Abstract
BackgroundCETP is a plasma protein that modulates atherosclerosis risk through its HDL-cholesterol reducing action. The aim of this work was to examine the effect of the PPARα agonist, ciprofibrate, on the CETP gene expression, in the presence and absence of apolipoprotein (apo) CIII induced hypertriglyceridemia, and its impact on the HDL metabolism.ResultsMice expressing apo CIII and/or CETP and non-transgenic littermates (CIII, CIII/CETP, CETP, non-Tg) were treated with ciprofibrate during 3 weeks. Drug treatment reduced plasma triglycerides (30-43%) and non-esterified fatty acids (19-47%) levels. Cholesterol (chol) distribution in plasma lipoprotein responses to ciprofibrate treatment was dependent on the genotypes. Treated CIII expressing mice presented elevation in VLDL-chol and reduction in HDL-chol. Treated CETP expressing mice responded with reduction in LDL-chol whereas in non-Tg mice the LDL-chol increased. In addition, ciprofibrate increased plasma post heparin lipoprotein lipase activity (1.3-2.1 fold) in all groups but hepatic lipase activity decreased in treated CETP and non-Tg mice. Plasma CETP activity and liver CETP mRNA levels were significantly increased in treated CIII/CETP and CETP mice (30-100%). Kinetic studies with 3H-cholesteryl ether (CEt) labelled HDL showed a 50% reduction in the 3H-CEt found in the LDL fraction in ciprofibrate treated compared to non-treated CETP mice. This means that 3H-CEt transferred from HDL to LDL was more efficiently removed from the plasma in the fibrate treated mice. Accordingly, the amount of 3H-CEt recovered in the liver 6 hours after HDL injection was increased by 35%.ConclusionTogether these data showed that the PPARα agonist ciprofibrate stimulates CETP gene expression and changes the cholesterol flow through the reverse cholesterol transport, increasing plasma cholesterol removal through LDL.
Highlights
Cholesteryl ester transfer protein (CETP) is a plasma protein that modulates atherosclerosis risk through its HDLcholesterol reducing action
Apolipoproteins CIII are small proteins mainly found on the surface of apoB containing lipoproteins, which strongly affect their metabolism
Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters (CE) from high density lipoprotein (HDL) to the apoB-containing lipoprotein particles, which are subsequently cleared from the circulation by the liver
Summary
CETP is a plasma protein that modulates atherosclerosis risk through its HDLcholesterol reducing action. Apolipoproteins (apo) CIII are small proteins mainly found on the surface of apoB containing lipoproteins (including VLDL, IDL and LDL), which strongly affect their metabolism. They inhibit catabolism of these lipoproteins by lipoprotein-lipase (LPL) and retard their clear-. Inhibitors of CETP have been tested in human subjects and shown to markedly increase the concentration of HDL cholesterol while decreasing that of LDL cholesterol and apo B [9,10], but the impact of CETP mediated lipid transfer reactions on atherogenesis remains controversial [11]. The effects of CETP expression in this species can be neutral, pro- or antiatherogenic depending upon the metabolic context [13,14,15,16,17]
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