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.

Institute for Clinical and Experimental Medicine Prague

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