Hepatic uptake and metabolism of ingested 24-hydroxycholesterol and 24(S),25-epoxycholesterol

Although two hepatic sterol metabolites, 24(S)-hydroxycholesterol and 24(S),25-epoxycholesterol, are thought to be important regulators of cholesterol biosynthesis, nothing is known of their degradation and disposal in liver, nor of the mechanisms that regulate their levels. As an initial approach to these questions the two sterols were administered intragastrically, as a bolus, to mice and their hepatic accumulation and conversion to more polar compounds were examined as a function of time. These results were compared to those obtained for cholesterol and for the unnatural epimer of one of the oxysterols, 24(R)-hydroxycholesterol. Maximum concentrations of the three oxysterols in liver were reached by approx. 4 h and then declined to control levels by 8 h. More polar neutral and acidic metabolites were found in the liver extracts. Radiolabeled oxysterols and their metabolites were found in bile glands. In comparison, the amounts of hepatic free and esterified cholesterol and of acidic products formed from it increased gradually over the measured period of time. Rates of conversion of the two 24-hydroxycholesterol epimers into acidic compounds by a liver mitochondrial fraction in vitro exceeded those of 24(S),25-epoxycholesterol and cholesterol. 24(S)-Hydroxycholesterol did not lower the level of hepatic HMG-CoA reductase activity, consistent with the absence of any significant accumulation of the free sterol. Accumulation of appreciable amounts of free 24(S),25-epoxycholesterol was associated with lowered levels of reductase. The existence of hepatic systems for the rapid inactivation and degradation of the oxysterols is consistent with their postulated role in the regulation of cholesterol synthesis.