MON-712 - Hepatocyte Erα Drives 17Α-Estradiol Mediated Metabolic Benefits in Male Mice

Metabolic diseases are one of the major risk factors for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD can progress from simple steatosis (fat accumulation) to metabolic dysfunction-associated steatohepatitis (MASH), characterized by inflammation, hepatocyte ballooning, and fibrosis, which significantly raises the risk of hepatocellular carcinoma (HCC). Currently no pharmacotherapy is approved for treating MASLD/MASH. Until recently, the FDA approved Resmiterom (a thyroid hormone receptor β-agonist) for MASH treatment, highlighting the need for more therapies targeting risk factors to mitigate MASLD development & progression. Men and postmenopausal women are at a higher risk of developing MASLD compared to premenopausal women, thereby indicating a role of endogenous estrogens in controlling the progression of MASLD and its associated diseases. Our previous work demonstrated that 17α-estradiol (17α-E2) can reverse liver fat deposition in male obese mice and ablation of estrogen receptor α (ERα) globally attenuates 17α-E2-mediated benefits. Therefore, we hypothesized that ERα-expressing hepatocytes in the liver mediate beneficial metabolic effects of 17α-E2 in male mice. To test this, we generated mice lacking ERα receptors in hepatocytes and evaluated the metabolic effects of 17α-E2 treatment. All mice were high-fat fed for 6 months prior to study initiation. Metabolic parameters were evaluated at baseline and throughout the 16-week intervention. Through liver transcriptomics and proteomics, the relevance of hepatic ERα in the metabolic response to 17α-E2 were analyzed. We found that 17α-E2 treatment decreased body mass and fat mass while improving glucose tolerance and hepatic fat deposition with altered proteomics and transcriptomics signature in wild-type male mice compared to no treatment group. Conversely, these beneficial effects were absent in both male & female hepatocyte ERαKO mice. Our findings indicate that 17α-E2 improves systemic metabolism at least partially through actions in the liver, which could play a protective role in reducing the risk of MASLD/MASH progression. Future studies are needed to determine the cell-type-specific mechanisms by which 17α-E2 affects fat deposition in the liver.

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