Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tacrolimus (TAC), also called FK506, is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation. However, it has been proved to be associated with post-transplant hyperlipemia. The mechanism behind this is unknown, and it is urgent to explore preventive strategies for hyperlipemia after transplantation. Therefore, we established a hyperlipemia mouse model to investigate the mechanism, by injecting TAC intraperitoneally for eight weeks. After TAC treatment, the mice developed hyperlipemia (manifested as elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c), as well as decreased high-density lipoprotein cholesterol (HDL-c)). Accumulation of lipid droplets was observed in the liver. In addition to lipid accumulation, TAC induced inhibition of the autophagy-lysosome pathway (microtubule-associated protein 1 light chain 3β (LC3B) II/I and LC3B II/actin ratios, transcription factor EB (TFEB), protein 62 (P62), and lysosomal-associated membrane protein 1 (LAMP1)) and downregulation of fibroblast growth factor 21 (FGF21) in vivo. Overexpression of FGF21 may reverse TAC-induced TG accumulation. In this mouse model, the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway. We conclude that TAC downregulates FGF21 and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway. Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.

Research Progress of β-Klotho in Energy Metabolism and Tumor Development / 中国生物化学与分子生物学报

β-Klotho (KLB) is a member of the Klotho protein family, which is mainly distributed in organs and tissues such as the liver, fat, pancreas, and brain. KLB is a single-pass transmembrane protein whose structural characteristics determine that KLB acts as a co-receptor for fibroblast growth factor (FGF) 19/21 targeting the activation of fibroblast growth factor receptor (FGFRs). KLB is involved in the regulation of blood glucose, lipids, body weight, bile acid circulation, and hepatocyte proliferation in the FGF21/19-KLB-FGFRs pathway. This paperwill review the structural characteristics and distribution of KLB, as well as the regulatory mechanism of material energy and its role in tumor formation in the FGF19/21-KLB-FGFRs pathways.

MicroRNA-100-5p Regulates Melanogenesis in Alpaca Melanocytes by Targeting FGF21 / 中国生物化学与分子生物学报

Although many microRNAs (miRNAs) are known to function as regulators of coat color and melanogenesis, the underlying molecular mechanisms of miR-100-5p governing melanogenesis were not completely known.The goal of this study was to determine the effect of miR-l()()-5p on melanogenesis in alpaca melanocytes.Fibroblast growth factor 21 (FGF21) is a predicted target gene of miR-100-5p and the luciferase reporter assay demonstrated that miR-100-5p regulates FGF21 by binding to its 3' untranslated region (3'UTR).In this study, alpaca melanocytes were transfected with miR-100-5p, inhibitor and negative control plasmid.Results showed that miR-100-5p overexpression significantly decreased mRNA and protein expression of FGF2\.Meanwhile, the ERK signal pathway was inhibited, with subsequent up-regulation of microphthalmia-associated transcription factor (MITF) , tyrosinase (TYR) and tyrosinase-related protein 2 (TYRP2), which increased melanin production.The results suggest that miR-100-5p may regulate melanogenesis by targeting FGF21 via extracellular regulated MAP kinase (ERK) signaling pathway.

Association between fibroblast growth factor 21 and islet β cell function in pregnant women with different glucose tolerance status / 中国糖尿病杂志

Objective To explore the relationship between fibroblast growth factor 21(FGF21) and islet β cell function in pregnant women with different glucose tolerance status.Methods A total of 441 pregnant women were selected in this study from our hospital.Their 50 g GCT at 24~28 gestational weeks were all positive.One week later,all the subjects were treated with 75 g OGTT,and divided into three groups according to their test results:GDM group (n=228),GIGT group (n=112) and GNGT group (n=91).Serum FGF21 level was tested by ELISA.Islet β cell function was evaluated by HOMA-IR,ISI-Matsuda,HOMA-IS,Stumvoll first,second phase secretion and ISSI.The correlation between FGF21 and islet β cell function was evaluated by Pearson correlation analysis.Results (1) BMI,0 h,1 h,2 h,3 hPG and 1 h,2 h,3 hIns were higher in GDM group and GIGT group than in GNGT group,and highest in GDM group (P0.05).(3)Pearson correlation analysis showed that FGF21 was positively correlated with HOMA-IR(r=0.255,P=0.030) and was negatively correlated with ISI-Matsuda,HOMA-β,Stumvoll first,second phase secretion and ISSI(r=-0.289,-0.256,-0.224,-0.230,-0.277,P=0.019,0.037,0.045,0.040,0.023).Conclusion Along with the worsening of glucose metabolic damage,the FGF21 level is increased gradually.FGF21 is related to islet β cell function,and may enroll in the occurrence and development of GDM.

Fibroblast growth factor 21 improves insulin resistance via inhibiting hepatic oxidative stress in obese mice / 西安交通大学学报(医学版)

Objective To explore the mechanism of insulin resistance regulated by fibroblast growth factor 21 (FGF21)and identify its role in oxidative stress.Methods High-fat diet-induced obese mice were treated with FGF21 ,and hepatic oxidative stress markers such as iNOS and insulin signaling molecules such as IRS-1 and Akt were assessed by Western blot and co-immunoprecipitation.Meanwhile,liver steatosis was assessed in liver sections stained with oil red O.Results Obese mice in FGF21 group showed reduced body weight,blood glucose and serum insulin levels,and improved insulin sensitivity as measured by glucose tolerance testing (GTT)and insulin tolerance testing (ITT)compared with obese mice in vehicle group.Meanwhile,FGF21 treatment in obese mice decreased protein expressions of iNOS and TNF-α,and increased insulin-stimulated IRS-1 tyrosine phosphorylation and Akt Ser-473 phosphorylation,indicating that FGF21 inhibited hepatic oxidative stress and restored impaired insulin signaling.Additionally,we found significantly reduced lipid accumulation in liver sections stained with oil red O in FGF21-treated obese mice.Conclusion Our results support the notion that FGF21 is an important regulator of insulin resistance and that FGF21 may reduce lipid accumulation in the liver,restore hepatic insulin signaling and improve insulin sensitivity in obese mice,at least in part,by inhibiting hepatic oxidative stress.Therefore,FGF21 has a potential value in clinical application.