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

• Published in: American journal of physiology: endocrinology and metabolism 2023-02, Vol.324 (2), p.E120-E134
• Main Authors: Ali Mondal, Samim, Sathiaseelan, Roshini, Mann, Shivani N, Kamal, Maria, Luo, Wenyi, Saccon, Tatiana D, Isola, José V V, Peelor, 3rd, Frederick F, Li, Tiangang, Freeman, Willard M, Miller, Benjamin F, Stout, Michael B
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Animals; Carbon tetrachloride; Cell activation; Coenzyme A; Collagen; Collagen - metabolism; Cross-linking; Crosslinking; Degradation; Desaturase; Estradiol - metabolism; Estradiol - pharmacology; Estrogens; Female; Fibrosis; Gelatinase A; Growth factors; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatocytes; Hormone replacement therapy; Immune system; Inflammation; Life span; Liver; Liver - metabolism; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver diseases; Longevity; Lysyl oxidase; Macrophages; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix metalloproteinases; Metalloproteinase; Mice; Polarity; Proteins; Sex hormones; Signaling; Synthesis; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1; Turnover rate
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00256.2022

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 (CCl )-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.