Tirzepatide attenuates estrogen deficiency-induced metabolic dysfunction-associated steatotic liver disease progression by reducing steatosis, inflammation, and fibrosis in obese-diabetic mice.

OBJECTIVE: To investigate the impact of estrogen deficiency on metabolic dysfunction-associated steatotic liver disease progression and evaluate the therapeutic potential of tirzepatide (Tzp), a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, in a murine model of postmenopausal metabolic dysfunction. METHODS: Female C57BL/6J mice were divided into obese-diabetic (Od) and ovariectomized Od groups, along with lean controls (control, CO). After 12 weeks of dietary intervention, mice received daily Tzp (10 nmol/kg) or vehicle for four weeks. Comprehensive assessments included plasma biochemistry, liver histopathology, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) complex 1 signaling analysis, and hepatic gene expressions. RESULTS: Od mice developed severe liver pathology, showing 2-3 fold increases in fat accumulation markers, extensive steatosis with hepatocyte ballooning, and 3-4 fold elevated inflammatory markers. Ovariectomy aggravated these effects, increasing fibrosis markers by 2.4-fold and apoptosis signals. Tzp reduced fat deposition by 50%-70%, inflammation by 60%-70%, and fibrosis by 55%. Molecular analyses revealed Tzp restored metabolic balance by: (1) normalizing key energy-sensing pathways (1.5-2 fold AMPK activation; 50% mTOR reduction), (2) reducing fat synthesis signals by 50%-60%, and (3) enhancing fat breakdown pathways (2-2.5 fold increase). Antioxidant defenses were fully restored to normal levels. Principal component analysis demonstrated metabolic improvement, with treated animals showing gene expression patterns closer to healthy controls. CONCLUSION: Estrogen deficiency synergizes with metabolic dysfunction to aggravate metabolic dysfunction-associated steatotic liver disease progression through AMPK/mTOR pathway dysregulation. Tzp demonstrates comprehensive hepatoprotective effects, ameliorating steatosis, inflammation, and fibrosis while restoring metabolic homeostasis in this model of postmenopausal liver disease.