The recent finding by our group that 26-hydroxycholesterol is normally present in adult plasma and is markedly reduce in amount in individuals with the genetically determined disease, Cerebrotendinous Xanthomatosis leads us to explore further the concept that oxygenated sterols may be part of the mechanism for in vivo regulation of cholesterol synthesis and tissue distribution. Our proposed studies will be done using (1) the Chinese Hamster Ovary Cell Culture Model, (2) a hamster and rat model (3) kinetic studies in nonhuman primates and (4) biliary secretion and intestinal absorption studies in humans. Also, we will seek to identify the presence of Cerebrotendinous Xanthomatosis in a population of children with the recent onset of unexplained neurologic (ataxic) disease. In cell culture we will compare the inhibitory effect of 26-hydroxycholesterol on HMG Co A reductase activity to its naturally occurring metabolites (7Alpha, 26-hydroxycholesterol, 3Beta-hydroxy-cholesten-5-oic acid, 3Beta-hydroxy-cholen-5-oic acid). In rats and hamsters we will correlate the concentration of 26-hydroxycholesterol in the liver with the rate of cholesterol synthesis and attempt to identify newly synthesized 26-hydroxycholesterol derived from the newly synthesized cholesterol using acteate-1-14C and mevalonate-5-13C. In the baboon, we will determine the 1/2-life, volume of distribution and synthesis rate of 26-hydroxycholesterol and the effect of a pharmacologic dose on cholesterol synthesis using isotope dilution techniques. In man, we will determine biliary secretion and intestinal absorption rates with triple lumen intubation technology. The findings in these studies will provide a complete evaluation of the role of the side chain pathway of cholesterol oxidation in the regulation of cholesterol synthesis. Data on the synthesis rate, turnover, volume of distribution, biliary excretion and reabsorption of 26-hydroxycholesterol in primates will be established.
| Esterman, A L; Cohen, B I; Javitt, N B (1985) Cholesterol metabolism: use of D2O for determination of synthesis rate in cell culture. J Lipid Res 26:950-4 |
