Speaker
Description
Background: Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disorder characterized by disrupted lipid metabolism. The aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, is involved in regulating various physiological processes, such as lipid metabolism and immune responses. Recent studies have highlighted the multifaceted regulatory role of AHR in liver diseases through the integration of metabolic and immune signaling pathways. However, the specific role of AHR in MAFLD remains to be elucidated.
Methods: We established a rat model of MAFLD by feeding wild-type (WT) and AHR knockout (AHR−/−) rats a high-fat, high-fructose, and high-cholesterol diet (HFHFrHCD) for 10 weeks. To elucidate the impact of AHR on the MAFLD progression, liver injury markers, lipid-related biochemical indices, and liver histopathological changes were evaluated.
Results: AHR deficiency was found to elevate plasma transaminase levels, increase hepatic triglyceride (TG) and total cholesterol (TC), and exacerbate insulin resistance (IR) under an overnutrition environment. Subsequently, liver transcriptome and RT-qPCR analyses further revealed that hepatic bile acid synthesis was inhibited in AHR−/− rats due to reduced expression of Cytochrome P450 Family 7 Subfamily A Member 1 (CYP7A1). Additionally, 16S sequencing revealed that AHR knockout can further exacerbate gut microbiota dysregulation induced by HFHFrCD, which might contribute to the hepatic cholesterol accumulation.
Conclusions: Our findings suggest that AHR is crucial for regulating cholesterol metabolism during MAFLD progression by modulating bile acid synthesis and maintaining gut microbiota homeostasis. These findings highlight the potential therapeutic significance of AHR in MAFLD and provide new insights into MAFLD pathogenesis.
Acknowledgments:
Supported by the High-level Innovative Research Institute of the Department of Science and Technology of Guangdong Province, grant number 2021B0909050003
Reference:
Xu et al.: Int. J. Mol. Sci. 2026, 27, 349
