Rhizoma Atractylodis Macrocephalae reduces HFD-induced MAFLD in mice through activated AMPK-mediated inhibition of fatty acid synthesis

Abstract

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic condition that can lead to cancer due to its complex pathogenesis. Therapeutic agents targeting AMP-activated protein kinase (AMPK) activation have been suggested as potential treatments for metabolic disorders such as metabolic dysfunction-associated steatohepatitis (MASH). Rhizoma Atractylodis Macrocephalae (RAM) has been clinically used to treat obesity-related health problems, but its therapeutic effects on MAFLD and the underlying mechanism remain unclear. Therefore, this study was conducted to evaluate the function and underlying mechanism of RAM in the treatment of MAFLD.

Methods: The effect of RAM decoction on MAFLD was evaluated using a high-fat diet (HFD)-induced MAFLD mouse model. In vitro studies were conducted using a palmitic acid/oleic acid-induced lipid accumulation model in the alpha mouse liver 12 cells and RAM-containing serum. The underlying mechanisms were elucidated through a combination of network pharmacology analysis, immunohistochemistry, western blotting, and polymerase chain reaction analysis.

Results: Administration of RAM decoction significantly reduced body weight gain in MAFLD mice without changing food intake. The weights of the liver and inguinal adipose tissues were also reduced after RAM treatment. Additionally, RAM administration decreased serum levels of alanine aminotransferase, aspartate transaminase, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and glucose, while reducing lipid droplet accumulation in the liver tissues of MAFLD mice. The underlying mechanisms included the activation of the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), and inhibition of the expression of sterol regulatory element binding protein 1 (SREBP1). However, RAM did not alter the protein expression levels of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1α. Furthermore, the RAM-induced upregulation of phosphorylated AMPK, phosphorylated ACC, and SREBP1 expression, as well as the downregulation of fatty acid synthase expression, were reversed by using an AMPK inhibitor.

Conclusions: Through a combination of network pharmacology and experimental validation, we demonstrated that RAM may exert therapeutic effects on MAFLD by inhibiting lipid synthesis and activating phosphorylated AMPK pathways.

Keywords

Metabolic dysfunction-associated fatty liver disease (MAFLD) / Rhizoma Atractylodis Macrocephalae (RAM) / AMP-activated protein kinase (AMPK) / Hepatic steatosis

Authors' contributions

Ke Zheng: Writing e original draft, Validation, Software, Investigation, Formal analysis, Data curation. Ruishuo Zhang: Software, Formal analysis, Data curation. Yijing Xin: Writing e original draft, Validation, Software, Investigation, Formal analysis, Data curation. Yuge Zhou: Investigation, Data curation. Jiacheng Lin: Visualization, Methodology, Funding acquisition. Weifan Huang: Investigation, Data curation. Fang Wang: Resources. Liu Yang: Visualization, Methodology. Xuehua Sun: Supervision, Project administration, Funding acquisition, Conceptualization. Xiaoni Kong: Writing e review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82370582 to Xiaoni Kong). The YangFan project from the Science and Technology Commission of Shanghai Municipality (No. 22YF1449600 to Jiacheng Lin). State Adminis-tration of Traditional Chinese Medicine High-level Key Disciplines Program (No. ZYYZDXK-2023060).

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