17β-Estradiol Improves Liver Function in T2DMNAFLD Mice via PGC-1α/ERRα Axis Activation While Preserving Cholestatic Safety.

INTRODUCTION

This study investigated the hepatoprotective effects and mechanisms of 17β-estradiol (E2) in a mouse model of type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD).

METHODS

Male C57BL/6J mice (n = 6/group) were fed a high-fat diet for 8 weeks and injected with streptozotocin (60 mg/kg for 3 days) to induce T2DM + NAFLD. Animals were randomized into control, model, E2 (20 μg/kg/day, i.p., 8 weeks), E2 + siNC, and E2 + siPGC-1α groups. Metabolic indices, liver enzymes, body weight, liver index, and pre-specified cholestasis-related safety endpoints (alkaline phosphatase [ALP], total bile acids [TBA], total bilirubin [TBil]) were quantified. H&E and Oil Red O staining were used to assess hepatic injury and steatosis. PGC-1α/ERRα signaling was evaluated by Western blotting, immunofluorescence, and ChIPqPCR.

RESULTS

Compared with the model group, E2 reduced fasting blood glucose by 54.7%, insulin by 36.3%, HOMA-IR by 71.1%, cholesterol by 25.9%, triglycerides by 46.2%, LDL-C by 36.6%, ALT by 47.2%, and AST by 39.9% (all P < 0.05). Body weight, liver index, hepatocyte injury, and lipid deposition were also decreased. E2 restored hepatic PGC-1α and ERRα expression and their co-localization; ChIP-qPCR confirmed ~7-fold enrichment of ERRα promoter regions by PGC-1α. For cholestasis-related indices, ALP and TBA exhibited only small, non-concerted changes while TBil remained stable; all values stayed within reference limits, indicating no cholestatic phenotype under our dosing paradigm. PGC-1α knockdown (E2 + siPGC-1α) blunted or abolished these metabolic, histological, and signaling benefits.

DISCUSSION: The study demonstrates that 17β-estradiol exerts hepatoprotective and metabolic regulatory effects in diabetic fatty liver via modulation of the PGC-1α/ERRα pathway.

CONCLUSION

This study demonstrates that E2 alleviates metabolic dysfunction and hepatic injury in T2DM-NAFLD mice by activating the PGC-1α/ERRα axis, while preserving cholestatic safety, as evidenced by non-concerted ALP/TBA/TBil changes within reference limits. PGC-1α is essential for mediating these effects, highlighting the PGC-1α/ERRα pathway as a promising therapeutic target for metabolic liver disease.