Cholesterol metabolism in the brain: importance of 24S-hydroxylation

During the last three to four decades there has been an increasing interest in the interaction of circulating and brain cholesterol. Recent in vivo and in vitro studies have furthered our knowledge of cholesterol metabolism in the central nervous system (CNS). As the CNS matures and cholesterol pools in the brain become constant, the rate of de novo synthesis of cholesterol in the brain markedly declines. Besides some excretion of apoE-bound cholesterol via the CSF, another quantitatively more important mechanism has been described - the conversion of cholesterol into 24S-hydroxycholesterol, that is, in contrast to cholesterol, able to traverse the blood-brain barrier (BBB). The enzyme (CYP46a1) mediating this conversion has been characterized at the molecular level and is mainly located in neurons. Like other oxysterols, 24S-hydroxycholesterol is efficiently converted into normal bile acids or excreted in bile in its sulfated and glucuronidated form. Within the last 10 years the interest in studying the mechanisms of this and other cholesterol transport systems has increased and the results from these in vivo and in vitro investigations are reviewed.