17?-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM(2023)
摘要
Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17I3-estradiol (17I3-E2) or combination hormone replacement therapies. We sought to determine if 17a- estradiol (17a-E2), a naturally occurring diastereomer of 17I3-E2, could attenuate liver fibrosis. We evaluated the effects of 17a-E2 treatment on collagen synthesis and degradation rates using tracer-based labeling approaches in male mice subjected to carbon tetrachloride (CCl4)-induced liver fibrosis. We also assessed the effects of 17a-E2 on markers of hepatic stellate cell (HSC) activa-tion, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17a-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor I31 (TGF-I31) and lysyl oxidase-like 2 (LOXL2) protein content in liver. These improvements were associated with increased matrix metalloproteinase 2 (MMP2) activity and suppressed stearoyl-coenzyme A desaturase 1 (SCD1) protein levels, the latter of which has been linked to the resolution of liver fibrosis. We also found that 17a-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-I31 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17a-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mecha-nisms. Future studies will be needed to determine if 17a-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits.
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关键词
carbon tetrachloride,hepatic stellate cells,nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,transforming growth fac-tor?1
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