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 re-sistance 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(βΔ)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 dimin-ished glycogen synthesis in insulin-stimulated HepG2 cells,which was restored by exogenous expression of the βΔ-chain.By contrast,AAV8-mediated hepatic βΔ-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.
维普
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