FGF21 ameliorates nonalcoholic fatty liver disease by inducing autophagy

Abstract

The aim of this study is to evaluate the role of fibroblast growth factor 21 (FGF21) in nonalcoholic fatty liver disease (NAFLD) and seek to determine if its therapeutic effect is through induction of autophagy. In this research, Monosodium L-glutamate (MSG)-induced obese mice or normal lean mice were treated with vehicle, Fenofibrate, and recombinant murine FGF21, respectively. After 5 weeks of treatment, metabolic parameters including body weight, blood glucose and lipid levels, hepatic and fat gene expression levels were monitored and analyzed. Also, fat-loaded HepG2 cells were treated with vehicle or recombinant murine FGF21. The expression levels of proteins associated with autophagy were detected by western blot, real-time PCR, and transmission electron microscopy (TEM). Autophagic flux was monitored by laser confocal microscopy and western blot. Results showed that FGF21 significantly reduced body weight (P < 0.01) and serum triglyceride, improved insulin sensitivity, and reversed hepatic steatosis in the MSG model mice. In addition, FGF21 significantly increased the expression of several proteins related to autophagy both in MSG mice and fat-loaded HepG2 cells, such as microtubule associated protein 1 light chain 3, Bcl-2-interacting myosin-like coiled-coil protein-1 (Beclin-1), and autophagy-related gene 5. Furthermore, the evidence of TEM revealed an increased number of autophagosomes and lysosomes in the model cells treated with FGF21. In vitro experimental results also showed that FGF21 remarkably increased autophagic flux. Taken together, FGF21 corrects multiple metabolic parameters on NAFLD in vitro and in vivo by inducing autophagy.

Adiponectin improves insulin sensitivity via activation of autophagic flux

“…Importantly, we recently demonstrated that adiponectin stimulates autophagic flux in skeletal muscle and that increased autophagy contributed to insulin-sensitizing anti-diabetic effects (Liu et al 2015. Others have now also shown that boosting autophagy via a variety of approaches can enhance insulin sensitivity in skeletal muscle and other tissues (Wang et al 2015, Zhu et al 2016, Ghareghani et al 2017, Li et al 2017, Rosa-Caldwell et al 2017 and vice versa that decreased the levels of skeletal muscle autophagy were observed in type 2 diabetes and upon aging (Zhang et al 2016, Moller et al 2017, Zhou et al 2017.…”

Heat Shock Gene Sirtuin 1 Regulates Post-Prandial Lipid Metabolism with Relevance to Nutrition and Appetite Regulation in Diabetes

“…The repression of the anti-aging gene Sirt 1 involves p53/mTOR dysregulation of the other anti-aging genes (klotho, p66shc, FOXO3a) associated with hepatic lipid, heat shock protein and amyloid beta metabolism. FGF 21 treatment in diabetes has become important to NAFLD [38] and myocardial infarction treatment [39,40] but defective cell transcriptional ontogeny in the liver and brain related to mi-34a inhibition of Sirtuin 1/transcription factors interactions inactivates hepatic lipid metabolism with the induction of NAFLD, defective amyloid beta metabolism and neurodegenerative disease.…”

Dyslipidemia in retinal metabolic disorders

“…FGF21, induced with fasting, dephosphorylates transcription factor EB to induce genes involved in autophagy and lipid metabolism (Chen et al , ). In monosodium L‐glutamate‐induced obese mice, modeling nonalcoholic fatty liver disease, FGF21 induces autophagy to correct metabolic parameters (decreases triglycerides, improves insulin sensitivity) (Zhu et al , ). Further exploration of FGF21 in retinal lipid metabolism and autophagy is of great interest to evaluate its impact on retinal neurovascular stability.…”