Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice

Hepatic steatosis is a frequent complication in nonobese patients with brea st cancer treated with tamoxifen, a potent antagonist of estrogen. In addit ion, hepatic steatosis became evident spontaneously in the aromatase-defici ent (ArKO) mouse, which lacks intrinsic estrogen production. These clinical and laboratory observations suggest that estrogen helps to maintain consti tutive lipid metabolism. To clarify this hypothesis, me characterized the e xpression and activity in ArKO mouse liver of enzymes involved in peroxisom al and mitochondrial fatty acid beta-oxidation. Northern analysis showed re duced expression of mRNAs for very long fatty acyl-CoA synthetase, peroxiso mal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase, enzyme s required in fatty acid beta-oxidation. In vitro assays of fatty acid beta -oxidation activity using very long (C24:0), long (C16:0), or medium (C12:0 ) chain fatty acids as the substrates confirmed that the corresponding acti vities are also diminished. Impaired gene expression and enzyme activities of fatty acid beta-oxidation were restored to the wild-type levels, and hep atic steatosis was substantially diminished in animals treated with 17 beta -estradiol. Wild-type and ArKO mice showed no difference in the binding act ivities of the hepatic nuclear extracts to a peroxisome proliferator respon se element. These findings demonstrate the pivotal role of estrogen in supp orting constitutive hepatic expression of genes involved in lipid beta-oxid ation and in maintaining hepatic lipid homeostasis.