DIETARY-CHOLESTEROL AND DOWN-REGULATION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE AND CHOLESTEROL ABSORPTION IN AFRICAN-GREEN MONKEYS

In this study, hepatic production of bile acid was considered together with intestinal cholesterol absorption as potential regulatory sites responsive to dietary cholesterol. Sequential liver biopsies were take n from 45 feral African green monkeys studied during three different d iet periods. Low-fat Monkey Chow was fed during the baseline period, a cholesterol and fat-enriched diet was then fed for 12 wk during perio d 2, and finally, after a washout period of 10 wk, three subgroups wer e fed low-, moderate-, and high-cholesterol diets for 12 mo during per iod 3. The percentage of cholesterol absorbed in the intestine was sig nificantly lower when higher levels of cholesterol were fed; however, this percentage was significantly and positively correlated to plasma cholesterol concentration at each dietary cholesterol level. Hepatic f ree and esterified cholesterol content were significantly elevated by dietary cholesterol challenge and remained elevated even after 20 wk o f low-cholesterol diets. Hepatic mRNA abundance for cholesterol 7 alph a-hydroxylase (C7H) was significantly lower (similar to 60%) when the high-cholesterol diet was fed, with the decrease being greater than th at seen for low density lipoprotein (LDL) receptor mRNA. At the same t ime, hepatic mRNA abundance for apolipoprotein B and hepatic lipase we re not diet sensitive. C7H activity was decreased to a similar extent by diet as was C7H mRNA, although the correlation between enzyme activ ity and mRNA abundance was only r = 0.5, suggesting that dietary regul ation includes factors in addition to transcriptional regulation. Acti vity and mRNA abundance of C7H remained decreased when liver esterifie d cholesterol content was reduced to only a two- to three-fold elevati on over baseline, at a time when plasma cholesterol and hepatic LDL re ceptor mRNA abundance had returned to baseline levels. These data on l iver C7H, obtained in one of the few primate species predisposed to ch olesterol gallstone formation, support the hypothesis that the liver m ay attempt to downregulate intestinal cholesterol absorption by decrea sing bile acid production when increased amounts of absorbed dietary c holesterol reach the Liver. Presumably this represents attempted downr egulation of intestinal cholesterol absorption by limiting bile acid a vailability as a means to maintain hepatic cholesterol balance.