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Sathiaseelan, R.

Publications and source records attributed to Sathiaseelan, R..

3 recordsLinked to original sources
bioRxiv2023

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17-estradiol (17-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor is required for the majority of 17-E2-mediated benefits in male mice, but that 17-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor {beta} (ER{beta})-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17-E2-mediated benefits on systemic and hepatic metabolism are ER{beta}-dependent. We found that 17-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ER{beta}KO mice. ER{beta} ablation in male mice attenuated 17-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor {beta}1 (TGF-{beta}1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ER{beta} partially controls 17-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17-E2 likely signals through ER{beta} in HSCs to attenuate pro-fibrotic mechanisms.

physiology↗
bioRxiv2022

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

BackgroundEstrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17{beta}-estradiol (17{beta}-E2) or combination hormone replacement therapies. We sought to determine if 17-estradiol (17-E2), a naturally-occurring diastereomer of 17{beta}-E2, could attenuate liver fibrosis. MethodsWe evaluated the effects of 17-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 17-E2 on markers of hepatic stellate cell (HSC) activation, collagen crosslinking, collagen degradation, and liver macrophage content and polarity. FindingsWe found that 17-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor {beta}1 (TGF-{beta}1) 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-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-{beta}1 signaling, and reduced pro-inflammatory macrophage activation and cytokines expression in the liver. InterpretationWe conclude that 17-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits. FundingThis work was supported by the US National Institutes of Health and US Department of Veterans Affairs. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSThe 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 17{beta}-estradiol (17{beta}-E2) ameliorates hepatic steatosis and fibrogenesis. However, chronic administration of 17{beta}-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 17-estradiol (17-E2), a naturally-occurring, nonfeminizing, diastereomer of 17{beta}-E2, for the treatment of liver diseases. Added value of this studyIn this study, using tracer-based labeling approaches in male mice subjected to CCl4-induced liver fibrosis, we show that 17-E2 reduces liver fibrosis by attenuating collagen synthesis and enhancing collagen degradation mechanisms. Both transforming growth factor {beta}1 (TGF-{beta}1) and lysyl oxidase-like 2 (LOXL2) protein content in liver were reduced by 17-E2. We also found that 17-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 17-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-{beta}1 signaling, and reduced pro-inflammatory macrophage activation and cytokine expression in the liver. Implications of all the available evidenceThis study supports the idea that estrogens are protective against chronic liver diseases and that 17-E2 may have therapeutic utility for the treatment of liver fibrosis.

physiology↗
bioRxiv2020

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17-estradiol elicits these benefits remain unresolved. Herein, we show that 17-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor (ER) to that of 17{beta}-estradiol. In addition, we show that the ablation of ER completely attenuates the beneficial metabolic effects of 17-E2 in male mice. Our findings suggest that 17-E2 acts primarily through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17-E2 are not limited to mice. Collectively, these studies suggest ER may be a drug target for mitigating chronic diseases in male mammals.

physiology↗