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

Author:

Ali Mondal Samim1,Sathiaseelan Roshini12,Mann Shivani N.3,Kamal Maria4,Luo Wenyi4,Saccon Tatiana D.1,Isola José V. V.1,Peelor Frederick F.1,Li Tiangang5,Freeman Willard M.67,Miller Benjamin F.17ORCID,Stout Michael B.17ORCID

Affiliation:

1. Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma

2. Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

3. Department of Neuroscience, University of Arizona, Tucson, Arizona

4. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

5. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

6. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma

7. Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma

Abstract

Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17β-estradiol (17β-E2) or combination hormone replacement therapies. We sought to determine if 17α-estradiol (17α-E2), a naturally occurring diastereomer of 17β-E2, could attenuate liver fibrosis. We evaluated the effects of 17α-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 17α-E2 on markers of hepatic stellate cell (HSC) activation, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17α-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor β1 (TGF-β1) 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 17α-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-β1 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17α-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17α-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits.

Funder

HHS | NIH | National Institute on Aging

U.S. Department of Veterans Affairs

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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