Cholesterol metabolism in cells with different peroxisomal defects.
We showed previously that cholesterol biosynthesis in dermal fibroblasts from patients with metabolic disorders of peroxisomal origin is increased in steps prior to mevalonate, whereas low-density-lipoprotein(LDL)-receptor activities were not different from control fibroblasts. Here, the suppression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by lovastatin was studied both in dermal fibroblasts from patients with different peroxisomal defects and in a Chinese hamster ovary (CHO) cell line lacking morphologically intact peroxisomes. In addition, the formation of intracellular cholesteryl esters (a measure of acyl-CoA:cholesterol acyltransferase(ACAT)-activity) stimulated by exogenous LDL was investigated. A dose-dependent suppression of cholesterol biosynthesis by lovastatin at concentrations of 1-50 mumol/l was observed which was comparable in normal and peroxisomal-disease fibroblasts. ACAT activity was measured in the absence and presence of exogenous LDL using [3H]oleate as a substrate for cholesterol ester synthesis. The basal esterification rate was equal or lower in peroxisomal-defective fibroblasts compared with controls. In the presence of exogenous LDL, cholesterol esterification was significantly impaired in all defective cells in comparison with normal fibroblasts. We conclude that changes in cholesterol homeostasis in peroxisomal diseased fibroblasts be related to cholesterol ester formation.
Oettl
K
K
Institute for Medical Chemistry, Karl Franzens University Graz, Austria.
Malle
E
E
Grillhofer
H
H
Sattler
W
W
Kostner
G M
GM
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016466:CHO Cells; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins / Q000096:biosynthesis; D008148:Lovastatin / Q000494:pharmacology; D019301:Oleic Acid / Q000378:metabolism; D018901:Peroxisomal Disorders / Q000201:enzymology / Q000378:metabolism*
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D019301:Oleic Acid; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases