Cholesteryl ester transfer protein (CETP) may constitute a cardiometabolic risk factor through its ability to transfer cholesteryl esters from high density lipoproteins (HDL) towards apoB-containing lipoproteins(VLDL and LDL). Apolipoprotein C1 was identified earlier by this group as a potent physiological inhibitor of plasma CETP.
Recently, we observed that :
Whereas phospholipid transfer protein (PLTP) was studied initially for its implication in HDL metabolism and reverse cholesterol transport, we contributed to the demonstration of additional biological properties :
As a member of the LT/LBP gene family, PLTP was found to play a prominent and pivotal role in LPS and lipid A metabolism, thus modulating inflammation and innate immunity :
Both CETP and PLTP are target genes for LXR, and we observed that CETP expression in mice increases cholesterol biliary excretion after treatment with a pharmacological LXR agonist. We also observed that the LXR-mediated inductions of human CETP and PLTP expression are switched during the monocyte-to-macrophage differentiation, and are magnified by lipid loading. However, and unlike for PLTP, LXR-mediated upregulation of CETP expression is selectively lost in inflammatory macrophages.
By using a transcriptomic approach, our group recently identified the nuclear receptor RARα as new LXR target in macrophages, and the LXR/RARα pathway is able to stimulate macrophages efferocytosis.
Beside bile acid metabolism, CAR and PXR are able to modulate plasma cholesterol transport and lipoprotein metabolism. We observed that activation of PXR antagonizes the effects of bile acids on HDL in mice fed 1% cholic acid containing diet. We demonstrated that administration of a CAR agonist in normolipidic wild-type and HuAITg mice produces rapid and transient decreases in plasma HDL cholesterol and apoA1 levels.
Recently, we have shown that treatment of Ldlr-/- mice with a specific CAR agonist for two months is significantly reduced plasma cholesterol concentration and inhibited the development of atherosclerotic lesions in aortic valves. The decrease in plasma cholesterol was associated with a marked increase in the VLDL receptor gene expression in the liver and with faster elimination of HDL cholesterol via its conversion into bile acids.