Aloe-emodin ameliorates non-alcoholic fatty liver disease by regulating the ZNRF3/Wnt/β-catenin axis and suppressing hepatic lipogenesis.
Source: PubMed, NCBI / U.S. National Library of Medicine
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disorder with limited approved pharmacological treatment options, creating an urgent need for novel therapeutic agents. This study investigated the efficacy and underlying molecular mechanism of aloe-emodin, a natural anthraquinone from Rhei Radix et Rhizoma, in treating NAFLD. In a high-fat diet (HFD)-induced mouse model, aloe-emodin administration significantly reduced body and liver weight, ameliorated hepatic steatosis, lowered serum ALT and hepatic lipid levels, and suppressed the expression of key lipogenic genes. These protective effects were recapitulated in an in vitro model using free fatty acid (FFA)-treated hepatocytes, where aloe-emodin reduced intracellular lipid accumulation without affecting cell viability. Mechanistic investigation revealed that aloe-emodin restored AMPK activation, increased PPARα-associated fatty acid oxidation markers, and suppressed Wnt/β-catenin signaling. Functional rescue experiments further supported the involvement of the ZNRF3-Wnt/β-catenin axis in the anti-lipogenic effects of aloe-emodin. Molecular docking identified ZNRF3, a critical negative regulator of the Wnt pathway, as the top potential binding target for aloe-emodin. We confirmed that ZNRF3 expression, which was downregulated in NAFLD models, was significantly restored by aloe-emodin treatment. Crucially, rescue experiments demonstrated that the therapeutic and anti-lipogenic effect
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disorder with limited approved pharmacological treatment options, creating an urgent need for novel therapeutic agents. This study investigated the efficacy and underlying molecular mechanism of aloe-emodin, a natural anthraquinone from Rhei Radix et Rhizoma, in treating NAFLD. In a high-fat diet (HFD)-induced mouse model, aloe-emodin administration significantly reduced body and liver weight, ameliorated hepatic steatosis, lowered serum ALT and hepatic lipid levels, and suppressed the expression of key lipogenic genes. These protective effects were recapitulated in an in vitro model using free fatty acid (FFA)-treated hepatocytes, where aloe-emodin reduced intracellular lipid accumulation without affecting cell viability. Mechanistic investigation revealed that aloe-emodin restored AMPK activation, increased PPARα-associated fatty acid oxidation markers, and suppressed Wnt/β-catenin signaling. Functional rescue experiments further supported the involvement of the ZNRF3-Wnt/β-catenin axis in the anti-lipogenic effects of aloe-emodin. Molecular docking identified ZNRF3, a critical negative regulator of the Wnt pathway, as the top potential binding target for aloe-emodin. We confirmed that ZNRF3 expression, which was downregulated in NAFLD models, was significantly restored by aloe-emodin treatment. Crucially, rescue experiments demonstrated that the therapeutic and anti-lipogenic effects of aloe-emodin were abolished both in vivo and in vitro when ZNRF3 was genetically knocked down or when the Wnt pathway was pharmacologically activated. These findings suggest that aloe-emodin ameliorates NAFLD, at least in part, by restoring ZNRF3 expression and suppressing Wnt/β-catenin pathway-associated lipogenic activation.