Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFβ and PDGFRβ in reverse cholesterol transport and the maintenance of vascular wall integrity. Here we used a knockin mouse model to uncover a novel atheroprotective role for LRP1 in macrophages where tyrosine phosphorylation of an NPxY motif in its intracellular domain initiates a signaling cascade along an LRP1/SHC1/PI3K/AKT/PPARγ/LXR axis to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflammatory responses.

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.

The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosis-prone low-density lipoprotein receptor–deficient (Ldlr^−/−) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule–1 (VCAM-1) and intercellular adhesion molecule–1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor κB (NF-κB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.

Reduced low-density lipoprotein receptor–related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity in vitro and also promotes high-fat diet–induced hepatic insulin resistance and hepatic steatosis in vivo. The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. hLrp1^+/+ mice with normal LRP1 expression and hLrp1^−/− mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the hLrp1^−/− mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the hLrp1^+/+ mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in hLrp1^−/− mice. The accelerated liver pathology observed in HFHC-fed hLrp1^−/− mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional in vitro studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hLrp1^−/− hepatocytes than in hLrp1^+/+ hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.

Low‐density lipoprotein receptor‐related protein‐1 (LRP1) is thought to be correlated with hepatocellular carcinoma (HCC) invasion and metastasis. However, the precise mechanism through which LRP1 contributes to HCC progression remains unclear. Here, lower LRP1 levels are associated with malignant progression, and poor prognosis in patients with HCC is shown. LRP1 knockdown enhances the tumorigenicity of HCC cells in vitro and in vivo, whereas overexpression of either LRP1 or its β‐chain has the opposite effect. Mechanistically, LRP1 knockdown promotes the binding of ubiquitin‐like modifier 1 ligating enzyme 1 (UFL1) to OGA and accelerates ubiquitin‐mediated OGA degradation, leading to increased O‐GlcNAcylation of nuclear factor‐kappa B (NF‐κB) and subsequent inhibition of pro‐apoptotic gene expression. Conversely, exogenously expressed truncated β‐chain (β∆) stabilizes OGA by disrupting the association between UFL1 and OGA, consequently abolishing the anti‐apoptotic effects of O‐GlcNAcylated NF‐κB. The findings identify LRP1, particularly its β‐chain, as a novel upstream control factor that facilitates the stabilization of the OGA protein, thereby suppressing NF‐κB signaling and attenuating HCC progression, thus suggesting a novel therapeutic strategy for HCC.