ABSTRACT
We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R²) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R² = 0.22, P < 0.001) and CETP (R² = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R² = 0.16, P < 0.005) and LCAT/AI (R² = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific athero genic scenarios.
Subject(s)
Animals , Male , Mice , Apolipoprotein A-I/genetics , Atherosclerosis/genetics , Cholesterol Ester Transfer Proteins/genetics , Diet, Atherogenic , Phosphatidylcholine-Sterol O-Acyltransferase/genetics , Apolipoprotein A-I/metabolism , Atherosclerosis/metabolism , Biological Transport/genetics , Cholesterol Ester Transfer Proteins/metabolism , Disease Models, Animal , Genotype , Linear Models , Mice, Transgenic , Phosphatidylcholine-Sterol O-Acyltransferase/metabolism , Severity of Illness IndexABSTRACT
1. The dyslipoproteinemia commonly occurring in the hepatosplenic forms of schistosomiais mansoni in Brazilian patients is characterized by low plasma levels of choleteryl esters and of the cholesterol-esterifying enzyme, lecithin:cholesterol acyltransferase (LCATase, EC.2.3.1.43). 2. In the present study, normal helathy individual and patients sufferin from hepatosplenic schistosomiasis mansoni were comapred for the fatty acyl compositons of circulating plasma cholesteryl esters and of those formed in vitro by the action of LCATase on a) the endogenous plasma lipoprotins and b) an excess of lipoprotein substrate composed of heat-inactivated plasma. 3. In patient palsma the proportions of saturated and monounsaturated cholesteryl esters were higher and those of diunsaturated and polyunsaturated esters were lower than in the control group. 4. Similar differences were observed between patients and controls in the proportions of the cholesteryl ester subclasses formed in vitro by the action of LCATase on endogenous plasma lipoprotins. 5. Incubation of fresh normal or patient plasma with escess heat-inactivated plasma as substrate for LCATase produced proportions of cholesteryl ester subclasses similar to those formed dduring incubation of nonheated aliquots of the appropriate plasma. 6. We conclude that the alterations in fatty acyl composition of palsma cholesteryl estes in patients with hepatosplenic schistosomiasis mansoni do not appear to be direct consequence of the low levels of LCATase acivity in patient plasma