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Cholesterol metabolism in cells with different peroxisomal defects
K Oettl1, E Malle, H Grillhofer
1Institute for Medical Chemistry, Karl Franzens University Graz, Austria.
Summary
Peroxisomal disorders impair cholesterol ester formation in skin cells, even when cholesterol biosynthesis is suppressed. This suggests altered cholesterol homeostasis in these metabolic diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Disorders
Background:
- Cholesterol biosynthesis is elevated in peroxisomal disease fibroblasts before mevalonate.
- Low-density-lipoprotein (LDL) receptor activity is comparable in normal and peroxisomal-defective fibroblasts.
Purpose of the Study:
- To investigate the effect of lovastatin on 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity in peroxisomal-defective cells.
- To examine intracellular cholesteryl ester formation, an indicator of acyl-CoA:cholesterol acyltransferase (ACAT) activity, stimulated by exogenous LDL.
Main Methods:
- Studied lovastatin suppression of cholesterol biosynthesis in dermal fibroblasts and Chinese hamster ovary (CHO) cells lacking peroxisomes.
- Measured ACAT activity using [3H]oleate as a substrate for cholesterol ester synthesis, in the presence and absence of exogenous LDL.
Main Results:
- Lovastatin dose-dependently suppressed cholesterol biosynthesis similarly in normal and peroxisomal-defective fibroblasts.
- Basal esterification rates were similar or lower in defective cells.
- Cholesterol esterification was significantly impaired in defective cells when stimulated by exogenous LDL.
Conclusions:
- Cholesterol homeostasis changes in peroxisomal disease fibroblasts may be linked to impaired cholesterol ester formation.
- ACAT activity is affected in peroxisomal disorders, impacting cholesterol metabolism.