Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis

•Hepatic LRP1 deficiency in a mouse model (hLRP1KO) predisposes to diet-induced insulin resistance, dyslipidemia, and obesity.•Insulin resistance in the hLRP1KO mouse results from reduced cell surface expression of insulin receptor (IR) and impaired translocation of glucose transporter 2 (GLUT2).•Excess fatty acids in hLRP1KO mice shift hepatic fatty acid metabolism from an oxidative to a synthetic state, resulting in hepatic steatosis.LRP1 is a multifunctional transmembrane receptor with essential functions in lipoprotein metabolism and subcellular receptor tyrosine kinase trafficking. A mouse model of hepatic LRP1 deficiency integrates the hallmark findings in Metabolic Syndrome - insulin resistance, dyslipidemia, and hepatic steatosis - with impaired glucose metabolism and altered hepatic fatty acid metabolism as a consequence of reduced insulin receptor trafficking and signaling. These findings underscore the central role of LRP1 in overall energy homeostasis, and specifically liver glucose and fatty acid metabolism.

Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL) triglyceride secretion.