Cholesteryl ester transfer protein (CETP) is an important enzyme in the reverse cholesterol transport (RCT) pathway. Elevated plasma CETP levels are associated with decreased plasma HDL levels and an increased progression of coronary atherosclerosis. Furthermore, a common variation in the CETP gene, the Taq1B polymorphism, was found to be predictive for the response to lipid-lowering therapy with the HMG-CoA reductase inhibitor pravastatin. So far, preliminary data show that pravastatin treatment lowers plasma CETP concentrations significantly. Reports on the effects of fibric acid derivatives (fibrates) on plasma CETP concentrations have been contradictory, but most reports also point to a reduction of CETP activity. Very recent studies on the transcriptional regulation of CETP indicate that statins and fibrates may be able to act on CETP via transcription factors of the SREBP family or orphan members of the nuclear receptor superfamily respectively. A direct relation, however, has not been shown.
We will therefore address the following questions: 1. at which level (mRNA, protein or activity) do fibrates and statins affect CETP activity, and 2. which mechanisms are responsible for the observed effects?
We will take a systematic approach by first establishing at which level CETP regulation by fibrates and statins takes place both in vivo and in vitro This will comprise determination of CETP mRNA and protein levels by quantitative RT-PCRs and CETP mass assays in subjects treated with either a fibrate or statin, in healthy volunteers and in different cell lines. Next, we will assess the effects on CETP of different genetic and cell biological factors in combination with different drugs in vitro. Finally, we will study the mechanisms responsible for the observed effects at the appropriate level using reporter gene constructs, mRNA stability experiments, or functional analysis of CETP activity. This will result in a better understanding of the working mechanism of both drugs in relation to genetic and cell biological factors, which will ultimately lead to a refinement of lipid-lowering therapy. |
