REGULATION OF HEPATIC 7-ALPHA-HYDROXYLASE EXPRESSION AND RESPONSE TO DIETARY-CHOLESTEROL IN THE RAT AND HAMSTER

Although dietary cholesterol raises plasma total and low density lipoprotein (LDL) cholesterol concentrations, the response to a given intake of cholesterol varies enormously among different species and even among individuals of the same species. The mechanisms responsible for differing sensitivity to dietary cholesterol were examined by comparing the rat, which is able to adapt to large fluctuations in sterol intake or loss with little change in plasma LDL levels, with the hamster, where changes in sterol balance strongly influence plasma LDL concentrations. When fed the same cholesterol-free diet, hepatic 7 alpha-hydroxylase activity was 16-fold higher in the rat than in the hamster. As a consequence, rates of hepatic cholesterol synthesis were 20-fold higher in the rat than in the hamster, In both species, hepatic cholesterol synthesis was suppressed >90% in response to increasing loads of dietary cholesterol. However, the quantitative importance of this adaptive mechanism was much greater in the rat since the absolute reduction in hepatic cholesterol synthesis in the rat (2,110 nmol/h/g) was much larger than in the hamster (103 nmol/h/g). In the rat, the high basal level of 7 alpha-hydroxylase expression was further induced by substrate (cholesterol) allowing these animals to convert excess dietary cholesterol to bile acids efficiently. In contrast, the low basal level of enzyme expression in the hamster was not induced by dietary cholesterol. Thus, the low basal rates of bile acid and cholesterol synthesis coupled with a lack of 7 alpha-hydroxylase induction by cholesterol render the hamster much more sensitive than the rat to the cholesterolemic effects of dietary cholesterol.