Dietary fats modulate the regulatory potential of dietary cholesterol on cholesterol 7 alpha-hydroxylase gene expression

Abstract

Cholesterol 7 alpha-hydroxylase (cyp7) is the rate-limiting enzyme in bile acid biosynthesis. Previously, dietary cholesterol was shown to induce cyp7 gene expression. However, recent studies have produced data that are inconsistent with this observation, suggesting the possibility that other factors in the diet are also important in the regulation of cyp7 by dietary cholesterol. The effect of dietary fats on the ability of dietary cholesterol to regulate cyp7 activity and mRNA abundance was assessed. High fat diets composed primarily of polyunsaturated (PUFA), monounsaturated (MUFA), or saturated (SFA) fatty acids induced hypercholesterolemia regardless of whether cholesterol was present or not. However, the effects of each diet on bile composition and hepatic cholesterol content were variable. Microsomal fatty acid profiles reflected the fatty acid composition of the diets. Addition of cholesterol to the PUFA diet increased cyp7 mRNA abundance and activity, analogous with the results observed in mice fed a chow plus cholesterol diet. On the other hand, addition of cholesterol to diets high in MUFA or SFA caused a significant reduction of cyp7 mRNA abundance and activity. Addition of cholesterol to all the diets caused the expected changes in low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA abundance but was not correlated with the changes in cyp7 mRNA abundance. The relationship between cyp7 mRNA abundance and hepatic total cholesterol content or hepatic microsomal cholesterol content was evident, suggesting that cholesterol status does not necessarily determine cyp7 mRNA abundance. The results of this study illustrate that the type of dietary fat is important in elaborating the regulatory potential of dietary cholesterol on cyp7 gene expression and suggest that the regulation of cyp7 gene expression does not involve the classical sterol-mediated pathway.