GLUCOCORTICOIDS INHIBIT MITOCHONDRIAL MATRIX ACYL-COA DEHYDROGENASES AND FATTY-ACID BETA-OXIDATION

Glucocorticoid administration may produce fatty liver in humans. We in vestigated the effects of dexamethasone on hepatic mitochondria and li pid metabolism in mice. Dexamethasone 21-phosphate (20 mu M) did not i nhibit the mitochondrial inner membrane-bound very-long-chain acyl-CoA dehydrogenase but inhibited the matrix-located long-, medium-, and sh ort-chain dehydrogenases. Dexamethasone 21-phosphate (20 mu M) inhibit ed the first beta-oxidation cycle of [1-C-14]butyric acid and [1-C-14] octanoic acid but not that of [1-C-14]palmitic acid. Administration of dexamethasone 21-phosphate (100 mg/kg) decreased the in vivo oxidatio n of [1-C-14]butyric acid and [1-C-14]octanoic acid into [C-14]CO2 but not that of [1-C-14]palmitic acid and decreased the hepatic secretion of triglycerides. After 5 days of treatment (100 mg/kg daily), hepati c triglycerides were increased and both microvesicular steatosis and u ltrastructural mitochondrial lesions were present. In conclusion, gluc ocorticoids inhibit medium- and short-chain acyl-CoA dehydrogenation a nd hepatic lipid secretion in mice. These effects may account for thei r steatogenic effects in humans.