%0 Journal Article
%T LRP1 facilitates hepatic glycogenesis by improving the insulin signaling pathway in HFD-fed mice.
%A Guo X
%A Pu J
%A Tang Z
%A Jia C
%A Yang F
%A Liu T
%A Ding Y
%J Animal Model Exp Med
%V 0
%N 0
%D 2024 Apr 3
%M 38567757
暂无%R 10.1002/ame2.12408
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.