【Abstract】Background:Metabolic dysfunction–associated steatohepatitis (MASH) is a leading cause of chronic liver disease worldwide. The prevalence of MASLD is approximately 38% and is projected to reach 55% by 2040. MASH is characterized by increased hepatic inflammation, which significantly promotes fibrosis progression and the risk of cirrhosis and hepatocellular carcinoma. Adiponectin receptor 2 (AdipoR2) is highly expressed in the liver and activates the PPARα signaling pathway, enhancing fatty acid β-oxidation and improving lipid deposition. The AdipoR2-PPARα axis alleviates chronic ER stress by enhancing lipid clearance and reducing lipotoxicity, serving as a key link between lipid metabolism disorders and ER homeostasis disruption.Methods:Forty-eight male C57BL/6J mice were divided into a normal group (n = 8) and a modeling group (n = 40). The modeling group was fed a high-fat and high-cholesterol diet for 16 weeks to establish a MASH model, then randomly divided into model, Qizhu Formula low-, medium-, and high-dose, and essentiale groups (n = 8 per group). Treatments were administered by gavage for 8 consecutive weeks. Serum levels of ALT, AST, IL-6, IL-1β, TNF-α, and ADPN were measured. Histopathological changes in liver tissue were observed. mRNA and protein expression levels of AdipoR2, PPARα, ADPN, GRP78, IRE1, XBP1, CHOP, CPT1A, and CD36 in liver tissue were detected by real-time PCR and Western blot.Results:Compared with the normal group, the model group exhibited significant hepatic steatosis, inflammatory foci, and lipid accumulation. Serum AST, ALT, IL-6, IL-1β, and TNF-α levels were significantly increased, while ADPN levels were decreased. mRNA and protein expression levels of GRP78, IRE1, XBP1, CHOP, and CD36 were significantly upregulated, whereas those of AdipoR2, PPARα, ADPN, and CPT1α were significantly downregulated (P < 0.05). Compared with the model group, the Qizhu Formula groups and the essentiale group showed alleviated hepatic steatosis, significantly decreased serum AST, ALT, IL-6, IL-1β, and TNF-α levels, and increased ADPN levels. In the high-dose Qizhu Formula group, mRNA and protein expression levels of GRP78, IRE1, XBP1, CHOP, and CD36 were significantly decreased, while those of AdipoR2, PPARα, and CPT1α were significantly increased (P < 0.01, P < 0.05).Conclusion:Qizhu Formula may ameliorate hepatic lipid metabolic disorders and inflammation in MASH by activating the AdipoR2-PPARα signaling pathway, thereby alleviating endoplasmic reticulum stress in hepatocytes.

Methods:Forty-eight male C57BL/6J mice were divided into a normal group (n = 8) and a modeling group (n = 40). The modeling group was fed a high-fat and high-cholesterol diet for 16 weeks to establish a MASH model, then randomly divided into model, Qizhu Formula low-, medium-, and high-dose, and essentiale groups (n = 8 per group). Treatments were administered by gavage for 8 consecutive weeks. Serum levels of ALT, AST, IL-6, IL-1β, TNF-α, and ADPN were measured. Histopathological changes in liver tissue were observed. mRNA and protein expression levels of AdipoR2, PPARα, ADPN, GRP78, IRE1, XBP1, CHOP, CPT1A, and CD36 in liver tissue were detected by real-time PCR and Western blot.

Results:Compared with the normal group, the model group exhibited significant hepatic steatosis, inflammatory foci, and lipid accumulation. Serum AST, ALT, IL-6, IL-1β, and TNF-α levels were significantly increased, while ADPN levels were decreased. mRNA and protein expression levels of GRP78, IRE1, XBP1, CHOP, and CD36 were significantly upregulated, whereas those of AdipoR2, PPARα, ADPN, and CPT1α were significantly downregulated (P < 0.05). Compared with the model group, the Qizhu Formula groups and the essentiale group showed alleviated hepatic steatosis, significantly decreased serum AST, ALT, IL-6, IL-1β, and TNF-α levels, and increased ADPN levels. In the high-dose Qizhu Formula group, mRNA and protein expression levels of GRP78, IRE1, XBP1, CHOP, and CD36 were significantly decreased, while those of AdipoR2, PPARα, and CPT1α were significantly increased (P < 0.01, P < 0.05).

Conclusion:Qizhu Formula may ameliorate hepatic lipid metabolic disorders and inflammation in MASH by activating the AdipoR2-PPARα signaling pathway, thereby alleviating endoplasmic reticulum stress in hepatocytes.