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.

Intermittent calorie restriction largely counteracts the adverse health effects of a moderate‐fat diet in aging C57BL/6J mice

“…Similar to what we performed in the previous study 30, prior to sacrifice each mouse was first fasted for 4 h after which they received an intragastric gavage of either solvent (0.5% carboxymethyl cellulose) or Wy‐14 643 dispersed in solvent (160 mg Wy‐14 643/kg body weight), then fasted again for another 6 h. Only mock‐treated animals were included in the molecular analysis, since the Wy‐14 643 treatment have an immediate effect on the gene expression levels 38. The purpose of this treatment is to examine PPARα adaptive capacity analysis, which has been covered in a separate publication 39. After sedation with a mixture of isoflurane (1.5%) in nitrous oxide (70%) and oxygen (30%), blood samples were collected by cardiac puncture, then followed by neck dislocation.…”

Nonalcoholic Fatty Liver Disease Is Not Associated with Thyroid Hormone Levels and Hypothyroidism: A Systematic Review and Meta-Analysis

“…Fibroblast growth factor-21, a member of fibroblast growth factor family, could also provide a role in this association as increased serum fibroblast growth factor-21 levels were observed in patients with hypothyroidism [31]. Its level was also correlated with intrahepatic triglyceride content and associated with increased vulnerability to metabolic stressors that could accelerate the progression of NAFLD [32]. Further large-scale studies are needed to clarify this potential association and should adjust for all potential confounding factors and include comparisons between different ethnicities and gender.…”

A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats

“…There is consensus that the pathogenesis of NAFLD is as a multi-hit process that includes lipotoxicity, oxidative challenge and endoplasmic reticulum (ER) stress [40]. In the current study, taurine administration inhibited the NAFLD multi-hit process, based on lipid profile optimization, improvement of glycemic indices, increased adiponectin level, mitigation of hepatic oxidative stress markers (through reduction of MDA), inflammation (IL-6&TNF-α), apoptosis (caspase-3), and enhanced hepatic GSH, IL-10 and Bcl-2 levels.…”