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

Abstract

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.

News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1

“…Similar observations were later made in hepatocytes [50]. Conversely, LRP1 also regulates the surface expression of the insulin receptor in neurons [51] and in the liver [52**]. In LRP1-deficient livers, reduced surface expression of the insulin receptor, and subsequently diminished expression of the glucose transporter GLUT2 (Fig.…”

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

“…So we aimed to determine whether this is also a contributing factor to the impaired β cell function and proliferation after HFD. Loss of LRP1 has been shown to cause apoE accumulation in mouse embryonic fibroblasts (MEFs) and neurons (11) as well as reduced apoE-lipoprotein secretion from liver (14). However, apoE levels were similar between control and Lrp1-βKO islets after HFD (Supplemental Figure 7, A, C-E).…”

“…LRP1 deficiency disrupts lipid metabolism in multiple tissues (9)(10)(11)(12)14). So we aimed to determine whether this is also a contributing factor to the impaired β cell function and proliferation after HFD.…”

“…Highly diverse functions of LRP1 have been reported in different tissues. For example, LRP1 is a major suppressor of aneurysm formation and atherosclerosis in vascular smooth muscle (9) and supports glucose and lipid metabolism in neurons (10,11) and adipose tissue (12) as well as liver (13,14). However, the mechanistic role or roles and impact on cellular physiology of LRP1 receptors in β cells have not been addressed.…”

Postprandial dysmetabolism: Too early or too late?

“…This will account for the fact that in experimental animals with inactivated LRP1 receptors, consumption of a high-fat diet results in insulin resistance and metabolic syndrome. 42 Given that most people consume fat-containing meals frequently during the day, the usual metabolic state of lipids is postprandial, since after a typical fatty meal, consumption serum triglycerides rise within an hour and remain elevated for 5-8 hours. This contrasts with glucose metabolism which displays transient elevations after a meal.…”