Cholesterol 7α-hydroxylase (CYP7A1), the key regulatory enzyme of bile acid synthesis, displays a pronounced diurnal variation. To better understand the regulation of CYP7A1 activity, three daylong examinations were carried out in 12 healthy men. The concentrations of 7α-hydroxycholest-4-en-3-one (C4), a surrogate marker of CYP7A1 activity, bile acids (BA), insulin, glucose, nonesterified fatty acids, triglycerides, and cholesterol were measured in serum in 90-min intervals from 7 AM till 10 PM. To lower and to increase BA concentration during the study, the subjects received cholestyramine and chenodeoxycholic acid (CDCA), respectively, in two examinations. No drug was used in the control examination. There was a pronounced diurnal variation of C4 concentration with a peak around 1 PM in most of the subjects. The area under the curve (AUC) of C4 concentration was five times higher and three times lower when subjects were treated with cholestyramine and CDCA, respectively. No relationship was found between AUC of C4 and AUC of BA concentration, but AUC of C4 correlated positively with that of insulin. Moreover, short-term treatment with cholestyramine resulted in about 10 % suppression of glycemia throughout the day. Our results suggest that insulin is involved in the regulation of diurnal variation of CYP7A1 activity in humans., J. Kovář ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
To understand the pathogenesis of hypercholesterolemia in Prague hereditary hypercholesterolemic (PHHC) rat, we analyzed the response of hepatic transcriptome to dietary cholesterol in PHHC and control Wistar rats. Male PHHC and Wistar rats were fed chow (C), 5 % fat (palm kernel oil) (CF) or 1 % cholesterol + 5 % fat (CHOL) diet for three weeks. Hepatic transcriptome was analyzed using Affymetrix GeneChip arrays. No differences were found in the effect of both control diets (C and CF) on lipid metabolism and gene expression of 6500 genes. Therefore, these data were pooled for further analysis. Dietary cholesterol induced accumulation of cholesterol and triacylglycerols in the liver in both strains and hypercholesterolemia in PHHC rats. However, there were no differences in response of hepatic transcriptome to CHOL diet. On the other hand, several genes were found to be differently expressed between both strains independently of the diet. Two of those genes, Apof and Aldh1a7, were studied in more detail, and their role in pathogenesis of hypercholesterolemia in PHHC rats could not been corroborated. In conclusion, the hypercholesterolemia in PHHC rats is due to physiological response of hepatic transcriptome to dietary cholesterol in different genetic background., M. Vlachová, M. Heczková, M. Jirsa, R. Poledne, J. Kovář., and Obsahuje bibliografii