Antiatherogenic effect of simvastatin is not due to decrease of LDL cholesterol in ovariectomized golden Syrian hamster.

The changes of the composition of blood lipoproteins caused by menopause could also change the effect of hypolipidemic therapy. Using an experimental model we studied the changes of serum lipids and the effect of immediate or delayed treatment with simvastatin on atherosclerosis after surgical menopause. Female golden Syrian hamster aged 6 months were fed hypercholesterolemic diet during the whole study. Atherosclerotic changes in thoracic and abdominal aortas were assessed by stereomicroscopic method after 12 weeks. Four experimental groups were studied: sham-operated animals (n = 5), ovariectomized animals (n = 9), ovariectomized animals treated for 12 weeks (n = 10), and ovariectomized animals treated 4 weeks after ovariectomy for 8 weeks (n = 9). The dose of simvastatin was 10 mg/kg of body weight. After 12 weeks, ovariectomized animals had tenfold higher concentration of triglycerides in LDL fraction and significantly higher prevalence of atherosclerosis than animals without ovariectomy. Treatment with simvastatin substantially decreased the prevalence of atherosclerotic changes, but otherwise did not change individual serum lipids including LDL cholesterol. However, it improved proportions of pro- and antiatherogenic serum lipids mainly by the increase of HDL cholesterol. The timing of simvastatin treatment had no significant effect on atherosclerotic changes or lipid parameters. Simvastatin treatment partly prevented atherosclerotic changes induced by ovariectomy. This effect was not mediated by decrease of LDL cholesterol, but by increase in HDL cholesterol.

Differences in expression of cholesterol 7alpha-hydroxylase between PHHC and Wistar rats.

PHHC rats represent a suitable experimental model of polygenic hypercholesterolemia. It has been found that its metabolic defect is not related to alimentary cholesterol absorption and LDL clearance. We have tested possible changes in cholesterol clearance from the liver to bile acids by analysis of the expression of the cholesterol 7alpha-hydroxylase (cyp7A1) gene in PHHC (N = 20) and Wistar (controls) (N = 19) male rats. The animals were fed standard laboratory diet (CD) or control diet containing 5% fat and 2% cholesterol (HCD) for two weeks. SSCP and RT-PCR were used for mutation analysis and study of gene expression, respectively. Although the basal cholesterolemia in PHHC was similar to controls (1.80 +/- 0.48 and 1.52 +/- 0.39 mmol/l, respectively), it rose in rats fed on HCD to 9.81 +/- 1.65 mmol/l in PHHC rats and only to 2.19 +/- 0.41 mmol/l in controls. Similarly to the basal cholesterol concentration, the gene expression of cyp7A1 in the liver of rats on CD was the same in both compared groups on the control diet. In controls on HCD, cyp7A1 gene expression increased almost 4-fold immediately on the first day and achieved up to approximately 20-multiple basal expression in the end of the feeding period. Compared to the controls, after switching to HCD the cyp7A1 gene expression in PHHC rats did not change dramatically. These results suggest that the cyp7A1 gene plays an important role in development of hypercholesterolemia in PHHC rats.

Effect of diets on lipoprotein concentrations in heterozygous apolipoprotein E-deficient mice.

Loss of apolipoprotein E synthesis causes increased serum cholesterol concentrations and the sensitivity to high-fat diet in mice. We analyzed the changes in lipoprotein and hepatic structures in apolipoprotein E-deficient mice kept on control diet and cholesterol diets. Basal cholesterolemia of heterozygous (+/-) mice (2.2+/-0.28 mmol/l) was the same compared to wild-type (+/+) mice (2.3+/-0.15 mmol/l), but was lower compared to homozygous (-/-) mice (10.3+/-1.40 mmol/l). In +/- mice, cholesterolemia rose to 3.2 mmol/l on cholesterol diet and to 9 mmol/l on cholate diet, to 3 mmol/l and 3.6 mmol/l in +/+ mice, and to 23.4 mmol/l and 70.5 mmol/l in -/- mice, respectively. While the ratio of cholesterol/triglyceride concentrations in VLDL, IDL and LDL fractions was not increased in +/- mice and +/+ mice, it was increased in -/- mice on control diet. On the cholesterol diet, this ratio rose and was dramatically increased by cholate diet in all groups of mice. Even though cholate supplementation increased cholesterol concentration, it led to substantial toxic changes in hepatic morphology of all animals. In conclusion, one functional apo E allele in +/- mice is effective in keeping serum cholesterol concentrations in normal range on a control diet, but not on the cholesterol and cholate diets.

[Lipid metabolism in atherogenesis]. / Metabolismus lipidu a aterogeneze.

Lipoprotein (LP) metabolism plays a pivotal role in atherogenesis. Breakdown of triglyceride (TG) rich lipoproteins, both of exogenous--chylomicrones and endogenous--very low density lipoproteiny (VLDL) produces remnant lipoproteins after repeated action of lipoprotein lipase (LPL). Atherogenity of remnant lipoprotein has been proved. Also atheroprotective high density lipoproteins (HDL) are produced from surface of TG rich lipoproteins during their lipolysis. Protective role of HDL particles in atherogenesis is manifested by reverse cholesterol transport from all extrahepatic cells to the liver including cells of the arterial wall. Plasma concentration of atherogenic low density lipoproteins (LPL) is regulated by the production rate of VLDL in the liver on the one hand and their utilization by selective LDL receptors (mainly in the liver) on the other hand. Number of functioning LDL receptors is regulated genetically (gene for own LDL receptor and gene for both ligands--apoprotein B and apoprotein E) and also by environmental factors. Diet low in saturated fat and cholesterol and rich in dietary fibres increases number of LDL receptors and consequently decreases LDL cholesterol concentration. Monocytes entering arterial wall when intravasal and then subendothelial concentration of LDL is increased absorb LDL and predominantly oxidized LDL by scavenger receptors. During this repeated process they are changed to macrophages, residual macrophages and foam cells. Production of foam cells represents a starting point in atherogenesis but their high presence is typical also for advanced vulnerable atherosclerotic lesions, which are prone to rupture producing clinical complication--myocardial infarction and stroke.