Cinnabarinic acid protects against metabolic dysfunction-associated steatohepatitis by activating aryl hydrocarbon receptor-dependent AMPK signaling

• DOI: 10.1152/ajpgi.00337.2024
• Publication Date: 2025-03-10T11:51:02Z
• Authors: Nikhil Y. Patil; Iulia Rus; Felix Ampadu; Hassan M. Abu Shu...; Sarah Bonvicino; Richard S. Brush; Elena Eaton; Martin-Paul Agbaga; Tae Gyu Oh; Jacob E. Friedman; Aditya D. Joshi
• Keywords: Steatohepatitis; Steatosis; Lipogenesis; Hepatic fibrosis; AMP-Activated Protein Kinase

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic steatotic liver disease (MASLD) characterized by accumulation fats in liver, chronic inflammation, hepatocytic ballooning, and fibrosis. This study investigates the significance hepatic Aryl hydrocarbon Receptor (AhR) signaling cinnabarinic acid (CA)-mediated protection against MASH. Here, we report that livers high-fat, high-fructose, high-cholesterol diet-fed hepatocyte-specific knockout mice (AhR-hKO) exhibited aggravated steatosis, fibrosis compared to control AhR-floxed livers. Moreover, treatment with a tryptophan catabolite, CA reduced body weight gain significantly attenuated fibrosis, injury only but not AhR-hKO mice, strongly indicating CA-mediated AhR-dependent. Furthermore, lipotoxicity CA-activated AhR was confirmed utilizing vitro human hepatocyte model MASLD. Mechanistically, CA-induced AhR-dependent augmented AMP-activated protein kinase (AMPK) leading upregulation peroxisome proliferator-activated receptor-c coactivator-1a (PGC1α) attenuation sterol regulatory element-binding protein-1 (SREBP1) regulate lipid metabolism. Collectively, our findings indicate MASH dependent on selective endogenous agonists lipogenesis can serve as promising future therapeutics