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We sought to determine if 17\u03b1-estradiol (17\u03b1-E2), a naturally occurring diastereomer of 17\u03b2-E2, could attenuate liver fibrosis. We evaluated the effects of 17\u03b1-E2 treatment on collagen synthesis and degradation rates using tracer-based labeling approaches in male mice subjected to carbon tetrachloride (CCl\n                    <jats:sub>4<\/jats:sub>\n                    )-induced liver fibrosis. We also assessed the effects of 17\u03b1-E2 on markers of hepatic stellate cell (HSC) activation, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17\u03b1-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor \u03b21 (TGF-\u03b21) 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 17\u03b1-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-\u03b21 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17\u03b1-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17\u03b1-E2 acts directly in hepatocytes, HSCs, and\/or immune cells to elicit these benefits.\n                  <\/jats:p>","DOI":"10.1152\/ajpendo.00256.2022","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T17:39:15Z","timestamp":1671039555000},"page":"E120-E134","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["17\u03b1-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice"],"prefix":"10.1152","volume":"324","author":[{"given":"Samim","family":"Ali Mondal","sequence":"first","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshini","family":"Sathiaseelan","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma"},{"name":"Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivani N.","family":"Mann","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Arizona, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kamal","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana D.","family":"Saccon","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 V. 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