title: Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets.
abstract: OBJECTIVE
  Nonalcoholic fatty liver disease is a common consequence of human and rodent obesity. Disruptions in lipid metabolism lead to accumulation of triglycerides and fatty acids, which can promote inflammation and fibrosis and lead to nonalcoholic steatohepatitis. Circulating levels of fibroblast growth factor (FGF)21 increase in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis; therefore, we assessed the role of FGF21 in the progression of murine fatty liver disease, independent of obesity, caused by methionine and choline deficiency.
  
  
  METHODS
  C57BL/6 wild-type and FGF21-knockout (FGF21-KO) mice were placed on methionine- and choline-deficient (MCD), high-fat, or control diets for 8-16 weeks. Mice were weighed, and serum and liver tissues were collected and analyzed for histology, levels of malondialdehyde and liver enzymes, gene expression, and lipid content.
  
  
  RESULTS
  The MCD diet increased hepatic levels of FGF21 messenger RNA more than 50-fold and serum levels 16-fold, compared with the control diet. FGF21-KO mice had more severe steatosis, fibrosis, inflammation, and peroxidative damage than wild-type C57BL/6 mice. FGF21-KO mice had reduced hepatic fatty acid activation and β-oxidation, resulting in increased levels of free fatty acid. FGF21-KO mice given continuous subcutaneous infusions of FGF21 for 4 weeks while on an MCD diet had reduced steatosis and peroxidative damage, compared with mice not receiving FGF21. The expression of genes that regulate inflammation and fibrosis were reduced in FGF21-KO mice given FGF21, similar to those of wild-type mice.
  
  
  CONCLUSIONS
  FGF21 regulates fatty acid activation and oxidation in livers of mice. In the absence of FGF21, accumulation of inactivated fatty acids results in lipotoxic damage and increased steatosis.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: Mfisher3@bidmc.harvard.edu.
authors.forename: Ffolliott M
authors.initials: FM
authors.lastname: Fisher
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Chui
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Imad A
authors.initials: IA
authors.lastname: Nasser
authors.affiliation: Department of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yury
authors.initials: Y
authors.lastname: Popov
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Cunniff
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundasen
authors.affiliation: Eli Lilly and Company, Diabetes Research, Indianapolis, Indiana.
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.affiliation: Department of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Institute of Molecular and Translational Medicine, Department of Medicine I, University of Mainz Medical School, Mainz, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
mesh_terms: D000818:Animals; D002796:Choline Deficiency / Q000150:complications*; D004195:Disease Models, Animal; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D055104:Infusions, Subcutaneous; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008715:Methionine / Q000172:deficiency*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D005227:Fatty Acids; D018836:Inflammation Mediators; D012333:RNA, Messenger; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D008715:Methionine
keywords: Acyl-CoA; Fatty Acid Metabolism; Long Chain Fatty Acid
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