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Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity
Yukio Yamamoto1, Rick Moore, Holly A Hess
1Laboratories of Reproductive and Developmental Toxicology, NIEHS/National Institutes of Health, Research Triangle Park, NC 27709, USA.
The Journal of Biological Chemistry
|April 12, 2006
Summary
Estrogen receptor alpha (ERalpha) mediates estrogen-induced liver injury by repressing bile acid transporters and altering bile acid synthesis. Mice lacking ERalpha were protected from estrogen toxicity, highlighting ERalpha
Area of Science:
- Hepatology
- Endocrinology
- Toxicology
Background:
- Estrogens can cause liver damage (hepatotoxicity), including intrahepatic cholestasis.
- Nuclear receptors like FXR, PXR, and CAR are crucial for liver protection and bile acid balance.
- The specific nuclear receptor involved in estrogen-induced hepatotoxicity remained unidentified.
Purpose of the Study:
- To investigate the role of nuclear receptors, particularly estrogen receptors (ERalpha and ERbeta), in estrogen-induced hepatotoxicity.
- To elucidate the molecular mechanisms by which estrogens cause liver damage.
Main Methods:
- Utilized knockout mice lacking estrogen receptor alpha (Era(-/-)), estrogen receptor beta (Erb(-/-)), farnesoid X receptor (Fxr(-/-)), pregnane X receptor (Pxr(-/-)), and constitutive active/androstane receptor (Car(-/-)).
- Administered synthetic estrogen 17alpha-ethynylestradiol (EE2) to these mice and assessed for hepatotoxic phenotypes.
- Analyzed the expression of genes involved in bile acid and cholesterol transport and bile acid synthesis.
Main Results:
- Era(-/-) mice were resistant to EE2-induced hepatotoxicity, showing no hepatomegaly, elevated serum bile acids, or liver inflammation.
- EE2 treatment repressed the expression of key bile acid and cholesterol transporters (BSEP, NTCP, OATP1, OATP2, ABCG5, ABCG8) in wild-type mice, but not in Era(-/-) mice.
- ERalpha modulated bile acid synthesis pathways by up-regulating CYP7B1 and down-regulating CYP7A1 and CYP8B1, leading to increased beta-muricholic acid levels. ERbeta, FXR, PXR, and CAR were not implicated.
Conclusions:
- Estrogen receptor alpha (ERalpha) plays a critical role in mediating estrogen-induced hepatotoxicity.
- ERalpha-dependent repression of hepatic transporters and alterations in bile acid biosynthesis contribute to liver injury caused by estrogens like EE2.
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