Abstract 14918: A Non-Conservative Mutation (R611C) in Low-Density Lipoprotein Receptor Related Protein (LRP6) Causes Hyperlipidemia by Impaired LDL Clearance and Increased De Novo Hepatic Lipogenesis

Abstract

Hyperlipidemia is a major risk factor for coronary artery disease (CAD), the leading cause of morbidity and mortality worldwide. Very little is known about the genetic causes of familial combined hyperlipidemia, which is the most common dyslipidemia in the general population and is characterized by elevated serum low-density lipoprotein (LDL) and triglyceride (TG). We recently identified a rare non-conservative mutation (R611C) in the low-density lipoprotein related protein 6 (LRP6) gene, which is the cause of early onset of atherosclerosis, diabetes, and elevated serum LDL and TG in a large outlier kindred. Since discovery of this mutation, the role of LRP6 protein and its genetic variation in lipoprotein homeostasis and atherosclerosis of the general population has been emerging. We have created a humanoid mouse model of R611C mutation (LRP6_R611C) by homologous recombination. LRP6_R611C mice exhibit elevated serum LDL and TG concentration compared to wildtype littermates (all P < 0.05). Dramatic increase of TG levels after inhibition of lipoprotein lipase and greater uptake and incorporation of [¹⁴C]-acetate and [¹⁴C]-palmitate in primary hepatocytes of LRP6_R611C mice suggested increased triglyceride synthesis compared to wildtype mice. Accordingly, mRNA and protein expressions of enzymes regulating de novo fatty acid synthesis (ACC and FASN), long chain fatty acid modification (ELOVL6 and SCD1), and TG synthesis (DGAT1) were all significantly increased in the liver of LRP6_R611C mice compared to wildtype mice. These enzymes are regulated by SREBP-1c, which was expressed at significantly higher levels in LRP6_R611C mice liver compared to wildtype mice. Hepatic [¹²⁵I]-LDL uptake was significantly reduced in LRP6_R611C mice compared to wildtype mice. In conclusion, LRP6_R611C mutation causes hyperlipidemia by impaired LDL clearance and increased de novo hepatic lipogenesis.