EFFECT OF DIETARY-CHOLESTEROL AND FAT ON THE EXPRESSION OF HEPATIC STEROL 27-HYDROXYLASE AND OTHER HEPATIC CHOLESTEROL-RESPONSIVE GENES IN BABOONS (PAPIO SPECIES)

Our studies of baboons with low and high responses to dietary choleste rol and fat suggest that low-responding baboons increase the activity of hepatic sterol n-hydroxylase, an important enzyme of bile acid synt hesis, considerably more than do high-responding baboons when challeng ed with a high-cholesterol, high-fat (HCHF) diet. The present studies were conducted to determine whether hepatic sterol n-hydroxylase mRNA levels and plasma 27-hydroxycholesterol concentrations also differed w ith dietary responsiveness. Sixteen adult male baboons with a wide ran ge of VLDL cholesterol plus LDL cholesterol (VLDL+LDL cholesterol) res ponse 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 w eeks on the HCHF diet. Plasma and lipoprotein cholesterol concentratio ns increased rapidly during the first 3 weeks and stabilized thereafte r. On the basis of the response in VLDL+LDL cholesterol, we selected f ive low-responding, four medium-responding, and five high-responding b aboons for more intensive study in more detail. In low responders, the major increase in serum cholesterol concentration was in HDL choleste rol, whereas in medium and high responders it was in both VLDL;LDL and HDL cholesterol. In low and medium responders, serum or VLDL+LDL chol esterol did not change after 3 weeks of consumption of the HCHF diet, whereas in high responders VLDL+LDL cholesterol declined between 78 an d 104 weeks. In low and medium responders, plasma 27-hydroxycholestero l concentrations and hepatic sterol 27-hydroxylase mRNA levels increas ed rapidly during the first 10 weeks, declined thereafter, and stabili zed at 26 weeks in low responders and at 40 weeks in medium responders . In high responders, plasma 27-hydroxycholesterol concentration did n ot increase. The increases in hepatic sterol 27-hydroxylase mRNA and p lasma 27-hydroxycholesterol in medium responders were intermediate bet ween those in high- and low-responding baboons. The expression of hepa tic mRNA for other cholesterol-responsive genes did not differ between high and low-responding baboons. Plasma LDL cholesterol concentration s were negatively correlated with plasma 27-hydroxycholesterol concent rations and hepatic sterol n-hydroxylase mRNA levels when the animals had been on the HCHF diet for 10 weeks. These studies suggest that hep atic sterol 27-hydroxylase may be an important regulator of responsive ness to dietary cholesterol and fat in baboons.