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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice
Abstract:
Hepatic steatosis is a frequent complication in nonobese patients with breast cancer treated with tamoxifen, a potent antagonist of estrogen. In addition, hepatic steatosis became evident spontaneously in the aromatase-deficient (ArKO) mouse, which lacks intrinsic estrogen production. These clinical and laboratory observations suggest that estrogen helps to maintain constitutive lipid metabolism. To clarify this hypothesis, we characterized the expression and activity in ArKO mouse liver of enzymes involved in peroxisomal and mitochondrial fatty acid beta-oxidation. Northern analysis showed reduced expression of mRNAs for very long fatty acyl-CoA synthetase, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase, enzymes 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 activities are also diminished. Impaired gene expression and enzyme activities of fatty acid beta-oxidation were restored to the wild-type levels, and hepatic steatosis was substantially diminished in animals treated with 17beta-estradiol. Wild-type and ArKO mice showed no difference in the binding activities of the hepatic nuclear extracts to a peroxisome proliferator response element. These findings demonstrate the pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in lipid beta-oxidation and in maintaining hepatic lipid homeostasis.
Insights
Estrogen supports healthy liver fat metabolism by regulating fatty acid oxidation. This study shows estrogen deficiency impairs lipid metabolism, leading to hepatic steatosis, which is reversible with estrogen treatment.
Area of Science:
- Biochemistry
- Endocrinology
- Hepatology
Background:
- Hepatic steatosis is a common side effect of tamoxifen treatment in breast cancer patients.
- Aromatase-deficient (ArKO) mice spontaneously develop hepatic steatosis, suggesting a role for endogenous estrogen in lipid metabolism.
Purpose of the Study:
- To investigate the role of estrogen in regulating hepatic lipid metabolism.
- To characterize the impact of estrogen deficiency on fatty acid beta-oxidation pathways in the liver.
Main Methods:
- Gene expression analysis (Northern blot) of key fatty acid beta-oxidation enzymes in ArKO mice.
- In vitro enzyme activity assays for peroxisomal and mitochondrial fatty acid beta-oxidation.
- Assessment of hepatic steatosis and gene/enzyme activity restoration following 17beta-estradiol treatment.
Main Results:
- ArKO mice exhibited reduced mRNA expression and enzyme activity of fatty acid beta-oxidation enzymes.
- Impaired fatty acid beta-oxidation and hepatic steatosis in ArKO mice were normalized by 17beta-estradiol administration.
- Estrogen deficiency did not affect binding activity to the peroxisome proliferator response element.
Conclusions:
- Estrogen is crucial for maintaining constitutive hepatic expression of genes involved in lipid beta-oxidation.
- Estrogen plays a vital role in preserving hepatic lipid homeostasis.
- Estrogen replacement therapy may be a strategy to mitigate tamoxifen-induced hepatic steatosis.
