17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice

• DOI: 10.1101/2022.06.16.496423
• Publication Date: 2022-06-17T15:00:41Z
• Authors: Samim Ali Mondal; Roshini Sathiaseelan; Shivani N. Mann; Maria Kamal; Wenyi Luo; Tatiana D. Saccon; José V.V. Isola; Frederick F. Peelor; Tiangang Li; Willard M. Freeman; Benjamin F. Miller; Michael B. Stout
• Keywords: Hepatic stellate cell; MMP2; Lysyl Oxidase; Hepatic fibrosis

ABSTRACT Background Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for treatment with 17β-estradiol (17β-E2) or combination hormone replacement therapies. We sought to determine if 17α-estradiol (17α-E2), naturally-occurring diastereomer 17β-E2, could attenuate fibrosis. Methods evaluated the effects 17α-E2 on collagen synthesis degradation rates using tracer-based labeling approaches in male mice subjected carbon tetrachloride (CCl 4 )-induced also assessed markers hepatic stellate cell (HSC) activation, crosslinking, degradation, macrophage content polarity. Findings found that significantly reduced increased rates, which was mirrored by declines transforming growth factor β1 (TGF-β1) lysyl oxidase-like 2 (LOXL2) protein liver. These improvements were associated matrix metalloproteinase (MMP2) activity suppressed stearoyl-coenzyme A desaturase 1 (SCD1) levels, latter has been linked resolution fetuin-A protein, strong inhibitor TGF-β1 signaling, pro-inflammatory activation cytokines expression Interpretation conclude reduces fibrotic burden suppressing HSC enhancing mechanisms. Future studies will be needed acts directly hepatocytes, HSCs, and/or immune cells elicit these benefits. Funding This work supported US National Institutes Health Department Veterans Affairs. RESEARCH IN CONTEXT Evidence before this study The prevalence severity diseases greater than twice as likely die from diseases. However, nonalcoholic fatty disease (NAFLD), steatohepatitis (NASH), fibrosis becomes comparable between sexes following menopause, particularly when therapies (HRT) not initiated. observations suggest estrogen onset progression, rodents demonstrating ameliorates steatosis fibrogenesis. administration 17β-E2 HRTs unrealistic due feminization risk stroke prostate cancer, female population at an breast cancer cardiovascular events HRTs. Therefore, we have begun exploring therapeutic potential naturally-occurring, nonfeminizing, Added value In study, CCl -induced fibrosis, show attenuating Both 17α-E2. cytokine Implications all available evidence supports idea estrogens may utility