title: Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice.
abstract: Acetaminophen (APAP) overdose is a leading cause of drug-induced hepatotoxicity and acute liver failure worldwide, but its pathophysiology remains incompletely understood. Fibroblast growth factor 21 (FGF21) is a hepatocyte-secreted hormone with pleiotropic effects on glucose and lipid metabolism. This study aimed to investigate the pathophysiological role of FGF21 in APAP-induced hepatotoxicity in mice. In response to APAP overdose, both hepatic expression and circulating levels of FGF21 in mice were dramatically increased as early as 3 hours, prior to elevations of the liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). APAP overdose-induced liver damage and mortality in FGF21 knockout (KO) mice were markedly aggravated, which was accompanied by increased oxidative stress and impaired antioxidant capacities as compared to wild-type (WT) littermates. By contrast, replenishment of recombinant FGF21 largely reversed APAP-induced hepatic oxidative stress and liver injury in FGF21 KO mice. Mechanistically, FGF21 induced hepatic expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent up-regulation of several antioxidant genes. The beneficial effects of recombinant FGF21 on up-regulation of Nrf2 and antioxidant genes and alleviation of APAP-induced oxidative stress and liver injury were largely abolished by adenovirus-mediated knockdown of hepatic PGC-1α expression, whereas overexpression of PGC-1α was sufficient to counteract the increased susceptibility of FGF21 KO mice to APAP-induced hepatotoxicity.
  
  
  CONCLUSIONS
  The marked elevation of FGF21 by APAP overdose may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, by enhancing PGC-1α/Nrf2-mediated antioxidant capacity in the liver.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China; Department of Medicine, University of Hong Kong, Hong Kong, China; Department of Pharmacology & Pharmacy, University of Hong Kong, Hong Kong, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Ye
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wang
authors.forename: Huating
authors.initials: H
authors.lastname: Li
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D004357:Drug Synergism; D005346:Fibroblast Growth Factors / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D000082:Acetaminophen; D005346:Fibroblast Growth Factors