rhoa is a modulator of the cholesterol-lowering effects of statinrhoa调制器的降低胆固醇的他汀类药物的影响.pdfVIP

RHOA Is a Modulator of the Cholesterol-Lowering Effects of Statin 1 1 1 1 1 Marisa W. Medina *, Elizabeth Theusch , Devesh Naidoo , Frederick Bauzon , Kristen Stevens , 2 1 1 Lara M. Mangravite , Yu-Lin Kuang , Ronald M. Krauss * 1 Children’s Hospital Oakland Research Institute, Oakland, California, United States of America, 2 Sage Bionetworks, Seattle, Washington, United States of America Abstract Although statin drugs are generally efficacious for lowering plasma LDL-cholesterol levels, there is considerable variability in response. To identify candidate genes that may contribute to this variation, we used an unbiased genome-wide filter approach that was applied to 10,149 genes expressed in immortalized lymphoblastoid cell lines (LCLs) derived from 480 participants of the Cholesterol and Pharmacogenomics (CAP) clinical trial of simvastatin. The criteria for identification of candidates included genes whose statin-induced changes in expression were correlated with change in expression of HMGCR, a key regulator of cellular cholesterol metabolism and the target of statin inhibition. This analysis yielded 45 genes, from which RHOA was selected for follow-up because it has been found to participate in mediating the pleiotropic but not the lipid-lowering effects of statin treatment. RHOA knock-down in hepatoma cell lines reduced HMGCR, LDLR, and SREBF2 mRNA expression and increased intracellular cholesterol ester content as well as apolipoprotein B (APOB) concentrations in the conditioned media. Furthermore, inter-individual variation in statin-induced RHOA mRNA expression measured in vitro in CAP LCLs was correlated with the change