Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway

Abstract

Purpose In this study, we aimed to investigate the effect of follistatin (FST) on hepatic steatosis in NAFLD and the underlying mechanism, which has rarely been reported before. Methods Liver samples from NAFLD patients and normal liver samples (from liver donors) were collected to investigate hepatic FST expression in humans. Additionally, human liver cells (LO2) were treated with free fatty acid (FFA) to induce lipid accumulation. Furthermore, lentivirus with FST overexpression or knockdown vectors were used to generate stable cell lines, which were subsequently treated with FFA or FFA and rapamycin. In the animal experiments, male C57BL/6J mice were fed with a high-fat diet (HFD) to induce NAFLD, after which the adeno-associated virus (AAV) gene vectors for FST overexpression were administered. In both cell culture and mice, we evaluated morphological changes and the protein expression of sterol regulatory element-binding protein1 (SREBP1), acetyl-CoA carboxylase1 (ACC1), carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase (FASN), and Akt/mTOR signaling. The body weight and serum parameters of the mice were also measured. Results Hepatic FST expression level was higher in NAFLD patients compared to normal samples. In LO2 cells, FST overexpression alleviated lipid accumulation and lipogenesis, whereas FST knockdown aggravated hepatic steatosis. FST could regulate Akt/mTOR signaling, and the mTOR inhibitor rapamycin abolished the effect of FST knockdown on hepatic de novo lipogenesis (DNL). Furthermore, FST expression was increased in HFD mice compared to the corresponding controls. FST overexpression in mice reduced body weight gain, hyperlipidemia, hepatic DNL, and suppressed Akt/mTOR signaling. Conclusion Hepatic FST expression increases in NAFLD and plays a protective role in hepatic steatosis. FST overexpression gene therapy alleviates hepatic steatosis via the mTOR pathway.Therefore, gene therapy for FST is a promising treatment in NAFLD.

Myokines: Crosstalk and Consequences on Liver Physiopathology

“…Finally, in this review we focused on the cytokines secreted by the muscle and having an effect on the liver, however, physical exercise also has an impact on the over-expression of liver-secreted cytokines, the hepatokines, which in turn, can have beneficial autocrine effects on the liver. For example, hepatic follistatin, whose expression is increased in NAFLD patients, inhibits lipid accumulation and lipogenesis through the mTOR pathway [ 79 ]. Thus, according to the effects of physical exercise on the expression of liver cytokines and of other organ-derived cytokines, it could be of interest to also study their effects on NAFLD’s different stages, to explore the range of possible NAFLD therapeutic strategies.…”

Recent Insights into the Biomarkers, Molecular Targets and Mechanisms of Non-Alcoholic Steatohepatitis-Driven Hepatocarcinogenesis

“…Yano et al demonstrated that fibroblast growth factor 21 (FGF21), an endocrine growth factor, induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed mTOR at ser2448, which downregulated mTORC1 signaling and contributed to improved liver steatosis in HFD-fed mice [ 136 ]. In addition, overexpression of follistatin, (FST), a gonadal protein that specifically inhibits follicle-stimulating hormone release, alleviated lipid accumulation and lipogenesis, whereas FST knockdown aggravated hepatic steatosis via suppressing the mTOR pathway, therefore, may have a potential to become a therapeutic target in NAFLD/NASH [ 137 ]. Very recently Chen et al have shown that Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), which are putative targets of ubiquitin-fold modifier 1 (Ufm1), prevent liver fibrosis, subsequent steatohepatitis, and HCC development in diethylnitrosamine DEN-treated mice by inhibiting the mTOR pathway [ 138 ].…”