Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet

Naoki Tanaka, Shogo Takahashi, Yuan Zhang, Kristopher W. Krausz, Philip B. Smith, Andrew D. Patterson, Frank J. Gonzalez

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Fibroblast growth factor 21 (FGF21) is a modulator of energy homeostasis and is increased in human nonalcoholic liver disease (NAFLD) and after feeding of methionine- and choline-deficient diet (MCD), a conventional inducer of murine nonalcoholic steatohepatitis (NASH). However, the significance of FGF21 induction in the occurrence of MCD-induced NASH remains undetermined. C57BL/6J Fgf21-null and wild-type mice were treated with MCD for 1. week. Hepatic Fgf21 mRNA was increased early after commencing MCD treatment independent of peroxisome proliferator-activated receptor (PPAR) α and farnesoid X receptor. While no significant differences in white adipose lipolysis were seen in both genotypes, hepatic triglyceride (TG) contents were increased in Fgf21-null mice, likely due to the up-regulation of genes encoding CD36 and phosphatidic acid phosphatase 2a/2c, involved in fatty acid (FA) uptake and diacylglycerol synthesis, respectively, and suppression of increased mRNAs encoding carnitine palmitoyl-CoA transferase 1α, PPARγ coactivator 1α, and adipose TG lipase, which are associated with lipid clearance in the liver. The MCD-treated Fgf21-null mice showed increased hepatic endoplasmic reticulum (ER) stress. Exposure of primary hepatocytes to palmitic acid elevated the mRNA levels encoding DNA damage-inducible transcript 3, an indicator of ER stress, and FGF21 in a PPARα-independent manner, suggesting that lipid-induced ER stress can enhance hepatic FGF21 expression. Collectively, FGF21 is elevated in the early stage of MCD-induced NASH likely to minimize hepatic lipid accumulation and ensuing ER stress. These results provide a possible mechanism on how FGF21 is increased in NAFLD/NASH.

Original languageEnglish (US)
Pages (from-to)1242-1252
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number7
DOIs
StatePublished - Jul 1 2015

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Keywords

  • ATGL
  • ER stress
  • Lipotoxicity
  • PGC1α
  • PPARα

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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