Effects of ethanol on lipid metabolism

Summary

Principal Investigator: Min You
Abstract: DESCRIPTION (provided by applicant): During the last grant period, we discovered that chronic ethanol feeding causes the development and maintenance of fatty liver in mice by affecting several important liver transcription factors and co-factors;namely, sterol regulatory element binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor alpha (PPAR-alpha) and PPAR-gamma co-activator-alpha (PGC-1-alpha.) We demonstrated that the effects of ethanol on these transcriptional regulators are mediated partially by inhibition of hepatic AMP-activated kinase (AMPK), a key "metabolic switch" that controls pathways of hepatic lipid metabolism. It is intriguing that ethanol metabolism is required for each of these effects to occur, as ethanol metabolism has also been unequivocally associated with the development of alcoholic fatty liver disease. However, the identity of a potential bridging molecule that might link ethanol metabolism with downstream effects (including activation of said transcriptional regulators and the expression of genes that ultimately promote lipid accumulation) is still unknown. Sirtuin 1 (SIRT1), a class III NAD+-dependent protein deacetylase, is emerging as a master lipid regulator. The requirement of NAD+ for SIRT1 enzymatic activity implies a potential link between ethanol metabolism and SIRT1. Therefore, the objective of the current proposal is to test the hypothesis that ethanol metabolism significantly down regulates SIRT1 in the liver. Such inhibition of SIRT1 may lead to impairment of hepatic fat metabolism through modulation of the above-described signaling molecules, thereby contributing to increased hepatic lipid synthesis and reduced oxidation and export of fatty acids. This hypothesis will be tested in both animal and cell culture models of chronic ethanol exposure. In the mouse liver, we will examine the effects of chronic ethanol feeding on SIRT1--in terms of its mRNA and protein levels, enzymatic activity, and responsiveness to a potent SIRT1 agonist (resveratrol). The effects of ethanol will be correlated with hepatic lipid content and histology. In primary cultured hepatocytes and in hepatoma cells, the molecular mechanisms by which ethanol metabolism inhibits SIRT1 and alters signaling events will be investigated. Since SIRT1 can be manipulated by both pharmacological agents and dietary polyphenols, testing this hypothesis could possibly lead to novel therapies for human alcoholic fatty liver disease and steatohepatitis. PUBLIC HEALTH RELEVANCE: This project investigates the effect of chronic ethanol exposure of animal liver or liver cells on the function of Sirtuin 1 (SIRT1) and its signaling that are associated with the development of alcoholic fatty liver disease.
Funding Period: 2002-04-01 - 2014-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Alcohol and lipid metabolism
    David W Crabb
    Indiana Alcohol Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA
    J Gastroenterol Hepatol 21:S56-60. 2006
  2. ncbi Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity
    Hong Min Ni
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
    Am J Pathol 183:1815-25. 2013
  3. pmc Ethanol administration exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice
    Hannah Everitt
    Department of Molecular Pharmacology, University of South Florida Health Sciences Center, Tampa, FL 33612, USA
    Am J Physiol Gastrointest Liver Physiol 304:G38-47. 2013
  4. pmc MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1
    Huquan Yin
    Department of Molecular Pharmacology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA
    J Biol Chem 287:9817-26. 2012
  5. pmc Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice
    Ming Hu
    Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, FL, USA
    Hepatology 55:437-46. 2012
  6. pmc Role of SIRT1-FoxO1 signaling in dietary saturated fat-dependent upregulation of liver adiponectin receptor 2 in ethanol-administered mice
    Xiaomei Liang
    Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA
    Antioxid Redox Signal 15:425-35. 2011
  7. pmc Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice
    Zheng Shen
    Department of Molecular Pharmacology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA
    Am J Physiol Gastrointest Liver Physiol 298:G364-74. 2010
  8. pmc Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse
    Farah Esfandiari
    Department of Internal Medicine, 5303 Genome and Biomedical Science Facility, 451 E Health Sciences Drive, University of California, Davis, Davis, CA 95616, USA
    Hepatology 51:932-41. 2010
  9. ncbi Does LKB1 mediate activation of hepatic AMP-protein kinase (AMPK) and sirtuin1 (SIRT1) after Roux-en-Y gastric bypass in obese rats?
    Yanhua Peng
    Department of Surgery, James A Haley Veterans Affairs Medical Center, University of South Florida, C O Tampa General Hospital, P O Box 1289, Tampa, FL 33606, USA
    J Gastrointest Surg 14:221-8. 2010
  10. ncbi Downregulation of adiponectin/AdipoR2 is associated with steatohepatitis in obese mice
    Yanhua Peng
    Department of Surgery, University of South Florida, Tampa, FL, USA
    J Gastrointest Surg 13:2043-9. 2009

Research Grants

  1. Cytochrome P4501B1 and basal liver PPARa activity
    COLIN ROBERT JEFCOATE; Fiscal Year: 2013

Detail Information

Publications18

  1. ncbi Alcohol and lipid metabolism
    David W Crabb
    Indiana Alcohol Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA
    J Gastroenterol Hepatol 21:S56-60. 2006
    ..Adenosine monophosphate-dependent protein kinase was inhibited in alcohol-treated animals and cells. The mechanisms by which ethanol affects AMPK and the transcription factors are as yet incompletely understood...
  2. ncbi Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity
    Hong Min Ni
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
    Am J Pathol 183:1815-25. 2013
    ..FoxO3a thus plays a critical role in ethanol-induced autophagy in mouse liver. Modulating the FoxO3a autophagy pathway may offer novel therapeutic approaches for treating alcoholic liver pathogenesis...
  3. pmc Ethanol administration exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice
    Hannah Everitt
    Department of Molecular Pharmacology, University of South Florida Health Sciences Center, Tampa, FL 33612, USA
    Am J Physiol Gastrointest Liver Physiol 304:G38-47. 2013
    ..Taken together, our novel findings suggest that ethanol administration to obese mice exacerbates fatty liver via impairment of the hepatic lipid metabolism pathways mediated largely by a central signaling system, the SIRT1-AMPK axis...
  4. pmc MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1
    Huquan Yin
    Department of Molecular Pharmacology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA
    J Biol Chem 287:9817-26. 2012
    ..Taken together, our novel findings suggest that miR-217 is a specific target of ethanol action in the liver and may present as a potential therapeutic target for treating human alcoholic fatty liver disease...
  5. pmc Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice
    Ming Hu
    Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, FL, USA
    Hepatology 55:437-46. 2012
    ..Chromatin immunoprecipitation assays further revealed that ethanol exposure significantly increased the association of acetylated histone H3 at lysine 9 with the SRE-containing region in the promoter of the lipin-1 gene...
  6. pmc Role of SIRT1-FoxO1 signaling in dietary saturated fat-dependent upregulation of liver adiponectin receptor 2 in ethanol-administered mice
    Xiaomei Liang
    Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA
    Antioxid Redox Signal 15:425-35. 2011
    ....
  7. pmc Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice
    Zheng Shen
    Department of Molecular Pharmacology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA
    Am J Physiol Gastrointest Liver Physiol 298:G364-74. 2010
    ..Enhanced hepatic adiponectin-SIRT1-AMPK signaling contributes, at least in part, to the protective action of rosiglitazone against alcoholic fatty liver in mice...
  8. pmc Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse
    Farah Esfandiari
    Department of Internal Medicine, 5303 Genome and Biomedical Science Facility, 451 E Health Sciences Drive, University of California, Davis, Davis, CA 95616, USA
    Hepatology 51:932-41. 2010
    ..The messenger RNA expression of the histone H3K9 methyltransferase EHMT2 (G9a) was selectively decreased in ethanol-fed mice...
  9. ncbi Does LKB1 mediate activation of hepatic AMP-protein kinase (AMPK) and sirtuin1 (SIRT1) after Roux-en-Y gastric bypass in obese rats?
    Yanhua Peng
    Department of Surgery, James A Haley Veterans Affairs Medical Center, University of South Florida, C O Tampa General Hospital, P O Box 1289, Tampa, FL 33606, USA
    J Gastrointest Surg 14:221-8. 2010
    ..LKB1 phosphorylates AMPK and may activate SIRT1. We hypothesize that RYGB in obese rats is associated with an upregulation of the LKB1-AMPK-SIRT1 signaling pathway...
  10. ncbi Downregulation of adiponectin/AdipoR2 is associated with steatohepatitis in obese mice
    Yanhua Peng
    Department of Surgery, University of South Florida, Tampa, FL, USA
    J Gastrointest Surg 13:2043-9. 2009
    ..Adiponectin regulates fat storage, energy expenditure, and inflammation. We propose that high fat diet induces steatohepatitis, reduces serum adiponectin, and liver adiponectin receptors...
  11. ncbi Adiponectin: a key adipokine in alcoholic fatty liver
    Min You
    Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, College of Medicine, Box 8, University of South Florida, Tampa, FL 33612, USA
    Exp Biol Med (Maywood) 234:850-9. 2009
    ....
  12. pmc Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-alpha production in cultured macrophage cell lines
    Zheng Shen
    Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA
    Am J Physiol Gastrointest Liver Physiol 296:G1047-53. 2009
    ..Our study provides new insights into understanding the molecular mechanisms underlying the development of alcoholic steatohepatitis...
  13. pmc Resveratrol alleviates alcoholic fatty liver in mice
    Joanne M Ajmo
    Dept of Molecular Pharmacology, School of Basic Biomedical Sciences, College of Medicine, Box 8, Univ of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
    Am J Physiol Gastrointest Liver Physiol 295:G833-42. 2008
    ..Our study suggests that resveratrol may serve as a promising agent for preventing or treating human alcoholic fatty liver disease...
  14. ncbi Adiponectin and alcoholic fatty liver disease
    Christopher Q Rogers
    Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, FL 33612, USA
    IUBMB Life 60:790-7. 2008
    ..We will conclude with a discussion of potential strategies for treating human alcoholic fatty liver disease (AFLD), including nutritional and pharmacological modulation of adiponectin and its receptors...
  15. ncbi Mammalian sirtuin 1 is involved in the protective action of dietary saturated fat against alcoholic fatty liver in mice
    Min You
    Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, FL 33612, USA
    J Nutr 138:497-501. 2008
    ....
  16. ncbi Involvement of mammalian sirtuin 1 in the action of ethanol in the liver
    Min You
    Dept of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, College of Medicine, Box 8, Univ of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
    Am J Physiol Gastrointest Liver Physiol 294:G892-8. 2008
    ..Hence, SIRT1 may represent a novel therapeutic target for treatment of human alcoholic fatty liver disease...
  17. ncbi S-adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet
    Farah Esfandiari
    Department of Internal Medicine, University of California Davis, Davis, CA 95616, USA
    Alcohol Clin Exp Res 31:1231-9. 2007
    ....
  18. pmc Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver
    Huquan Yin
    Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida
    Gastroenterology 146:801-11. 2014
    ..We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls)...

Research Grants30

  1. Cytochrome P4501B1 and basal liver PPARa activity
    COLIN ROBERT JEFCOATE; Fiscal Year: 2013
    ..Serum markers applicable to clinical studies will be used in probing these liver changes. ..