Hepatitis C virus inhibits the E2F2/PI3K/AKT signaling pathway through miR-378b and leads to glycolipid metabolism disorders in the liver

Glycolipid metabolism and microRNAs (miRNAs) play important roles in hepatitis C virus (HCV)-induced type 2 diabetes mellitus (T2DM). Our study aimed to explore the mechanism of action of miR-378b in liver glycolipid metabolism disorders caused by HCV infection.

An in vitro model was established by HCV infection of HepG2 cells, and an animal model was constructed by HCV infection of hCD81/hOccludin double-transgenic mice. The levels of related genes, proteins and glycolipid metabolism products were detected by RT‒qPCR, Western blotting, pathological tissue staining and reagent kits.

Our findings revealed increased expression of miR-378b in T2DM patients, mice, and liver cells infected with HCV. Reducing miR-378b levels in liver cells and mice infected with HCV can increase glycogen production and decrease lipid accumulation and TG concentrations. Additionally, reductions in TG, TC, LDL, and FFA levels, along with increased HDL levels, were detected in the serum of mice infected with HCV with miR-378b knockdown. The findings revealed that HCV triggers glycolipid metabolism dysregulation in the liver through increased miR-378b expression. From a mechanistic standpoint, HCV inhibits the activation of the E2F2/PI3K/AKT signaling pathway by upregulating miR-378b expression, thereby causing disorders of glycolipid metabolism in the liver.

The results of this study provide theoretical support for the use of miR-378b as a new target for the treatment of HCV-induced liver glycolipid metabolism dysregulation.