RT Journal Article
SR Electronic
T1 17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.16.496423
DO 10.1101/2022.06.16.496423
A1 Samim Ali Mondal
A1 Roshini Sathiaseelan
A1 Shivani N. Mann
A1 Maria Kamal
A1 Wenyi Luo
A1 Tatiana D. Saccon
A1 José V.V. Isola
A1 Frederick F. Peelor III
A1 Tiangang Li
A1 Willard M. Freeman
A1 Benjamin F. Miller
A1 Michael B. Stout
YR 2022
UL http://biorxiv.org/content/early/2022/06/17/2022.06.16.496423.abstract
AB Background 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.Methods 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 crosslinking, collagen degradation, and liver macrophage content and polarity.Findings 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 pro-inflammatory macrophage activation and cytokines expression in the liver.Interpretation 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.Funding This work was supported by the US National Institutes of Health and US Department of Veterans Affairs.Evidence before this study The prevalence and severity of chronic liver diseases are greater in men than women and men are twice as likely to die from chronic liver diseases. However, the prevalence and severity of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and liver fibrosis becomes comparable between the sexes following menopause, particularly when hormone replacement therapies (HRT) are not initiated. These observations suggest that estrogen signaling is protective against liver disease onset and progression, which is supported by studies in rodents demonstrating that 17β-estradiol (17β-E2) ameliorates hepatic steatosis and fibrogenesis. However, chronic administration of 17β-E2 or combination HRTs are unrealistic in men due to feminization and increased risk for stroke and prostate cancer, and a subset of the female population are also at an increased risk for breast cancer and cardiovascular events when on HRTs. Therefore, we have begun exploring the therapeutic potential of 17α-estradiol (17α-E2), a naturally-occurring, nonfeminizing, diastereomer of 17β-E2, for the treatment of liver diseases.Added value of this study In this study, using tracer-based labeling approaches in male mice subjected to CCl4-induced liver fibrosis, we show that 17α-E2 reduces liver fibrosis by attenuating collagen synthesis and enhancing collagen degradation mechanisms. Both transforming growth factor β1 (TGF-β1) and lysyl oxidase-like 2 (LOXL2) protein content in liver were reduced by 17α-E2. We also found that 17α-E2 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 pro-inflammatory macrophage activation and cytokine expression in the liver.Implications of all the available evidence This study supports the idea that estrogens are protective against chronic liver diseases and that 17α-E2 may have therapeutic utility for the treatment of liver fibrosis.Competing Interest StatementThe authors have declared no competing interest.