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Atherosclerosis

CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression inxa0vitro and inxa0vivo through a SREBP2 dependent mechanism.


PMID 24950000

Abstract

CETP inhibitors block the transfer of cholesteryl ester from HDL-C to VLDL-C and LDL-C, thereby raising HDL-C and lowering LDL-C. In this study, we explored the effect of CETP inhibitors on hepatic LDL receptor (LDLR) and PCSK9 expression and further elucidated the underlying regulatory mechanism. We first examined the effect of anacetrapib (ANA) and dalcetrapib (DAL) on LDLR and PCSK9 expression in hepatic cells inxa0vitro. ANA exhibited a dose-dependent inhibition on both LDLR and PCSK9 expression in CETP-positive HepG2 cells and human primary hepatocytes as well as CETP-negative mouse primary hepatocytes (MPH). Moreover, the induction of LDLR protein expression by rosuvastatin in MPH was blunted by cotreatment with ANA. In both HepG2 and MPH ANA treatment reduced the amount of mature form of SREBP2 (SREBP2-M). Inxa0vivo, oral administration of ANA to dyslipidemic C57BL/6J mice at a daily dose of 50xa0mg/kg for 1 week elevated serum total cholesterol by approximately 24.5% (pxa0