CAFESTOL, THE CHOLESTEROL-RAISING FACTOR IN BOILED COFFEE, SUPPRESSESBILE-ACID SYNTHESIS BY DOWN-REGULATION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE AND STEROL 27-HYDROXYLASE IN RAT HEPATOCYTES

Consumption of boiled coffee raises serum cholesterol levels in humans . The diterpenes cafestol and kahweol in boiled coffee have been found to be responsible for the increase. To investigate the biochemical ba ckground of this effect, we studied the effects of cafestol and a mixt ure of cafestol/kahweol/isokahweol (48:47:5 w/w) on bile acid synthesi s and cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase in cul tured rat hepatocytes. Dose-dependent decreases of bile acid mass prod uction and cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase a ctivity were found, showing a maximal reduction of -91%, -79%, and -49 % respectively, at a concentration of 20 mu g/mL cafestol. The decreas e in 7 alpha-hydroxylase and 27-hydroxylase activity paralleled well t he suppression of the respective mRNAs, being -79% and -77%, and -49% and -46%, respectively, at 20 mu g/mL cafestol. Run-on data showed a r eduction in 7 alpha-hydroxylase and 27-hydroxylase gene transcriptiona l activity after incubation with cafestol. The mixture of cafestol/kah weol/isokahweol was less potent in suppression of bile acid synthesis and cholesterol 7 alpha-hydroxylase. Cafestol (20 mu g/mL) had no effe ct on lithocholic acid 6 beta-hydroxylase mRNA, another enzyme involve d in bile acid synthesis. LDL-receptor, HMG-CoA reductase, and HMG-CoA synthase mRNAs were significantly decreased by cafestol (-18%, -20%, and -43%, respectively). We conclude that cafestol suppresses bile aci d synthesis by downregulation of cholesterol 7 alpha-hydroxylase and o f, to a lesser extent, sterol 27-hydroxylase in cultured rat hepatocyt es, whereas kahweol and isokahweol are less active. We suggest that su ppression of bile acid synthesis may provide an explanation for the ch olesterol-raising effect of cafestol in humans.