Abstract 15600: Roles of LR11 Receptor in Atherosclerosis Development of Familial Hypercholesterolemia Subjects
LR11, also called SORLA, is a 250-kDa single transmembrane receptor, belonging to both LDL-receptor and Vps10p receptor family. LR11 is abundantly and specifically expressed in intima smooth muscle cells and regulates its migration. Plasma soluble form of LR11 (sLR11) is positively correlated with the intima-media thickness and has been promoted as a risk factor for coronary artery disease (CAD). Here we studied the role of LR11 in lipid-related gene expression and CAD development, using both Familial Hypercholesterolemia (FH) patients and animal models. LDLR-KO and ApoE-KO mice were fed with either chow or Western type diet (WTD) and their livers were examined. LR11 mRNA and protein expression were elevated in LDLR-KO mice on chow diet but not in ApoE-KO, compared to wild-type controls. WTD further increased LR11 level in both KO strains. SORT1, another Vps10p family member, expression was decreased only in LDLR-KO fed with WTD. To further elucidate the effect of diet, human hepatocytes and hepatic stellate cells were exposed to chylomicrons, LDL and crude fish oil. Chylomicrons increased LR11 mRNA expression in hepatocytes but not stellate cells. For human study, fasting plasma of adult FH patients with and without CAD when ‘off’ statin and of their healthy non-FH brothers were collected. Plasma sLR11 level of FH with CAD is higher when compared to their healthy brothers while no difference was shown in FH without CAD compared to their healthy brothers. A similar trend was observed in plasma sLR11 of LDLR-KO mice on chow diet. We concluded that LR11 is upregulated in an absence of LDL receptor which is markedly affected by diet and triglyceride-rich lipoprotein showed a similar effect in an in vitro setting. Plasma sLR11 correlated with the development of atherosclerosis/CAD. sLR11 may be used as an additional risk factor for CAD in FH patients.
- © 2012 by American Heart Association, Inc.