Effect of Dietary Cholesterol and Fat on the Expression of Hepatic Sterol 27-Hydroxylase and Other Hepatic Cholesterol-Responsive Genes in Baboons ( Papio Species)

Abstract

Abstract Our studies of baboons with low and high responses to dietary cholesterol and fat suggest that low-responding baboons increase the activity of hepatic sterol 27-hydroxylase, an important enzyme of bile acid synthesis, considerably more than do high-responding baboons when challenged with a high-cholesterol, high-fat (HCHF) diet. The present studies were conducted to determine whether hepatic sterol 27-hydroxylase mRNA levels and plasma 27-hydroxycholesterol concentrations also differed with dietary responsiveness. Sixteen adult male baboons with a wide range of VLDL cholesterol plus LDL cholesterol (VLDL+LDL cholesterol) response to an HCHF diet were selected. They were examined first while on a chow diet and then after 1, 3, 6, 10, 18, 26, 36, 52, 72, and 104 weeks on the HCHF diet. Plasma and lipoprotein cholesterol concentrations increased rapidly during the first 3 weeks and stabilized thereafter. On the basis of the response in VLDL+LDL cholesterol, we selected five low-responding, four medium-responding, and five high-responding baboons for more intensive study in more detail. In low responders, the major increase in serum cholesterol concentration was in HDL cholesterol, whereas in medium and high responders it was in both VLDL+LDL and HDL cholesterol. In low and medium responders, serum or VLDL+LDL cholesterol did not change after 3 weeks of consumption of the HCHF diet, whereas in high responders VLDL+LDL cholesterol declined between 78 and 104 weeks. In low and medium responders, plasma 27-hydroxycholesterol concentrations and hepatic sterol 27-hydroxylase mRNA levels increased rapidly during the first 10 weeks, declined thereafter, and stabilized at 26 weeks in low responders and at 40 weeks in medium responders. In high responders, plasma 27-hydroxycholesterol concentration did not increase. The increases in hepatic sterol 27-hydroxylase mRNA and plasma 27-hydroxycholesterol in medium responders were intermediate between those in high- and low-responding baboons. The expression of hepatic mRNA for other cholesterol-responsive genes did not differ between high- and low-responding baboons. Plasma LDL cholesterol concentrations were negatively correlated with plasma 27-hydroxycholesterol concentrations and hepatic sterol 27-hydroxylase mRNA levels when the animals had been on the HCHF diet for 10 weeks. These studies suggest that hepatic sterol 27-hydroxylase may be an important regulator of responsiveness to dietary cholesterol and fat in baboons.