title: Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver.
abstract: OBJECTIVE
  Sirtuin (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls).
  
  
  METHODS
  We induced alcoholic liver injury in male Sirt1LKO and control mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Liver and serum samples were collected. We also measured messenger RNA levels of SIRT1, SFRS10, and lipin-1β and lipin-1α in liver samples from patients with alcoholic hepatitis and individuals without alcoholic hepatitis (controls).
  
  
  RESULTS
  On the ethanol-containing diet, livers of Sirt1LKO mice accumulated larger amounts of hepatic lipid and expressed higher levels of inflammatory cytokines than control mice; serum of Sirt1LKO mice had increased levels of alanine aminotransferase and aspartate aminotransferase. Hepatic deletion of SIRT1 exacerbated ethanol-mediated defects in lipid metabolism, mainly by altering the function of lipin-1, a transcriptional regulator of lipid metabolism. In cultured mouse AML-12 hepatocytes, transgenic expression of SIRT1 prevented fat accumulation in response to ethanol exposure, largely by reversing the aberrations in lipin-1 signaling induced by ethanol. Liver samples from patients with alcoholic hepatitis had reduced levels of SIRT1 and a higher ratio of Lpin1β/α messenger RNAs than controls.
  
  
  CONCLUSIONS
  In mice, hepatic deletion of Sirt1 promotes steatosis, inflammation, and fibrosis in response to ethanol challenge. Ethanol-mediated impairment of hepatic SIRT1 signaling via lipin-1 contributes to development of alcoholic steatosis and inflammation. Reagents designed to increase SIRT1 regulation of lipin-1 can be developed to treat patients with alcoholic fatty liver disease.
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida.
authors.forename: Huquan
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Ajmo
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.affiliation: Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Gemma
authors.initials: G
authors.lastname: Odena
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Stevens
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida. Electronic address: myou@health.usf.edu.
authors.forename: Min
authors.initials: M
authors.lastname: You
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D000431:Ethanol / Q000009:adverse effects; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C097083:TRA2B protein, human; D000068103:Serine-Arginine Splicing Factors; D000431:Ethanol; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Alcoholic Fatty Liver; Inflammation; Lipid Metabolism; Signal Transduction