Ciprofibrate increases cholesteryl ester transfer protein gene expression and the indirect reverse cholesterol transport to the liver.

BACKGROUND: CETP 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 PPARalpha 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. RESULTS: Mice 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%. CONCLUSION: Together these data showed that the PPARalpha agonist ciprofibrate stimulates CETP gene expression and changes the cholesterol flow through the reverse cholesterol transport, increasing plasma cholesterol removal through LDL.

Effects of diabetes and CETP expression on diet-induced atherosclerosis in LDL receptor-deficient mice.

The role of CETP expression and diabetes in atherogenesis was investigated in mice with heterozygous disruption of the LDL receptor gene (LDLR1). LDLR1 mice with and without CETP expression were treated with streptozotocin (STZ) and maintained on a standard diet for one month before switching to an atherogenic diet for an additional month. STZ-sensitive mice had approximately 2.5-fold higher glycemia and 7.5- to 8.0-fold higher cholesterolemia. Factorial analysis of variance showed no significant effect of diabetes, CETP or diabetes-CETP interaction on the size of the atherosclerotic lesions. CETP expression in non-diabetic mice resulted in a 50% reduction in the area of the atherosclerotic lesions. Multiple regression analysis showed a positive and independent atherogenic effect of triglyceridemia in LDLR1 mice and of cholesterolemia in diabetic mice. Logistic analysis showed that elevated plasma cholesterol level significantly increased the risk of developing large lesion size (>75th percentile). In conclusion, CETP expression did not alter the lesion formation in response to diabetes, although it may be protective in the euglycemic state; the triglyceride level was an independent risk factor for LDL receptor-deficient mice but not for CETP-expressing mice; and elevated plasma cholesterol levels increased the risk of developing large atherosclerotic lesions, independently of CETP and diabetes.