Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet.
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.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Naoki
N
Tanaka
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Shogo
S
Takahashi
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, United States.
Yuan
Y
Zhang
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Kristopher W
KW
Krausz
Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
Philip B
PB
Smith
Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
Andrew D
AD
Patterson
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. Electronic address: gonzalef@mail.nih.gov.
Frank J
FJ
Gonzalez
D052438:Adipocytes, White / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000150:complications*; D004032:Diet / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated; D000217:Acyltransferases
D018955:CD36 Antigens; D005346:Fibroblast Growth Factors; D008049:Lipase; D008715:Methionine; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C485290:Ppargc1a protein, mouse; C414620:fibroblast growth factor 21; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
ATGL; ER stress; Lipotoxicity; PGC1α; PPARα