Cholesterol oxides inhibit cholesterol esterification by lecithin: cholesterol acyl transferase / Óxidos de colesterol por inibir a esterificação do colesterol lecitina: colesterol acil transferase

Cholesterol oxides are atherogenic and can affect the activity of diverse important enzymes for the lipidic metabolism. The effect of 7β-hydroxycholesterol, 7-ketocholesterol, 25-hydroxycholesterol, cholestan-3β,5α,6β-triol,5,6β-epoxycholesterol, 5,6α-epoxycholesterol and 7α-hydroxycholesterol on esterification of cholesterol by lecithin:cholesterol acyl transferase (LCAT, EC 2.3.1.43) and the transfer of esters of cholesterol oxides from high density lipoprotein (HDL) to low density lipoproteins (LDL) and very low density lipoproteins (VLDL) by cholesteryl ester transfer protein (CETP) was investigated. HDL enriched with increasing concentrations of cholesterol oxides was incubated with fresh plasma as source of LCAT. Cholesterol and cholesterol oxides esterification was followed by measuring the consumption of respective free sterol and oxysterols. Measurements of cholesterol and cholesterol oxides were done by gas-chromatography. 14C-cholesterol oxides were incorporated into HDL2 and HDL3 subfractions and then incubated with fresh plasma containing LCAT and CETP. The transfer of cholesterol oxide esters was followed by measuring the 14C-cholesterol oxide-derived esters transferred to LDL and VLDL. All the cholesterol oxides studied were esterified by LCAT after incorporation into HDL particles, competing with cholesterol by LCAT. Cholesterol esterification by LCAT was inversely related to the cholesterol oxide concentration. The esterification of 14C-cholesterol oxides was higher in HDL3 and the transfer of the derived esters was greater from HDL2 to LDL and VLDL. The results suggest that cholesterol esterification by LCAT is inhibited in cholesterol oxide-enriched HDL particles. Moreover, the cholesterol oxides-derived esters are efficiently transferred to LDL and VLDL. Therefore, we suggest that cholesterol oxides may exert part of their atherogenic effect by inhibiting cholesterol esterification...

Os óxidos de colesterol são aterogênicos e podem afetar a atividade de diversas enzimas importantes para o metabolismo lipídico. Este estudo investigou o efeito dos óxidos 7β-hidroxicolesterol, 7-cetocolesterol, 25-hidroxicolesterol, colestan-3β,5α,6β-triol, 5,6β-epoxicolesterol, 5,6α-epoxicolesterol e 7α-hidroxicolesterol na esterificação do colesterol por ação da lecitina colesterol aciltransferase (LCAT, EC 2.3.1.43) e a posterior transferência dos óxidos esterificados da lipoproteína de alta densidade (HDL) para as lipoproteínas de baixa densidade (LDL) e muito baixa densidade (VLDL) mediada pela proteína de transporte de éster de colesterol (CETP). Para atingir os objetivos, HDL enriquecida com concentrações crescentes de óxidos de colesterol foi incubada com plasma fresco pobre em lipoproteínas, como fonte de LCAT; posteriormente a esterificação do colesterol e dos óxidos de colesterol foi medida pelo consumo do colesterol livre e dos óxidos livres presentes na HDL. As determinações de colesterol e dos óxidos de colesterol foram realizadas por cromatografia gasosa. 14C-óxidos de colesterol foram incorporados nas subfrações HDL2 e HDL3 e posteriormente incubados com plasma fresco, contendo LCAT e CETP. A transferência dos ésteres de óxidos de colesterol foi medida e quantificada pela presença desses ésteres na LDL e VLDL. Todos os óxidos de colesterol estudados foram esterificados pela LCAT após incorporação nas partículas de HDL e competiram com a esterificação do colesterol nativo. A esterificação do colesterol pela LCAT foi inversamente relacionada à concentração de óxidos de colesterol. A esterificação dos óxidos de colesterol foi maior na HDL3 e a transferência desses ésteres foi maior a partir da HDL2 para a LDL e VLDL. Estes resultados indicam que a esterificação do colesterol pela LCAT é inibida nas partículas de HDL enriquecidas com óxidos de colesterol e que os ésteres de óxidos de colesterol...

Effect of experimental Schistosomiasis on 14C-4-cholesterol esterification by mouse liver homogenate

The effect of experimental schistosomiasis mansoni on cholesterol esterification by mouse liver homogenate was studied using 14C-4-cholesterol. The reaction was carried out in 0.85 ml containing 10 nCi labelled cholesterol (I64 nmol as an albumin-stabilized emulsion) with 30 mg tissue homogenate in 176 mM sodium phosphate buffer, pH 7.1, containing 59 micronM oleic acid, 0.3 mM CoASH and 8.8 mM ATP. In experiments with liver from infected mice(N = 22), the percentage of cholesterol esterification was 6.9 + or - 0.7%/h. This rate was 52% less than that observed in normal mice (14.4 + or - 0.6%/h, N = 21). The decrease may be due to the existence of inhibitors of the cholesterol esterifying in the infected liver, increased hydrolysis of cholesteryl esters or a decrease in the synthesis of the enzyme acyl CoA:cholesterol acyl transferase by the infected liver

Relationship between lecithin: cholesterol acyltransfer and lipid and lipoprotein levels in plasma of mammals susceptible or resistant to atherosclerosis

The initial fractional and molar rates of lecithin:cholesterol acyltransfer and the plasma concentrations of unesterified and esterified cholesterol, total phospholipids, triacylglycerol, high density lipoprotein-cholesterol and aplipoprotein B-linked cholesterol were determined for young healthy women and for groups of female pigs, rabbits, rats and cattle. Coefficients were calculated for the simple and partial correlations between acyltransfer rates and lipid and lipoprotein concentrations. In all species molar acyltransfer rates were significantly corrlated with unesterified cholesterol levels. For women, pigs and rabbits (atherosclerosis-susceptible species) acyltransfer rate was significantly correlated with triacylglycerol and apolipoprotein B-linked cholesterol levels, but not with high desnity lipoprotein-cholesterol. In contrast, acyltransfer rates for rats and bovines (atherosclerosis-resistant species) were significantly correlated with high density lipoprotein-cholesterol, but not with the other parameters. These results, together with the corresponding partial correlation analyses, suggest significant functional differences for lecithin:cholesterol acyltransfer in atherosclerosis-resistant and athrosclerosis-susceptible species and that in the latter group, this enzyme may be mainly invilved in the disposal of cholesterol from triacylglycerol-rich lipo-proteins rather than in removing excess tissue cholesterol for transport to the liver

Alterations in the fatty acyl composition of plasma cholesteryl esters in brazilian patients with hepatosplenic schistosomiasis mansoni

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