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

• Published in: Biochimica et biophysica acta Vol. 1852; no. 7; pp. 1242 - 1252
• Main Authors: Tanaka, Naoki, Takahashi, Shogo, Zhang, Yuan, Krausz, Kristopher W., Smith, Philip B., Patterson, Andrew D., Gonzalez, Frank J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2015
• Subjects: Adipocytes, White - metabolism; Animals; ATGL; CD36 Antigens - genetics; CD36 Antigens - metabolism; Cells, Cultured; Choline Deficiency - complications; Diet - adverse effects; Endoplasmic Reticulum Stress; ER stress; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Hepatocytes - metabolism; Lipase - genetics; Lipase - metabolism; Lipolysis; Lipotoxicity; Male; Methionine - deficiency; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PGC1α; Phosphatidate Phosphatase - genetics; Phosphatidate Phosphatase - metabolism; PPAR alpha - genetics; PPAR alpha - metabolism; PPARα; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Triglycerides - metabolism; APAP; FXR; NAFLD; PGC1α; ATGL; JNK; ALT; WAT; H2O2; TNF; OA; PPAR; BW; qPCR; Lipotoxicity; HSL; PBS; EGR1; FGF; MS; ER stress; DAG; NASH; PPARα; ER; PGC; MCD; PA; TG; BAT; FA; HBSS; MCS
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.02.012

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 1week. 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. •FGF21 does not affect white adipose lipolysis accompanying MCD-NASH.•Fgf21-null mice show severe steatosis and ER stress in the early stage of MCD-NASH.•Palmitate induces FGF21 independent of PPARα, likely through enhancing ER stress.•Oxidative stress induces FGF21 independent of PPARα.•A mechanism of FGF21 induction during NAFLD/NASH development is proposed.