Abstract
Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/β-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in metabolic regulation, specifically in the nutrient-sensing pathway, has recently garnered considerable interest. Patients carrying an LRP6 mutation exhibit elevated levels of LDL cholesterol, triglycerides, and fasting glucose, which cooperatively constitute the risk factors of metabolic syndrome and atherosclerosis. Since the discovery of this mutation, the general role of LRP6 in lipid homeostasis, glucose metabolism, and atherosclerosis has been thoroughly researched. These studies have demonstrated that LRP6 plays a role in LDL receptor-mediated LDL uptake. In addition, when the LRP6 mutant impaired Wnt-LRP6 signaling, hyperlipidemia, non-alcoholic fatty liver disease, and atherosclerosis developed. LRP6 regulates lipid homeostasis and body fat mass via the nutrient-sensing mechanistic target of the rapamycin (mTOR) pathway. Furthermore, the mutant LRP6 triggers atherosclerosis by activating platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell differentiation. This review highlights the exceptional opportunities to study the pathophysiologic contributions of LRP6 to metabolic syndrome and cardiovascular diseases, which implicate LRP6 as a latent regulator of lipid metabolism and a novel therapeutic target for nutritional intervention.
Highlights
Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor (LDLR) family with distinctive structure and ligand-binding functions, which plays a crucial role in lipoprotein endocytosis and in Wnt/β-catenin signaling as a co-receptor
Other studies have further uncovered the specific role of LRP6 in the regulation of vesicular LDL uptake [17,21]; hepatic lipogenesis and very low-density lipoprotein (VLDL) secretion [20]; glucose homeostasis [15,25]; and vascular smooth muscle cell (VSMC) growth [16] in vivo and in vitro
These findings suggest that the upregulation of LRP6 in coronary artery lesions is likely a compensatory mechanism to inhibit platelet-derived growth factor (PDGF) signaling
Summary
Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor (LDLR) family with distinctive structure and ligand-binding functions, which plays a crucial role in lipoprotein endocytosis and in Wnt/β-catenin signaling as a co-receptor. The canonical Wnt signaling pathway consists of cascades of events that follow the binding of Wnt proteins to their receptor, frizzled, and co-receptor, LRP5/6, activating the dishevelled protein family and inhibiting a protein complex that includes axin, glycogen synthase kinase (GSK)-3β, and adenomatous polyposis coli [1]. Activated LRP6 directly inhibits β-catenin phosphorylation by GSK-3β [2] These events stabilize the cytoplasmic pool of β-catenin and enhance its translocation to the nucleus to interact with other transcriptional regulators, including T-cell factor/lymphoid enhancer factor, triggering the expression of a variety of target genes for the regulation of gluconeogenesis, insulin secretion, and signaling [3,4,5]. This article aims to demonstrate the value of developing a nutritional intervention strategy for LRP6 by examining its function and underlying pathophysiology
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