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

Livers of mice lacking the aryl hydrocarbon receptor (AhR) showed aggravated metabolic dysfunction-associated steatohepatitis (MASH) when fed a high-fat, high-fructose, high-cholesterol diet.

• Cinnabarinic acid (CA) treatment reduced body weight gain and alleviated hepatic steatosis, inflammation, ballooning, fibrosis, and liver injury in mice with intact AhR.
• The protective effects of CA against MASH were not observed in mice lacking hepatic AhR, indicating that these effects are AhR-dependent.
• CA-activated AhR signaling was shown to enhance AMP-activated protein kinase (AMPK) activity, which is involved in regulating lipid metabolism in the liver.
• Increased AMPK activity led to upregulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1α) and reduction of sterol regulatory element-binding protein-1 (SREBP1), both of which are important for liver fat regulation.
• Findings suggest that selective endogenous AhR agonists may offer potential therapeutic strategies for managing metabolic dysfunction-associated steatotic liver disease (MASLD).

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