title: Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21.
abstract: OBJECTIVE
  The hepatocyte-derived hormone fibroblast growth factor 21 (FGF21) is a hormone-like regulator of metabolism. The nicotinamide adenine dinucleotide-dependent deacetylase SIRT1 regulates fatty acid metabolism through multiple nutrient sensors. Hepatic overexpression of SIRT1 reduces steatosis and glucose intolerance in obese mice. We investigated mechanisms by which SIRT1 controls hepatic steatosis in mice.
  
  
  METHODS
  Liver-specific SIRT1 knockout (SIRT1 LKO) mice and their wild-type littermates (controls) were divided into groups that were placed on a normal chow diet, fasted for 24 hours, or fasted for 24 hours and then fed for 6 hours. Liver tissues were collected and analyzed by histologic examination, gene expression profiling, and real-time polymerase chain reaction assays. Human HepG2 cells were incubated with pharmacologic activators of SIRT1 (resveratrol or SRT1720) and mitochondrion oxidation consumption rate and immunoblot analyses were performed. FGF21 was overexpressed in SIRT1 LKO mice using an adenoviral vector. Energy expenditure was assessed by indirect calorimetry.
  
  
  RESULTS
  Prolonged fasting induced lipid deposition in livers of control mice, but severe hepatic steatosis in SIRT1 LKO mice. Gene expression analysis showed that fasting up-regulated FGF21 in livers of control mice but not in SIRT1 LKO mice. Decreased hepatic and circulating levels of FGF21 in fasted SIRT1 LKO mice were associated with reduced hepatic expression of genes involved in fatty acid oxidation and ketogenesis, and increased expression of genes that control lipogenesis, compared with fasted control mice. Resveratrol or SRT1720 each increased the transcriptional activity of the FGF21 promoter (-2070/+117) and levels of FGF21 messenger RNA and protein in HepG2 cells. Surprisingly, SIRT1 LKO mice developed late-onset obesity with impaired whole-body energy expenditure. Hepatic overexpression of FGF21 in SIRT1 LKO mice increased the expression of genes that regulate fatty acid oxidation, decreased fasting-induced steatosis, reduced obesity, increased energy expenditure, and promoted browning of white adipose tissue.
  
  
  CONCLUSIONS
  SIRT1-mediated activation of FGF21 prevents liver steatosis caused by fasting. This hepatocyte-derived endocrine signaling appears to regulate expression of genes that control a brown fat-like program in white adipose tissue, energy expenditure, and adiposity. Strategies to activate SIRT1 or FGF21 could be used to treat fatty liver disease and obesity.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. Electronic address: liyu@gmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Wong
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Amber
authors.initials: A
authors.lastname: Giles
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Biology, Paul F. Glenn Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. Electronic address: mwzang1@bu.edu.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002153:Calorimetry, Indirect; D004734:Energy Metabolism / Q000502:physiology*; D005215:Fasting; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Ad; BAT; CPT1α; FAS; FGF21; Hepatocyte-Derived Hormone; Liver-Specific Disruption of Sirt1; MCAD; MEF; Metabolic Homeostasis; NAD; NAD-dependent protein deacetylase sirtuin-1; Obesity; PPARα; SIRT1; SIRT1 LKO mice; SREBP-1; Vco(2); Vo(2); WAT; WT; adenovirus; brown adipose tissue; carbon dioxide production; carnitine palmitoyltransferase 1α; fatty acid synthase; fibroblast growth factor 21; liver-specific SIRT1 knockout mice; mRNA; medium-chain acyl-CoA dehydrogenase; messenger RNA; mouse embryonic fibroblast; nicotinamide adenine dinucleotide; oxygen consumption; peroxisome proliferator activated receptorα; sterol regulatory element binding protein-1; white adipose tissue; wild-type