From brain to bile - Evidence that conjugation and omega-hydroxylation areimportant for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans

The brain is the almost exclusive site of formation of 24S-hydroxycholester ol in man, and there is a continuous flux of this oxysterol across the bloo d-brain barrier into the circulation. The hepatic metabolism of 24S-hydroxy cholesterol was studied here by three different approaches: incubation of t ritium-labeled 24S-hydroxycholesterol with human primary hepatocytes, admin istration of tritium-labeled 24S-hydroxycholesterol to a human volunteer, a nd quantitation of free and conjugated 24S-hydroxycholesterol and its neutr al metabolites in ileocecal fluid from patients with ileal fistulae. 24S-Hy droxycholesterol as well as 24R-hydroxycholesterol were converted into bile acids by human hepatocytes at a rate of about 40% of that of the normal in termediate in bile acid synthesis, 7 alpha -hydroxycholesterol. There was a lso a conversion of 24S-hydroxycholesterol into conjugate(s) of 5-cholesten e-3 beta ,24S,27-triol at a rate similar to the that of conversion into bil e acids. When administered to a human volunteer, labeled 24S-hydroxycholest erol was converted into bile acids at about half the rate of simultaneously administered labeled 7 alpha -hydroxycholesterol. Free, sulfated, and gluc uronidated 24S-hydroxycholesterol and 5-cholestene-3 beta ,24,27-triol were identified in ileocecal fluid. The excretion of these steroids was about 3 .5 mg/24 h, amounting to more than 50% of the total estimated flux of 24S-h ydroxycholesterol from the brain. It is concluded that 24S-hydroxycholester ol is a less efficient precursor to bile acids and that about half of it is conjugated and eliminated in bile as such or as a conjugate of a 27-hydrox ylated metabolite. The less efficient metabolism of 24S-hydroxycholesterol may explain the surprisingly high levels of this oxysterol in the circulati on and is of interest in relation to the suggested role of 24S-hydroxychole sterol as a regulator of cholesterol homeostasis.