Cholesterol and prostaglandin synthesis by cultured human skin fibroblasts in the Alagille syndrome involving paucity of interlobular bile ducts.

Children with Alagille syndrome show high serum cholesterol (15-20 mmol/L). To establish correlation of this unusual level of cholesterol with the regulation of cholesterol metabolism, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity and synthesis of cholesterol, fatty acids and acidic steroids from [14C]acetate were determined in cultured skin fibroblasts from 2-3 year old children. Prostaglandin E2 (PGE2) synthesis and nucleic acid synthesis were determined in cells when they were growing in medium containing normal, Alagille or fetal bovine serum. These values were similar to values of controls. HMGR activity was found to be similar in cells of control and children with the syndrome, whether the cells were incubated in lipoprotein-deficient or normal medium. Incorporation of acetate into cholesterol was inhibited to a greater extent by lipoprotein-containing medium in control than in children with the syndrome. Fatty acid synthesis was similar in all conditions. 1-7% of the recovered lipid radioactivity in cells and medium separated as acidic steroids. Serum from a donor patient, when included in the medium, did not affect PGE2 or nucleic acid synthesis compared with normal human or fetal bovine serum. The data suggest that cells of children with Alagille syndrome may have a membrane defect of transfer of cholesterol (LDL receptor defect) leading to excessive cholesterol synthesis. Also, synthesis of acidic steroids (bile acid-like material) and their secretion into the medium occurs in normal fibroblasts and those from children with the syndrome.