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Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation
P Lettéron1, N Brahimi-Bourouina, M A Robin
1Institut National de la Santé et de la Recherche Médicale U. 24, Clichy, France.
Abstract:
Glucocorticoid administration may produce fatty liver in humans. We investigated the effects of dexamethasone on hepatic mitochondria and lipid metabolism in mice. Dexamethasone 21-phosphate (20 microM) did not inhibit the mitochondrial inner membrane-bound very-long-chain acyl-CoA dehydrogenase but inhibited the matrixlocated long-, medium-, and short-chain dehydrogenases. Dexamethasone 21-phosphate (20 microM) inhibited the first beta-oxidation cycle of [1-(14C)]butyric acid and [1-(14C)]octanoic acid but not that of [1-(14C)]palmitic acid. Administration of dexamethasone 21-phosphate (100 mg/kg) decreased the in vivo oxidation of [1-(14C)]butyric acid and [1-(14C)]octanoic acid into [14C]CO2 but not that of [1-(14C)]palmitic acid and decreased the hepatic secretion of triglycerides. After 5 days of treatment (100 mg/kg daily), hepatic triglycerides were increased and both microvesicular steatosis and ultrastructural mitochondrial lesions were present. In conclusion, glucocorticoids inhibit medium- and short-chain acyl-CoA dehydrogenation and hepatic lipid secretion in mice. These effects may account for their steatogenic effects in humans.
Insights
Glucocorticoids like dexamethasone impair fatty acid metabolism in mice, inhibiting key enzymes and reducing triglyceride secretion. This leads to fatty liver, explaining their steatogenic effects in humans.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Glucocorticoid administration is linked to fatty liver development in humans.
- Understanding the molecular mechanisms behind glucocorticoid-induced steatosis is crucial.
Purpose of the Study:
- To investigate the effects of dexamethasone on hepatic mitochondria and lipid metabolism in mice.
- To elucidate the role of specific acyl-CoA dehydrogenases in glucocorticoid-induced fatty liver.
Main Methods:
- In vitro enzyme inhibition assays using dexamethasone 21-phosphate.
- In vivo studies measuring fatty acid oxidation and triglyceride secretion in mice treated with dexamethasone.
- Histopathological and ultrastructural analysis of liver tissues.
Main Results:
- Dexamethasone 21-phosphate inhibited matrix-located long-, medium-, and short-chain acyl-CoA dehydrogenases, but not very-long-chain acyl-CoA dehydrogenase.
- Dexamethasone inhibited the beta-oxidation of short- and medium-chain fatty acids, but not long-chain fatty acids.
- In vivo, dexamethasone decreased the oxidation of short- and medium-chain fatty acids and reduced hepatic triglyceride secretion. Chronic treatment led to increased hepatic triglycerides, microvesicular steatosis, and mitochondrial damage.
Conclusions:
- Glucocorticoids, exemplified by dexamethasone, inhibit medium- and short-chain acyl-CoA dehydrogenation in the liver.
- These inhibitory effects on fatty acid metabolism and reduced hepatic lipid secretion contribute to the steatogenic (fatty liver-inducing) effects observed in humans.