LRP1 facilitates hepatic glycogenesis by improving the insulin signaling pathway in HFD‐fed mice

Abstract Background LDL receptor‐related protein‐1 (LRP1) is a cell‐surface receptor that functions in diverse physiological pathways. We previously demonstrated that hepatocyte‐specific LRP1 deficiency (hLRP1KO) promotes diet‐induced insulin resistance and increases hepatic gluconeogenesis in mice. However, it remains unclear whether LRP1 regulates hepatic glycogenesis. Methods Insulin signaling, glycogenic gene expression, and glycogen content were assessed in mice and HepG2 cells. The pcDNA 3.1 plasmid and adeno‐associated virus serotype 8 vector (AAV8) were used to overexpress the truncated β‐chain (β∆) of LRP1 both in vitro and in vivo. Results On a normal chow diet, hLRP1KO mice exhibited impaired insulin signaling and decreased glycogen content. Moreover, LRP1 expression in HepG2 cells was significantly repressed by palmitate in a dose‐ and time‐dependent manner. Both LRP1 knockdown and palmitate treatment led to reduced phosphorylation of Akt and GSK3β, increased levels of phosphorylated glycogen synthase (GYS), and diminished glycogen synthesis in insulin‐stimulated HepG2 cells, which was restored by exogenous expression of the β∆‐chain. By contrast, AAV8‐mediated hepatic β∆‐chain overexpression significantly improved the insulin signaling pathway, thus activating glycogenesis and enhancing glycogen storage in the livers of high‐fat diet (HFD)‐fed mice. Conclusion Our data revealed that LRP1, especially its β‐chain, facilitates hepatic glycogenesis by improving the insulin signaling pathway, suggesting a new therapeutic strategy for hepatic insulin resistance‐related diseases.