SEX STEROIDS INCREASE CHOLESTEROL 7-ALPHA-HYDROXYLASE MESSENGER-RNA IN NONHUMAN-PRIMATES

One mechanism that may account for our prior observation that oral con traceptives decrease the hepatic cholesterol concentration independent ly of the low-density lipoprotein (LDL) receptor in sexually intact no nhuman primates is that sex hormones increase biliary cholesterol secr etion by increasing hepatic mRNA abundance for cholesterol 7 alpha-hyd roxylase, the rate-limiting enzyme in the conversion of cholesterol in to bile acids. To examine the independent effect of estrogen, progesti n, and combined estrogen and progestin on the hepatic cholesterol conc entration and cholesterol 7 alpha-hydroxylase mRNA abundance, 34 ovari ectomized adult female cynomolgus monkeys were fed a moderately athero genic diet for 12 weeks with either oral conjugated equine estrogen ([ CEE] n = 8), medroxyprogesterone acetate ([MPA] n = 9), or combined CE E + MPA (n = 9) and compared with a control group (n = 8) that did not receive exogenous sex hormones. After 12 weeks, hepatic cholesterol w as significantly lower in GEE-treated (6.2 +/- 1.2 mg/g liver) and CEE + MPA-treated (6.4 +/- 0.9 mg/g liver) animals compared with the cont rol (12.6 +/- 1.9 mg/g liver) and MPA-treated (14.6 +/- 1.6 mg/g liver ) groups, Hepatic cholesterol 7 alpha-hydroxylase mRNA abundance was s ignificantly increased in GEE-treated (0.553 +/- 0.08 pg/mu g RNA), MP A-treated (0.734 +/- 0.12 pg/mu g RNA), and GEE + MPA-treated (0.487 /- 0.07 pg/mu g RNA) animals compared with the controls (0.318 +/- 0.0 3 pg/mu g RNA), There was no significant difference in the plasma LDL cholesterol concentration and hepatic LDL receptor mRNA abundance betw een the groups, These data support but do not prove the hypothesis tha t low-dose oral estrogen induces an increase in cholesterol 7 alpha-hy droxylase mRNA abundance, which is correlated with biliary cholesterol secretion and may result in depletion of hepatic cholesterol. Copyrig ht (C) 1998 by W.B. Saunders Company.