title: Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice.
abstract: Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARα challenge demonstrated the dysregulation of PPARα signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21's crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver.
authors.affiliation: Nutrition, Metabolism &Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Fenni
authors.initials: F
authors.lastname: Rusli
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Nutrition, Metabolism &Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Evi
authors.initials: E
authors.lastname: Andriyani
authors.affiliation: Nutrition, Metabolism &Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boekschoten
authors.affiliation: Nutrition, Metabolism &Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Carolien
authors.initials: C
authors.lastname: Lute
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.|The Delft Bioinformatics Lab, Delft University of Technology, Mekelweg 4, 2628 CD, Delft, The Netherlands.
authors.forename: Erik B
authors.initials: EB
authors.lastname: van den Akker
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Nutrition, Metabolism &Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Wilma T
authors.initials: WT
authors.lastname: Steegenga
mesh_terms: D000375:Aging / Q000097:blood; D000818:Animals; D004032:Diet; D015536:Down-Regulation / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047493:PPAR alpha; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors