inflammatory pathways.
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Affiliation(s)
- Brendan Le Daré
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
- Forensic and Toxicology Laboratory, Rennes University Hospital, 2 rue Henri Le Guilloux, F-35033 Rennes, France
| | - Pierre-Jean Ferron
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
| | - Thomas Gicquel
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
- Forensic and Toxicology Laboratory, Rennes University Hospital, 2 rue Henri Le Guilloux, F-35033 Rennes, France
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11
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Casey CA, Donohue TM, Kubik JL, Kumar V, Naldrett MJ, Woods NT, Frisbie CP, McNiven MA, Thomes PG. Lipid droplet membrane proteome remodeling parallels ethanol-induced hepatic steatosis and its resolution. J Lipid Res 2021; 62:100049. [PMID: 33617872 PMCID: PMC8010705 DOI: 10.1016/j.jlr.2021.100049] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 01/29/2021] [Accepted: 02/10/2021] [Indexed: 10/25/2022] Open
Abstract
Lipid droplets (LDs) are composed of neutral lipids enclosed in a phospholipid monolayer, which harbors membrane-associated proteins that regulate LD functions. Despite the crucial role of LDs in lipid metabolism, remodeling of LD protein composition in disease contexts, such as steatosis, remains poorly understood. We hypothesized that chronic ethanol consumption, subsequent abstinence from ethanol, or fasting differentially affects the LD membrane proteome content and that these changes influence how LDs interact with other intracellular organelles. Here, male Wistar rats were pair-fed liquid control or ethanol diets for 6 weeks, and then, randomly chosen animals from both groups were either refed a control diet for 7 days or fasted for 48 h before euthanizing. From all groups, LD membrane proteins from purified liver LDs were analyzed immunochemically and by MS proteomics. Liver LD numbers and sizes were greater in ethanol-fed rats than in pair-fed control, 7-day refed, or fasted rats. Compared with control rats, ethanol feeding markedly altered the LD membrane proteome, enriching LD structural perilipins and proteins involved in lipid biosynthesis, while lowering LD lipase levels. Ethanol feeding also lowered LD-associated mitochondrial and lysosomal proteins. In 7-day refed (i.e., ethanol-abstained) or fasted-ethanol-fed rats, we detected distinct remodeling of the LD proteome, as judged by lower levels of lipid biosynthetic proteins, and enhanced LD interaction with mitochondria and lysosomes. Our study reveals evidence of significant remodeling of the LD membrane proteome that regulates ethanol-induced steatosis, its resolution after withdrawal and abstinence, and changes in LD interactions with other intracellular organelles.
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Affiliation(s)
- Carol A Casey
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Terrence M Donohue
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jacy L Kubik
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Vikas Kumar
- Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA; Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael J Naldrett
- Nebraska Center for Biotechnology, University of Nebraska-Lincoln, NE, USA
| | - Nicholas T Woods
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Cole P Frisbie
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mark A McNiven
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Paul G Thomes
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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12
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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13
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Aizawa S, Brar G, Tsukamoto H. Cell Death and Liver Disease. Gut Liver 2020; 14:20-29. [PMID: 30917630 PMCID: PMC6974333 DOI: 10.5009/gnl18486] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/14/2018] [Accepted: 12/17/2018] [Indexed: 12/13/2022] Open
Abstract
Cell death is now reclassified into several types based on the mechanisms and morphologic phenotype. Understanding of such classifications offers insights into the pathogenesis of liver disease, as well as diagnostic or therapeutic implications. Apoptosis is recognized relatively easily due to its unique morphology, but lytic cell death may occur in the form of accidental necrosis, mitochondria permeability transition-driven necrosis, necroptosis, pyroptosis, ferroptosis, and parthanatos. The cell may be engulfed by neighboring cells due to a loss of integrin signaling or cancer cell competition by entosis, a type of cell death. The classification also includes mechanistically termed cell death such as autophagy-dependent cell death and lysosome-dependent cell death. These different types of cell death may occur uniquely in certain liver diseases but may coexist in the evolution of the disease. They occur in parenchymal and non-parenchymal liver cells, as well as inflammatory cells, causing distinct pathologic consequences. This review briefly covers the recently revised classifications of cell death and discusses their relevance to liver diseases of different etiologies.
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Affiliation(s)
- Satoka Aizawa
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, USA
| | - Gurmehr Brar
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, USA.,Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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14
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Role of autophagy in alcohol and drug-induced liver injury. Food Chem Toxicol 2019; 136:111075. [PMID: 31877367 DOI: 10.1016/j.fct.2019.111075] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/16/2019] [Accepted: 12/20/2019] [Indexed: 02/07/2023]
Abstract
Alcohol-related liver disease (ALD) and drug-induced liver injury (DILI) are common causes of severe liver disease, and successful treatments are lacking. Autophagy plays a protective role in both ALD and DILI by selectively removing damaged mitochondria (mitophagy), lipid droplets (lipophagy), protein aggregates and adducts in hepatocytes. Autophagy also protects against ALD by degrading interferon regulatory factor 1 (IRF1) and damaged mitochondria in hepatic macrophages. Specifically, we will discuss selective autophagy for removal of damaged mitochondria and lipid droplets in hepatocytes and autophagy-mediated degradation of IRF1 in hepatic macrophages as protective mechanisms against alcohol-induced liver injury and steatosis. In addition, selective autophagy for removal of damaged mitochondria and protein adducts for protection against DILI is discussed in this review. Development of new therapeutics for ALD and DILI is greatly needed, and selective autophagy pathways may provide promising targets. Drug and alcohol effects on autophagy regulation as well as protective mechanisms of autophagy against DILI and ALD are highlighted in this review.
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15
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Abstract
The rising incidence of alcohol-related liver disease (ALD) demands making urgent progress in understanding the fundamental molecular basis of alcohol-related hepatocellular damage. One of the key early events accompanying chronic alcohol usage is the accumulation of lipid droplets (LDs) in the hepatocellular cytoplasm. LDs are far from inert sites of neutral lipid storage; rather, they represent key organelles that play vital roles in the metabolic state of the cell. In this review, we will examine the biology of these structures and outline recent efforts being made to understand the effects of alcohol exposure on the biogenesis, catabolism, and motility of LDs and how their dynamic nature is perturbed in the context of ALD.
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Affiliation(s)
- Ryan J. Schulze
- Department of Biochemistry and Molecular Biology and the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Corresponding author. Department of Biochemistry and Molecular Biology and the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. (R.J. Schulze)
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
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16
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Donohue TM, Osna NA, Kharbanda KK, Thomes PG. Lysosome and proteasome dysfunction in alcohol-induced liver injury. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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17
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Yang L, Yang C, Thomes PG, Kharbanda KK, Casey CA, McNiven MA, Donohue TM. Lipophagy and Alcohol-Induced Fatty Liver. Front Pharmacol 2019; 10:495. [PMID: 31143122 PMCID: PMC6521574 DOI: 10.3389/fphar.2019.00495] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022] Open
Abstract
This review describes the influence of ethanol consumption on hepatic lipophagy, a selective form of autophagy during which fat-storing organelles known as lipid droplets (LDs) are degraded in lysosomes. During classical autophagy, also known as macroautophagy, all forms of macromolecules and organelles are sequestered in autophagosomes, which, with their cargo, fuse with lysosomes, forming autolysosomes in which the cargo is degraded. It is well established that excessive drinking accelerates intrahepatic lipid biosynthesis, enhances uptake of fatty acids by the liver from the plasma and impairs hepatic secretion of lipoproteins. All the latter contribute to alcohol-induced fatty liver (steatosis). Here, our principal focus is on lipid catabolism, specifically the impact of excessive ethanol consumption on lipophagy, which significantly influences the pathogenesis alcohol-induced steatosis. We review findings, which demonstrate that chronic ethanol consumption retards lipophagy, thereby exacerbating steatosis. This is important for two reasons: (1) Unlike adipose tissue, the liver is considered a fat-burning, not a fat-storing organ. Thus, under normal conditions, lipophagy in hepatocytes actively prevents lipid droplet accumulation, thereby maintaining lipostasis; (2) Chronic alcohol consumption subverts this fat-burning function by slowing lipophagy while accelerating lipogenesis, both contributing to fatty liver. Steatosis was formerly regarded as a benign consequence of heavy drinking. It is now recognized as the "first hit" in the spectrum of alcohol-induced pathologies that, with continued drinking, progresses to more advanced liver disease, liver failure, and/or liver cancer. Complete lipid droplet breakdown requires that LDs be digested to release their high-energy cargo, consisting principally of cholesteryl esters and triacylglycerols (triglycerides). These subsequently undergo lipolysis, yielding free fatty acids that are oxidized in mitochondria to generate energy. Our review will describe recent findings on the role of lipophagy in LD catabolism, how continuous heavy alcohol consumption affects this process, and the putative mechanism(s) by which this occurs.
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Affiliation(s)
- Li Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Changqing Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Paul G. Thomes
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Carol A. Casey
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Mark A. McNiven
- Division of Gastroenterology and Hepatology, Department of Biochemistry and Molecular Biology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN, United States
| | - Terrence M. Donohue
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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18
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Tomaipitinca L, Mandatori S, Mancinelli R, Giulitti F, Petrungaro S, Moresi V, Facchiano A, Ziparo E, Gaudio E, Giampietri C. The Role of Autophagy in Liver Epithelial Cells and Its Impact on Systemic Homeostasis. Nutrients 2019; 11:nu11040827. [PMID: 30979078 PMCID: PMC6521167 DOI: 10.3390/nu11040827] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/08/2019] [Accepted: 04/09/2019] [Indexed: 12/14/2022] Open
Abstract
Autophagy plays a role in several physiological and pathological processes as it controls the turnover rate of cellular components and influences cellular homeostasis. The liver plays a central role in controlling organisms’ metabolism, regulating glucose storage, plasma proteins and bile synthesis and the removal of toxic substances. Liver functions are particularly sensitive to autophagy modulation. In this review we summarize studies investigating how autophagy influences the hepatic metabolism, focusing on fat accumulation and lipids turnover. We also describe how autophagy affects bile production and the scavenger function within the complex homeostasis of the liver. We underline the role of hepatic autophagy in counteracting the metabolic syndrome and the associated cardiovascular risk. Finally, we highlight recent reports demonstrating how the autophagy occurring within the liver may affect skeletal muscle homeostasis as well as different extrahepatic solid tumors, such as melanoma.
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Affiliation(s)
- Luana Tomaipitinca
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Sara Mandatori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Federico Giulitti
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Simonetta Petrungaro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Viviana Moresi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Antonio Facchiano
- Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata IDI-IRCCS, 00167 Rome, Italy.
| | - Elio Ziparo
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
| | - Claudia Giampietri
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy.
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19
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Quercetin ameliorates autophagy in alcohol liver disease associated with lysosome through mTOR-TFEB pathway. J Funct Foods 2019. [DOI: 10.1016/j.jff.2018.10.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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20
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Zhong Z, Lemasters JJ. A Unifying Hypothesis Linking Hepatic Adaptations for Ethanol Metabolism to the Proinflammatory and Profibrotic Events of Alcoholic Liver Disease. Alcohol Clin Exp Res 2018; 42:2072-2089. [PMID: 30132924 PMCID: PMC6214771 DOI: 10.1111/acer.13877] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/13/2018] [Indexed: 02/06/2023]
Abstract
The pathogenesis of alcoholic liver disease (ALD) remains poorly understood but is likely a multihit pathophysiological process. Here, we propose a hypothesis of how early mitochondrial adaptations for alcohol metabolism lead to ALD pathogenesis. Acutely, ethanol (EtOH) feeding causes a near doubling of hepatic EtOH metabolism and oxygen consumption within 2 to 3 hours. This swift increase in alcohol metabolism (SIAM) is an adaptive response to hasten metabolic elimination of both EtOH and its more toxic metabolite, acetaldehyde (AcAld). In association with SIAM, EtOH causes widespread hepatic mitochondrial depolarization (mtDepo), which stimulates oxygen consumption. In parallel, voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane close. Together, VDAC closure and respiratory stimulation promote selective and more rapid oxidation of EtOH first to AcAld in the cytosol and then to nontoxic acetate in mitochondria, since membrane-permeant AcAld does not require VDAC to enter mitochondria. VDAC closure also inhibits mitochondrial fatty acid oxidation and ATP release, promoting steatosis and a decrease in cytosolic ATP. After acute EtOH, these changes revert as EtOH is eliminated with little hepatocellular cytolethality. mtDepo also stimulates mitochondrial autophagy (mitophagy). After chronic high EtOH exposure, the capacity to process depolarized mitochondria by mitophagy becomes compromised, leading to intra- and extracellular release of damaged mitochondria, mitophagosomes, and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP) molecules. mtDAMPs cause inflammasome activation and promote inflammatory and profibrogenic responses, causing hepatitis and fibrosis. We propose that persistence of mitochondrial responses to EtOH metabolism becomes a tipping point, which links initial adaptive EtOH metabolism to maladaptive changes initiating onset and progression of ALD.
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Affiliation(s)
- Zhi Zhong
- Department of Drug Discovery & Biomedical Sciences and
| | - John J. Lemasters
- Department of Drug Discovery & Biomedical Sciences and
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
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Chao X, Wang S, Zhao K, Li Y, Williams JA, Li T, Chavan H, Krishnamurthy P, He XC, Li L, Ballabio A, Ni HM, Ding WX. Impaired TFEB-Mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-Induced Liver Injury and Steatosis in Mice. Gastroenterology 2018; 155:865-879.e12. [PMID: 29782848 PMCID: PMC6120772 DOI: 10.1053/j.gastro.2018.05.027] [Citation(s) in RCA: 252] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/16/2018] [Accepted: 05/10/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Defects in lysosome function and autophagy contribute to the pathogenesis of alcoholic liver disease. We investigated the mechanisms by which alcohol consumption affects these processes by evaluating the functions of transcription factor EB (TFEB), which regulates lysosomal biogenesis. METHODS We performed studies with GFP-LC3 mice, mice with liver-specific deletion of TFEB, mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), mice with disruption of the Tefb and Tfe3 genes (TFEB and TFE3 double-knockout mice), and Tfebflox/flox albumin cre-negative mice (controls). TFEB was overexpressed from adenoviral vectors or knocked down with small interfering RNAs in mouse livers. Mice were placed on diets of regular ethanol feeding plus an acute binge to induce liver damage (ethanol diet); some mice also were given injections of torin-1, an inhibitor of the kinase activity of the mechanistic target of rapamycin (mTOR). Liver tissues were collected and analyzed by immunohistochemistry, immunoblots, and quantitative real-time polymerase chain reaction to monitor lysosome biogenesis. We analyzed levels of TFEB in liver tissues from patients with alcoholic hepatitis and from healthy donors (controls) by immunohistochemistry. RESULTS Liver tissues from mice on the ethanol diet had lower levels of total and nuclear TFEB compared with control mice, and hepatocytes had decreased lysosome biogenesis and autophagy. Hepatocytes from mice on the ethanol diet had increased translocation of mTOR into lysosomes, resulting in increased mTOR activation. Administration of torin-1 increased liver levels of TFEB and decreased steatosis and liver injury induced by ethanol. Mice that overexpressed TFEB in the liver developed less severe ethanol-induced liver injury and had increased lysosomal biogenesis and mitochondrial bioenergetics compared with mice carrying a control vector. Mice with knockdown of TFEB and TFEB-TFE3 double-knockout mice developed more severe liver injury in response to the ethanol diet than control mice. Liver tissues from patients with alcohol-induced hepatitis had lower nuclear levels of TFEB than control tissues. CONCLUSIONS We found that ethanol feeding plus an acute binge decreased hepatic expression of TFEB, which is required for lysosomal biogenesis and autophagy. Strategies to block mTOR activity or increase levels of TFEB might be developed to protect the liver from ethanol-induced damage.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Katrina Zhao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Yuan Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Jessica A Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Hemantkumar Chavan
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Partha Krishnamurthy
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Xi C He
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Linheng Li
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Andrea Ballabio
- Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy,Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA,Correspondence to: Wen-Xing Ding, Ph.D., Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Blvd., Kansas City, Kansas 66160, Phone: 913-588-9813; Fax: 913-588-7501, ; Hong-Min Ni, MD., Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018 3901 Rainbow Blvd., Kansas City, Kansas 66160, Phone: 913-588-9813; Fax: 913-588-7501,
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
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Khambu B, Yan S, Huda N, Liu G, Yin XM. Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease. LIVER RESEARCH 2018; 2:112-119. [PMID: 31123622 PMCID: PMC6528826 DOI: 10.1016/j.livres.2018.09.004] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis. Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases. Impaired autophagy prevents the clearance of excessive lipid droplets (LDs), damaged mitochondria, and toxic protein aggregates, which can be generated during the progression of various liver diseases, thus contributing to the development of steatosis, injury, steatohepatitis, fibrosis, and tumors. In this review, we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases. We also examine the mechanisms of defects in autophagy, and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), focusing mainly on steatosis and liver injury. Finally, we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.
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Lemasters JJ, Zhong Z. Mitophagy in hepatocytes: Types, initiators and role in adaptive ethanol metabolism☆. LIVER RESEARCH 2018; 2:125-132. [PMID: 31157120 PMCID: PMC6541449 DOI: 10.1016/j.livres.2018.09.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mitophagy (mitochondrial autophagy) in hepatocytes is an essential quality control mechanism that removes for lysosomal digestion damaged, effete and superfluous mitochondria. Mitophagy has distinct variants. In type 1 mitophagy, typical of nutrient deprivation, cup-shaped sequestration membranes (phagophores) grow, surround and sequester individual mitochondria into mitophagosomes, often in coordination with mitochondrial fission. After sequestration, the outer compartment of the mitophagosome acidifies and the entrapped mitochondrion depolarizes, followed by fusion with lysosomes. By contrast, mitochondrial depolarization stimulates type 2 mitophagy, which is characterized by coalescence of autophagic microtubule-associated protein 1A/1B-light chain 3 (LC3)-containing structures on mitochondrial surfaces without the formation of a phagophore or mitochondrial fission. Oppositely to type 1 mitophagy, the inhibition of phosphoinositide-3-kinase (PI3K) does not block type 2 mitophagy. In type 3 mitophagy, or micromitophagy, mitochondria-derived vesicles (MDVs) enriched in oxidized proteins bud off from mitochondrial inner and outer membranes and incorporate into multivesicular bodies by vesicle scission into the lumen. In response to ethanol feeding, widespread ethanol-induced hepatocellular mitochondrial depolarization occurs to facilitate hepatic ethanol metabolism. As a consequence, type 2 mitophagy develops in response to the mitochondrial depolarization. After chronic high ethanol feeding, processing of depolarized mitochondria by mitophagy becomes compromised, leading to release of mitochondrial damage-associated molecular patterns (mtDAMPs) that promote inflammatory and profibrogenic responses. We propose that the persistence of mitochondrial responses for acute ethanol metabolism links initial adaptive ethanol metabolism to mitophagy and then to chronic maladaptive changes initiating onset and the progression of alcoholic liver disease (ALD).
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Affiliation(s)
- John J. Lemasters
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Zhi Zhong
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
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Shi X, Sun R, Zhao Y, Fu R, Wang R, Zhao H, Wang Z, Tang F, Zhang N, Tian X, Yao J. Promotion of autophagosome–lysosome fusion via salvianolic acid A-mediated SIRT1 up-regulation ameliorates alcoholic liver disease. RSC Adv 2018; 8:20411-20422. [PMID: 35541657 PMCID: PMC9080827 DOI: 10.1039/c8ra00798e] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 05/17/2018] [Indexed: 12/20/2022] Open
Abstract
Autophagosome and lysosome fusion was restored by salvianolic acid A-mediated SIRT1 up-regulation and protected against chronic ethanol-induced liver injury.
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25
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Rasineni K, Donohue TM, Thomes PG, Yang L, Tuma DJ, McNiven MA, Casey CA. Ethanol-induced steatosis involves impairment of lipophagy, associated with reduced Dynamin2 activity. Hepatol Commun 2017; 1:501-512. [PMID: 29152606 PMCID: PMC5678901 DOI: 10.1002/hep4.1063] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/11/2017] [Accepted: 05/17/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Lipid droplets (LDs), the organelles central to alcoholic steatosis, are broken down by lipophagy, a specialized form of autophagy. Here, we hypothesize that ethanol administration retards lipophagy by down-regulating Dynamin 2 (Dyn2), a protein that facilitates lysosome re-formation, contributing to hepatocellular steatosis. METHODS Primary hepatocytes were isolated from male Wistar rats fed Lieber-DeCarli control or EtOH liquid diets for 6-8 wk. Hepatocytes were incubated in complete medium (fed) or nutrient-free medium (fasting) with or without the Dyn2 inhibitor Dynasore or the Src inhibitor SU6656. Phosphorylated (active) forms of Src and Dyn2, and markers of autophagy were quantified by Western Blot. Co-localization of LDs-with autophagic machinery was determined by confocal microscopy. RESULTS In hepatocytes from pair-fed rats, LD breakdown was accelerated during fasting, as judged by smaller LDs and lower TG content when compared to hepatocytes in complete media. Fasting-induced TG loss in control hepatocytes was significantly blocked by either SU6656 or Dynasore. Compared to controls, hepatocytes from EtOH-fed rats had 66% and 40% lower content of pSrc and pDyn2, respectively, coupled with lower rate of fasting-induced TG loss. This slower rate of fasting-induced TG loss was blocked in cells co-incubated with Dynasore. Microscopic examination of EtOH-fed rat hepatocytes revealed increased co-localization of the autophagosome marker LC3 on LDs with a concomitant decrease in lysosome marker LAMP1. Whole livers and LD fractions of EtOH-fed rats exhibited simultaneous increase in LC3II and p62 over that of controls, indicating a block in lipophagy. CONCLUSION Chronic ethanol administration slowed the rate of hepatocyte lipophagy, owing in part to lower levels of phosphorylated Src kinase available to activate its substrate, Dyn2, thereby causing depletion of lysosomes for LD breakdown.
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Affiliation(s)
- Karuna Rasineni
- The Liver Study UnitVA Nebraska‐Western Iowa Health Care System (VA NWIHCS)OmahaNE
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
| | - Terrence M. Donohue
- The Liver Study UnitVA Nebraska‐Western Iowa Health Care System (VA NWIHCS)OmahaNE
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE
- Department of Pathology and MicrobiologyCollege of Medicine, University of Nebraska Medical CenterOmahaNE
- Center for Environmental ToxicologyCollege of Public Health, University of Nebraska Medical CenterOmahaNE
| | - Paul G. Thomes
- The Liver Study UnitVA Nebraska‐Western Iowa Health Care System (VA NWIHCS)OmahaNE
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
| | - Li Yang
- The Liver Study UnitVA Nebraska‐Western Iowa Health Care System (VA NWIHCS)OmahaNE
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
- Tongji HospitalTongji University School of MedicineShanghaiChina
| | - Dean J. Tuma
- The Liver Study UnitVA Nebraska‐Western Iowa Health Care System (VA NWIHCS)OmahaNE
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
| | - Mark A. McNiven
- Department of Biochemistry and Molecular BiologyMayo Clinic College of MedicineRochesterMN
| | - Carol A. Casey
- The Liver Study UnitVA Nebraska‐Western Iowa Health Care System (VA NWIHCS)OmahaNE
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE
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Schulze RJ, Rasineni K, Weller SG, Schott MB, Schroeder B, Casey CA, McNiven MA. Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7. Hepatol Commun 2017; 1:140-152. [PMID: 29404450 PMCID: PMC5721426 DOI: 10.1002/hep4.1021] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/29/2017] [Indexed: 12/20/2022] Open
Abstract
Alcohol consumption is a well-established risk factor for the onset and progression of fatty liver disease. An estimated 90% of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol-induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism. We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery. Nutrient starvation results in Rab7 activation on the surface of the LD and lysosomal compartments, resulting in the mobilization of triglycerides stored within the LDs for energy production. Here, we examine whether the steatotic effects of alcohol exposure are a result of perturbations to the Rab7-mediated lipophagic pathway. Rats chronically fed an ethanol-containing diet accumulated significantly higher levels of fat in their hepatocytes. Interestingly, hepatocytes isolated from these ethanol-fed rats contained juxtanuclear lysosomes that exhibited impaired motility. These changes are similar to those we observed in Rab7-depleted hepatocytes. Consistent with these defects in the lysosomal compartment, we observed a marked 80% reduction in Rab7 activity in cultured hepatocytes as well as a complete block in starvation-induced Rab7 activation in primary hepatocytes isolated from chronic ethanol-fed animals. Conclusion: A mechanism is supported whereby ethanol exposure inhibits Rab7 activity, resulting in the impaired transport, targeting, and fusion of the autophagic machinery with LDs, leading to an accumulation of hepatocellular lipids and hepatic steatosis. (Hepatology Communications 2017;1:140-152).
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Affiliation(s)
- Ryan J. Schulze
- Department of Biochemistry and Molecular Biology and the Center for Digestive DiseasesMayo ClinicRochesterMN
| | - Karuna Rasineni
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
| | - Shaun G. Weller
- Department of Biochemistry and Molecular Biology and the Center for Digestive DiseasesMayo ClinicRochesterMN
| | - Micah B. Schott
- Department of Biochemistry and Molecular Biology and the Center for Digestive DiseasesMayo ClinicRochesterMN
| | - Barbara Schroeder
- Department of Biochemistry and Molecular Biology and the Center for Digestive DiseasesMayo ClinicRochesterMN
- Present address:
Helmholtz Zentrum München, Institute of Biological and Medical ImagingNeuherbergGermany
| | - Carol A. Casey
- Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNE
- Research Service, VA Nebraska‐Western Iowa Health Care SystemOmahaNE
| | - Mark A. McNiven
- Department of Biochemistry and Molecular Biology and the Center for Digestive DiseasesMayo ClinicRochesterMN
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Sogut I, Uysal O, Oglakci A, Yucel F, Kartkaya K, Kanbak G. Prenatal alcohol-induced neuroapoptosis in rat brain cerebral cortex: protective effect of folic acid and betaine. Childs Nerv Syst 2017; 33:407-417. [PMID: 28062893 DOI: 10.1007/s00381-016-3309-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 11/29/2016] [Indexed: 10/20/2022]
Abstract
PURPOSE Alcohol consumption in pregnancy may cause fetal alcohol syndrome (FAS) in the infant. This study aims to investigate prenatal alcohol exposure related neuroapoptosis on the cerebral cortex tissues of newborn rats and possible neuroprotective effects of betaine, folic acid, and combined therapy. METHODS Pregnant rats were divided into five experimental groups: control, ethanol, ethanol + betaine, ethanol + folic acid, and ethanol + betaine + folic acid combined therapy groups. We measured cytochrome c release, caspase-3, calpain and cathepsin B and L. enzyme activities. In order to observe apoptotic cells in the early stages, TUNEL method was chosen together with histologic methods such as assessing the diameters of the apoptotic cells, their distribution in unit volume and volume proportion of cortical intact neuron nuclei. RESULTS Calpain, caspase-3 activities, and cytochrome c levels were significantly increased in alcohol group while cathepsin B and L. activities were also found to be elevated albeit not statistically significant. These increases were significantly reversed by folic acid and betaine + folic acid treatments. While ethanol increased the number of apoptotic cells, this increase was prevented in ethanol + betaine and ethanol + betaine + folic acid groups. Morphometric examination showed that the mean diameter of apoptotic cells was increased with ethanol administration while this increase was reduced by betaine and betaine + folic acid treatments. CONCLUSION We observed that ethanol is capable of triggering apoptotic cell death in the newborn rat brains. Furthermore, folic acid, betaine, and combined therapy of these supplements may reduce neuroapoptosis related to prenatal alcohol consumption, and might be effective on preventing fetal alcohol syndrome in infants.
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Affiliation(s)
- Ibrahim Sogut
- Vocational School of Health Services, Istanbul Bilim University, Yazarlar Sok. No:17, 34394, Istanbul, Turkey.
| | - Onur Uysal
- Vocational School of Health Services, Eskisehir Osmangazi University, 26480, Eskisehir, Turkey
| | - Aysegul Oglakci
- Medical School, Department of Biochemistry, Eskisehir Osmangazi University, 26480, Eskisehir, Turkey
| | - Ferruh Yucel
- Medical School, Department of Anatomy, Eskisehir Osmangazi University, 26480, Eskisehir, Turkey
| | - Kazim Kartkaya
- Medical School, Department of Biochemistry, Eskisehir Osmangazi University, 26480, Eskisehir, Turkey
| | - Gungor Kanbak
- Medical School, Department of Biochemistry, Eskisehir Osmangazi University, 26480, Eskisehir, Turkey
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28
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Barcia JM, Portolés S, Portolés L, Urdaneta AC, Ausina V, Pérez-Pastor GMA, Romero FJ, Villar VM. Does Oxidative Stress Induced by Alcohol Consumption Affect Orthodontic Treatment Outcome? Front Physiol 2017; 8:22. [PMID: 28179886 PMCID: PMC5263147 DOI: 10.3389/fphys.2017.00022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/10/2017] [Indexed: 12/26/2022] Open
Abstract
HIGHLIGHTS Ethanol, Periodontal ligament, Extracellular matrix, Orthodontic movement. Alcohol is a legal drug present in several drinks commonly used worldwide (chemically known as ethyl alcohol or ethanol). Alcohol consumption is associated with several disease conditions, ranging from mental disorders to organic alterations. One of the most deleterious effects of ethanol metabolism is related to oxidative stress. This promotes cellular alterations associated with inflammatory processes that eventually lead to cell death or cell cycle arrest, among others. Alcohol intake leads to bone destruction and modifies the expression of interleukins, metalloproteinases and other pro-inflammatory signals involving GSKβ, Rho, and ERK pathways. Orthodontic treatment implicates mechanical forces on teeth. Interestingly, the extra- and intra-cellular responses of periodontal cells to mechanical movement show a suggestive similarity with the effects induced by ethanol metabolism on bone and other cell types. Several clinical traits such as age, presence of systemic diseases or pharmacological treatments, are taken into account when planning orthodontic treatments. However, little is known about the potential role of the oxidative conditions induced by ethanol intake as a possible setback for orthodontic treatment in adults.
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Affiliation(s)
- Jorge M. Barcia
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Sandra Portolés
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Laura Portolés
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Alba C. Urdaneta
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Verónica Ausina
- Facultad de Ciencias de la Salud, Universidad Europea de ValenciaValencia, Spain
| | - Gema M. A. Pérez-Pastor
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Francisco J. Romero
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
- Facultad de Ciencias de la Salud, Universidad Europea de ValenciaValencia, Spain
| | - Vincent M. Villar
- Department of Biomedical Sciences, Universidad Cardenal Herrera, CEUMoncada, Spain
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Neuman MG, French SW, Zakhari S, Malnick S, Seitz HK, Cohen LB, Salaspuro M, Voinea-Griffin A, Barasch A, Kirpich IA, Thomes PG, Schrum LW, Donohue TM, Kharbanda KK, Cruz M, Opris M. Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage. Exp Mol Pathol 2017; 102:162-180. [PMID: 28077318 DOI: 10.1016/j.yexmp.2017.01.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 01/04/2017] [Indexed: 02/06/2023]
Abstract
This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | | | | | - Stephen Malnick
- Department Internal Medicine, Kaplan Medical Centre and Hebrew University of Jerusalem, Rehovot, Israel
| | - Helmut K Seitz
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Lawrence B Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mikko Salaspuro
- Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland
| | - Andreea Voinea-Griffin
- Public Health Science Texas A&M University, College of Dentistry, Dallas University, TX, USA
| | - Andrei Barasch
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Paul G Thomes
- Department of Internal Medicine, Carolinas Medical Center, Charlotte, NC, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Laura W Schrum
- Department of Internal Medicine, Carolinas Medical Center, Charlotte, NC, USA
| | - Terrence M Donohue
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Marcus Cruz
- In Vitro Drug Safety and Biotechnology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mihai Opris
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Family Medicine Clinic CAR, Bucharest, Romania
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Osna NA, Donohue TM, Kharbanda KK. Alcoholic Liver Disease: Pathogenesis and Current Management. Alcohol Res 2017; 38:147-161. [PMID: 28988570 PMCID: PMC5513682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35 percent develop advanced liver disease because a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking (i.e., abstinence) is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease.
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Affiliation(s)
- Natalia A Osna
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
| | - Terrence M Donohue
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
| | - Kusum K Kharbanda
- Natalia A. Osna, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and an Associate Professor in the Department of Internal Medicine, University of Nebraska Medical Center, both in Omaha, Nebraska. Terrence M. Donohue, Jr., Ph.D., is a Research Biochemist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska. Kusum K. Kharbanda, Ph.D., is a Research Biologist in the Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, and a Professor in the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Nebraska Medical Center, both in Omaha, Nebraska
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Li Y, Ding WX. A Gene Transcription Program Decides the Differential Regulation of Autophagy by Acute Versus Chronic Ethanol? Alcohol Clin Exp Res 2016; 40:47-9. [PMID: 26727521 DOI: 10.1111/acer.12931] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 10/15/2015] [Indexed: 12/14/2022]
Affiliation(s)
- Yuan Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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Nagy LE, Ding WX, Cresci G, Saikia P, Shah VH. Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes. Gastroenterology 2016; 150:1756-68. [PMID: 26919968 PMCID: PMC4887335 DOI: 10.1053/j.gastro.2016.02.035] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 01/28/2016] [Accepted: 02/09/2016] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) develops in approximately 20% of alcoholic patients, with a higher prevalence in females. ALD progression is marked by fatty liver and hepatocyte necrosis, as well as apoptosis, inflammation, regenerating nodules, fibrosis, and cirrhosis.(1) ALD develops via a complex process involving parenchymal and nonparenchymal cells, as well as recruitment of other cell types to the liver in response to damage and inflammation. Hepatocytes are damaged by ethanol, via generation of reactive oxygen species and induction of endoplasmic reticulum stress and mitochondrial dysfunction. Hepatocyte cell death via apoptosis and necrosis are markers of ethanol-induced liver injury. We review the mechanisms by which alcohol injures hepatocytes and the response of hepatic sinusoidal cells to alcohol-induced injury. We also discuss how recent insights into the pathogenesis of ALD will affect the treatment and management of patients.
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Affiliation(s)
- Laura E. Nagy
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195,Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195,Department of Medicine, Cleveland Clinic, Cleveland, OH 44195
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
| | - Gail Cresci
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195,Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195,Department of Medicine, Cleveland Clinic, Cleveland, OH 44195
| | - Paramananda Saikia
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195,Department of Medicine, Cleveland Clinic, Cleveland, OH 44195
| | - Vijay H. Shah
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
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Abstract
Ethanol metabolism in hepatocytes causes the generation of reactive oxygen species, endoplasmic reticulum stress and alterations in mitochondrial energy and REDOX metabolism. In ethanol-exposed liver disease, autophagy not only acts as a cleanser to remove damaged organelles and cytosolic components, but also selectively clears specific targets such as lipid droplets and damaged mitochondria. Moreover, ethanol appears to play a role in protecting hepatocytes from apoptosis at certain concentrations. This article describes the evidence, function and potential mechanism of autophagy in ethanol-exposed liver disease and the controversy surrounding the effects of ethanol on autophagy.
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Affiliation(s)
- Li-Ren Wang
- Department of Infection and Liver Diseases, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
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Oxidative Stress in the Healthy and Wounded Hepatocyte: A Cellular Organelles Perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:8327410. [PMID: 26788252 PMCID: PMC4691634 DOI: 10.1155/2016/8327410] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 09/10/2015] [Indexed: 02/06/2023]
Abstract
Accurate control of the cell redox state is mandatory for maintaining the structural integrity and physiological functions. This control is achieved both by a fine-tuned balance between prooxidant and anti-oxidant molecules and by spatial and temporal confinement of the oxidative species. The diverse cellular compartments each, although structurally and functionally related, actively maintain their own redox balance, which is necessary to fulfill specialized tasks. Many fundamental cellular processes such as insulin signaling, cell proliferation and differentiation and cell migration and adhesion, rely on localized changes in the redox state of signal transducers, which is mainly mediated by hydrogen peroxide (H2O2). Therefore, oxidative stress can also occur long before direct structural damage to cellular components, by disruption of the redox circuits that regulate the cellular organelles homeostasis. The hepatocyte is a systemic hub integrating the whole body metabolic demand, iron homeostasis and detoxification processes, all of which are redox-regulated processes. Imbalance of the hepatocyte's organelles redox homeostasis underlies virtually any liver disease and is a field of intense research activity. This review recapitulates the evolving concept of oxidative stress in the diverse cellular compartments, highlighting the principle mechanisms of oxidative stress occurring in the healthy and wounded hepatocyte.
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Thomes PG, Trambly CS, Fox HS, Tuma DJ, Donohue TM. Acute and Chronic Ethanol Administration Differentially Modulate Hepatic Autophagy and Transcription Factor EB. Alcohol Clin Exp Res 2015; 39:2354-63. [PMID: 26556759 DOI: 10.1111/acer.12904] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 09/10/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic ethanol (EtOH) consumption decelerates the catabolism of long-lived proteins, indicating that it slows hepatic macroautophagy (hereafter called autophagy) a crucial lysosomal catabolic pathway in most eukaryotic cells. Autophagy and lysosome biogenesis are linked. Both are regulated by the transcription factor EB (TFEB). Here, we tested whether TFEB can be used as a singular indicator of autophagic activity, by quantifying its nuclear content in livers of mice subjected to acute and chronic EtOH administration. We correlated nuclear TFEB to specific indices of autophagy. METHODS In acute experiments, we gavaged GFP-LC3(tg) mice with a single dose of EtOH or with phosphate buffered saline (PBS). We fed mice chronically by feeding them control or EtOH liquid diets. RESULTS Compared with PBS-gavaged controls, livers of EtOH-gavaged mice exhibited greater autophagosome (AV) numbers, a higher incidence of AV-lysosome co-localization, and elevated levels of free GFP, all indicating enhanced autophagy, which correlated with a higher nuclear content of TFEB. Compared with pair-fed controls, livers of EtOH-fed mice exhibited higher AV numbers, but had lower lysosome numbers, lower AV-lysosome co-localization, higher P62/SQSTM1 levels, and lower free GFP levels. The latter findings correlated with lower nuclear TFEB levels in EtOH-fed mice. Thus, enhanced autophagy after acute EtOH gavage correlated with a higher nuclear TFEB content. Conversely, chronic EtOH feeding inhibited hepatic autophagy, associated with a lower nuclear TFEB content. CONCLUSIONS Our findings suggest that the effect of acute EtOH gavage on hepatic autophagy differs significantly from that after chronic EtOH feeding. Each regimen distinctly affects TFEB localization, which in turn, regulates hepatic autophagy and lysosome biogenesis.
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Affiliation(s)
- Paul G Thomes
- Liver Study Unit, Department of Veterans Affairs, VA Nebraska-Western Iowa Health Care System (NWIHCS), Omaha, Nebraska.,Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Casey S Trambly
- Liver Study Unit, Department of Veterans Affairs, VA Nebraska-Western Iowa Health Care System (NWIHCS), Omaha, Nebraska.,Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Howard S Fox
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Dean J Tuma
- Liver Study Unit, Department of Veterans Affairs, VA Nebraska-Western Iowa Health Care System (NWIHCS), Omaha, Nebraska.,Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.,Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Terrence M Donohue
- Liver Study Unit, Department of Veterans Affairs, VA Nebraska-Western Iowa Health Care System (NWIHCS), Omaha, Nebraska.,Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.,Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.,Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.,The Center for Environmental Health and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska
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Ji C. Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage. Biomolecules 2015; 5:1099-121. [PMID: 26047032 PMCID: PMC4496712 DOI: 10.3390/biom5021099] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 05/23/2015] [Accepted: 05/26/2015] [Indexed: 12/20/2022] Open
Abstract
Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries.
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Affiliation(s)
- Cheng Ji
- GI/Liver Division, Research Center for Liver Disease, Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA.
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37
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Donohue TM, Thomes PG. Ethanol-induced oxidant stress modulates hepatic autophagy and proteasome activity. Redox Biol 2014; 3:29-39. [PMID: 25462063 PMCID: PMC4297932 DOI: 10.1016/j.redox.2014.10.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 10/27/2014] [Accepted: 10/28/2014] [Indexed: 02/07/2023] Open
Abstract
In this review, we describe research findings on the effects of alcohol exposure on two major catabolic systems in liver cells: the ubiquitin-proteasome system (UPS) and autophagy. These hydrolytic systems are not unique to liver cells; they exist in all eukaryotic tissues and cells. However, because the liver is the principal site of ethanol metabolism, it sustains the greatest damage from heavy drinking. Thus, the focus of this review is to specifically describe how ethanol oxidation modulates the activities of the UPS and autophagy and the mechanisms by which these changes contribute to the pathogenesis of alcohol-induced liver injury. Here, we describe the history and the importance of cellular hydrolytic systems, followed by a description of each catabolic pathway and the differential modulation of each by ethanol exposure. Overall, the evidence for an involvement of these catabolic systems in the pathogenesis of alcoholic liver disease is quite strong. It underscores their importance, not only as effective means of cellular recycling and eventual energy generation, but also as essential components of cellular defense.
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Affiliation(s)
- Terrence M Donohue
- Research Service (151), VA-Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; Department of Internal Medicine, College of Medicine, USA; Department of Biochemistry and Molecular Biology, College of Medicine, USA; Department of Pathology and Microbiology, College of Medicine, USA; The Center for Environmental Health and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
| | - Paul G Thomes
- Research Service (151), VA-Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; Department of Internal Medicine, College of Medicine, USA
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38
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Autophagy in alcohol-induced multiorgan injury: mechanisms and potential therapeutic targets. BIOMED RESEARCH INTERNATIONAL 2014; 2014:498491. [PMID: 25140315 PMCID: PMC4124834 DOI: 10.1155/2014/498491] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 06/29/2014] [Indexed: 12/21/2022]
Abstract
Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.
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Abstract
Oxidative stress and inflammation underpin most diseases; their mechanisms are inextricably linked. Chronic inflammation is associated with oxidation, anti-inflammatory cascades are linked to decreased oxidation, increased oxidative stress triggers inflammation, and redox balance inhibits the inflammatory cellular response. Whether or not oxidative stress and inflammation represent the cause or consequence of cellular pathology, they contribute significantly to the pathogenesis of noncommunicable diseases (NCD). The incidence of obesity and other related metabolic disturbances are increasing, as are age-related diseases due to a progressively aging population. Relationships between oxidative stress, inflammatory signaling, and metabolism are, in the broad sense of energy transformation, being increasingly recognized as part of the problem in NCD. In this chapter, we summarize the pathologic consequences of an imbalance between circulating and cellular paraoxonases, the system for scavenging excessive reactive oxygen species and circulating chemokines. They act as inducers of migration and infiltration of immune cells in target tissues as well as in the pathogenesis of disease that perturbs normal metabolic function. This disruption involves pathways controlling lipid and glucose homeostasis as well as metabolically driven chronic inflammatory states that encompass several response pathways. Dysfunction in the endoplasmic reticulum and/or mitochondria represents an important feature of chronic disease linked to oxidation and inflammation seen as self-reinforcing in NCD. Therefore, correct management requires a thorough understanding of these relationships and precise interpretation of laboratory test results.
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40
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Neuman MG, French SW, Casey CA, Kharbanda KK, Nanau RM, Rasineni K, McVicker BL, Kong V, Donohue TM. Changes in the pathogenesis of alcohol-induced liver disease — Preclinical studies. Exp Mol Pathol 2013; 95:376-84. [DOI: 10.1016/j.yexmp.2013.10.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Accepted: 10/15/2013] [Indexed: 12/14/2022]
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Thomes PG, Ehlers RA, Trambly CS, Clemens DL, Fox HS, Tuma DJ, Donohue TM. Multilevel regulation of autophagosome content by ethanol oxidation in HepG2 cells. Autophagy 2013; 9:63-73. [PMID: 23090141 PMCID: PMC3542219 DOI: 10.4161/auto.22490] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Acute and chronic ethanol administration increase autophagic vacuole (i.e., autophagosome; AV) content in liver cells. This enhancement depends on ethanol oxidation. Here, we used parental (nonmetabolizing) and recombinant (ethanol-metabolizing) Hep G2 cells to identify the ethanol metabolite that causes AV enhancement by quantifying AVs or their marker protein, microtubule-associated protein 1 light chain 3-II (LC3-II). The ethanol-elicited rise in LC3-II was dependent on ethanol dose, was seen only in cells that expressed alcohol dehydrogenase (ADH) and was augmented in cells that coexpressed cytochrome CYP2E1 (P450 2E1). Furthermore, the rise in LC3-II was inversely related to a decline in proteasome activity. AV flux measurements and colocalization of AVs with lysosomes or their marker protein Lysosomal-Associated Membrane Protein 1 (LAMP1) in ethanol-metabolizing VL-17A cells (ADH (+) /CYP2E1 (+) ) revealed that ethanol exposure not only enhanced LC3-II synthesis but also decreased its degradation. Ethanol-induced accumulation of LC3-II in these cells was similar to that induced by the microtubule inhibitor, nocodazole. After we treated cells with either 4-methylpyrazole to block ethanol oxidation or GSH-EE to scavenge reactive species, there was no enhancement of LC3-II by ethanol. Furthermore, regardless of their ethanol-metabolizing capacity, direct exposure of cells to acetaldehyde enhanced LC3-II content. We conclude that both ADH-generated acetaldehyde and CYP2E1-generated primary and secondary oxidants caused LC3-II accumulation, which rose not only from enhanced AV biogenesis, but also from decreased LC3 degradation by the proteasome and by lysosomes.
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Affiliation(s)
- Paul G Thomes
- Liver Study Unit, Department of Veterans Affairs, VA Nebraska-Western Iowa Health Care System (NWIHCS), Omaha, NE, USA.
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CYP2E1-catalyzed alcohol metabolism: role of oxidant generation in interferon signaling, antigen presentation and autophagy. Subcell Biochem 2013; 67:177-97. [PMID: 23400922 DOI: 10.1007/978-94-007-5881-0_6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cytochrome P450 2E1 (CYP2E1) is one of two major enzymes that catalyze ethanol oxidation in the liver. CYP2E1 is also unique because it is inducible, as its hepatic content rises after continuous (chronic) ethanol administration, thereby accelerating the rate of ethanol metabolism and affording greater tolerance to heavy alcohol consumption. However, the broad substrate specificity of CYP2E1 and its capacity to generate free radicals from alcohol and other hepatotoxins, places CYP2E1 as a central focus of not only liver toxicity, but also as an enzyme that regulates cytokine signaling, antigen presentation, and macromolecular degradation, all of which are crucial to liver cell function and viability. Here, we describe our own and other published work relevant to the importance of CYP2E1-catalyzed ethanol oxidation and how this catalysis affects the aforementioned cellular processes to produce liver injury.
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Wu D, Wang X, Zhou R, Yang L, Cederbaum AI. Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy. Free Radic Biol Med 2012; 53:1346-57. [PMID: 22819980 PMCID: PMC3436962 DOI: 10.1016/j.freeradbiomed.2012.07.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 07/06/2012] [Accepted: 07/06/2012] [Indexed: 02/07/2023]
Abstract
The goal of the current study was to evaluate whether CYP2E1 plays a role in binge-ethanol induced steatosis and if autophagy impacts CYP2E1-mediated hepatotoxicity, oxidative stress and fatty liver formation produced by ethanol. Wild type (WT), CYP2E1 knockin (KI) and CYP2E1 knockout (KO) mice were gavaged with 3g/kg body wt ethanol twice a day for four days. This treatment caused fatty liver, elevation of CYP2E1 and oxidative stress in WT and KI mice but not KO mice. Autophagy was impaired in ethanol-treated KI mice compared to KO mice as reflected by a decline in the LC3-II/LC3-I ratio and lower total LC-3 and Beclin-1 levels coupled to increases in P62, pAKT/AKT and mTOR. Inhibition of macroautophagy by administration of 3-methyladenine enhanced the binge ethanol hepatotoxicity, steatosis and oxidant stress in CYP2E1 KI, but not CYP2E1 KO mice. Stimulation of autophagy by rapamycin blunted the elevated steatosis produced by binge ethanol. Treatment of HepG2 E47 cells which express CYP2E1 with 100mM ethanol for 8 days increased fat accumulation and oxidant stress but decreased autophagy. Ethanol had no effect on these reactions in HepG2 C34 cells which do not express CYP2E1. Inhibition of autophagy elevated ethanol toxicity, lipid accumulation and oxidant stress in the E47, but not C34 cells. The antioxidant N-acetylcysteine, and CYP2E1 inhibitor chlormethiazole blunted these effects of ethanol. These results indicate that CYP2E1 plays an important role in binge ethanol-induced fatty liver. We propose that CYP2E1-derived reactive oxygen species inhibit autophagy, which subsequently causes accumulation of lipid droplets. Inhibition of autophagy promotes binge ethanol induced hepatotoxicity, steatosis and oxidant stress via CYP2E1.
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Affiliation(s)
- Defeng Wu
- Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029
| | - Xiaodong Wang
- Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029
| | - Richard Zhou
- Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029
| | - Lili Yang
- Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029
| | - Arthur I. Cederbaum
- Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029
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Interrelationships between paraoxonase-1 and monocyte chemoattractant protein-1 in the regulation of hepatic inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 660:5-18. [PMID: 20221866 DOI: 10.1007/978-1-60761-350-3_2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Oxidative stress and inflammation play a central role in the onset and development of liver diseases irrespective of the agent causing the hepatic impairment. The monocyte chemoattractant protein-1 is intimately involved in the inflammatory reaction and is directly correlated with the degree of hepatic inflammation in patients with chronic liver disease. Recent studies showed that hepatic paraoxonase-1 may counteract the production of the monocyte chemoattractant protein-1, thus playing an anti-inflammatory role. The current review summarises experiments suggesting how paraoxonase-1 activity and expression are altered in liver diseases, and their relationships with the monocyte chemoattractant protein-1 and inflammation.
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Osna NA, Thomes PG, Jr TMD. Involvement of autophagy in alcoholic liver injury and hepatitis C pathogenesis. World J Gastroenterol 2011; 17:2507-14. [PMID: 21633655 PMCID: PMC3103808 DOI: 10.3748/wjg.v17.i20.2507] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Revised: 03/23/2011] [Accepted: 03/30/2011] [Indexed: 02/06/2023] Open
Abstract
This review describes the principal pathways of macroautophagy (i.e. autophagy), microautophagy and chaperone-mediated autophagy as they are currently known to occur in mammalian cells. Because of its crucial role as an accessory digestive organ, the liver has a particularly robust autophagic activity that is sensitive to changes in plasma and dietary components. Ethanol consumption causes major changes in hepatic protein and lipid metabolism and both are regulated by autophagy, which is significantly affected by hepatic ethanol metabolism. Ethanol exposure enhances autophagosome formation in liver cells, but suppresses lysosome function. Excessive ethanol consumption synergizes with hepatitis C virus (HCV) to exacerbate liver injury, as alcohol-consuming HCV patients frequently have a longer course of infection and more severe manifestations of chronic hepatitis than abstinent HCV patients. Alcohol-elicited exacerbation of HCV infection pathogenesis is related to modulation by ethanol metabolism of HCV replication. Additionally, as part of this mechanism, autophagic proteins have been shown to regulate viral (HCV) replication and their intracellular accumulation. Because ethanol induces autophagosome expression, enhanced levels of autophagic proteins may enhance HCV infectivity in liver cells of alcoholics and heavy drinkers.
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Atlantic salmon (Salmo salar) muscle structure integrity and lysosomal cathepsins B and L influenced by dietary n-6 and n-3 fatty acids. Food Chem 2009. [DOI: 10.1016/j.foodchem.2008.11.039] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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47
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Abstract
The majority of ethanol metabolism occurs in the liver. Consequently, this organ sustains the greatest damage from ethanol abuse. Ethanol consumption disturbs the delicate balance of protein homeostasis in the liver, causing intracellular protein accumulation due to a disruption of hepatic protein catabolism. Evidence indicates that ethanol or its metabolism impairs trafficking events in the liver, including the process of macroautophagy, which is the engulfment and degradation of cytoplasmic constituents by the lysosomal system. Autophagy is an essential, ongoing cellular process that is highly regulated by nutrients, endocrine factors and signaling pathways. A great number of the genes and gene products that govern the autophagic response have been characterized and the major metabolic and signaling pathways that activate or suppress autophagy have been identified. This review describes the process of autophagy, its regulation and the possible mechanisms by which ethanol disrupts the process of autophagic degradation. The implications of autophagic suppression are discussed in relation to the pathogenesis of alcohol-induced liver injury.
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Marsillach J, Camps J, Ferré N, Beltran R, Rull A, Mackness B, Mackness M, Joven J. Paraoxonase-1 is related to inflammation, fibrosis and PPAR delta in experimental liver disease. BMC Gastroenterol 2009; 9:3. [PMID: 19144177 PMCID: PMC2632645 DOI: 10.1186/1471-230x-9-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2008] [Accepted: 01/14/2009] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Paraoxonase-1 (PON1) is an antioxidant enzyme synthesized by the liver. It protects against liver impairment and attenuates the production of the pro-inflammatory monocyte chemoattractant protein-1 (MCP-1). We investigated the relationships between hepatic PON1 and MCP-1 expression in rats with liver disease and explored the possible molecular mechanisms involved. METHODS CCl4 was administered for up to 12 weeks to induce liver damage. Serum and hepatic levels of PON1 and MCP-1, their gene and protein expression, nuclear transcription factors, and histological and biochemical markers of liver impairment were measured. RESULTS High levels of PON1 and MCP-1 expression were observed at 12th week in the hepatocytes surrounding the fibrous septa and inflammatory areas. CCl4-administered rats had an increased hepatic PON1 concentration that was related to decreased gene transcription and inhibited protein degradation. Decreased PON1 gene transcription was associated with PPARdelta expression. These changes were accompanied by increased hepatic MCP-1 concentration and gene expression. There were significant direct relationships between hepatic PON1 and MCP-1 concentrations (P = 0.005) and between PON1 and the amount of activated stellate cells (P = 0.001). CONCLUSION Our results from this experimental model suggest a hepato-protective role for PON1 against inflammation, fibrosis and liver disease mediated by MCP-1.
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Affiliation(s)
- Judit Marsillach
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
| | - Jordi Camps
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
| | - Natàlia Ferré
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
| | - Raul Beltran
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
| | - Anna Rull
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
| | - Bharti Mackness
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
| | - Michael Mackness
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
| | - Jorge Joven
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan s/n, 43201 Reus, Spain
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Marsillach J, Camps J, Ferré N, Beltran R, Rull A, Mackness B, Mackness M, Joven J. Paraoxonase-1 is related to inflammation, fibrosis and PPAR delta in experimental liver disease. BMC Gastroenterol 2009. [PMID: 19144177 DOI: 10.1186/1471-230x-9-351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Paraoxonase-1 (PON1) is an antioxidant enzyme synthesized by the liver. It protects against liver impairment and attenuates the production of the pro-inflammatory monocyte chemoattractant protein-1 (MCP-1). We investigated the relationships between hepatic PON1 and MCP-1 expression in rats with liver disease and explored the possible molecular mechanisms involved. METHODS CCl4 was administered for up to 12 weeks to induce liver damage. Serum and hepatic levels of PON1 and MCP-1, their gene and protein expression, nuclear transcription factors, and histological and biochemical markers of liver impairment were measured. RESULTS High levels of PON1 and MCP-1 expression were observed at 12th week in the hepatocytes surrounding the fibrous septa and inflammatory areas. CCl4-administered rats had an increased hepatic PON1 concentration that was related to decreased gene transcription and inhibited protein degradation. Decreased PON1 gene transcription was associated with PPARdelta expression. These changes were accompanied by increased hepatic MCP-1 concentration and gene expression. There were significant direct relationships between hepatic PON1 and MCP-1 concentrations (P = 0.005) and between PON1 and the amount of activated stellate cells (P = 0.001). CONCLUSION Our results from this experimental model suggest a hepato-protective role for PON1 against inflammation, fibrosis and liver disease mediated by MCP-1.
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Affiliation(s)
- Judit Marsillach
- Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C, Sant Joan s/n, 43201 Reus, Spain.
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Gendron TF, McCartney S, Causevic E, Ko LW, Yen SH. Ethanol enhances tau accumulation in neuroblastoma cells that inducibly express tau. Neurosci Lett 2008; 443:67-71. [PMID: 18672021 DOI: 10.1016/j.neulet.2008.07.052] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2008] [Revised: 07/11/2008] [Accepted: 07/21/2008] [Indexed: 11/25/2022]
Abstract
Chronic alcohol consumption causes pathological changes in the brain and neuronal loss. Ethanol toxicity may partially result from the perturbation of microtubule-associated proteins, like tau. Tau dysfunction is well known for its involvement in certain neurodegenerative diseases, such as Alzheimer's disease. In the present study, the effect of ethanol on tau was examined using differentiated human neuroblastoma cells that inducibly express the 4R0N isoform of tau via a tetracycline-off expression system. During tau induction, ethanol exposure (1.25-5mg/ml) dose-dependently increased tau protein levels and reduced cell viability. The increase in cell death likely resulted from tau accumulation since increased levels of tau were sufficient to reduce cell viability and ethanol was toxic to cells expressing tau but not to non-induced controls. Tau accumulation did not result from greater tetracycline-off induction since ethanol increased neither tau mRNA expression nor the expression of the tetracycline-controlled transactivator. Additionally, ethanol increased endogenous tau protein levels in neuroblastoma cells lacking the tetracycline-off induction system for tau. Ethanol delayed tau clearance suggesting ethanol impedes its degradation. Though ethanol inhibited neither cathepsin B, cathepsin D, nor chymotrypsin-like activity, it did significantly reduce calpain I expression and activity. Calpain I knockdown by shRNA increased tau levels indicating that calpain participates in tau degradation in this model. Moreover, the activation of calpain, by the calcium ionophore A23187, partially reversed the accumulation of tau resulting from ethanol exposure. Impaired calpain-mediated degradation may thus contribute to the increased accumulation of tau caused by ethanol.
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Affiliation(s)
- Tania F Gendron
- Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
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