Indole-3-Propionic Acid Alleviates Metabolic Dysfunction-Associated Fatty Liver Disease via AHR/AMPK Signaling Activation.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a health problem worthy of attention worldwide, characterized by excessive lipid accumulation in the liver. Previous studies have shown that indole-3-propionic acid (IPA) can ameliorate MAFLD; however, the regulatory mechanism by which IPA affects lipid synthesis requires further investigation. In vitro, FFA-induced HepG2 cells were treated with IPA (15-35 μM), and hepatic lipid accumulation was evaluated by Oil Red O staining. RNA-seq and Western blotting were employed to analyze AHR/AMPK signaling activation, and pharmacological inhibitors and agonists targeting AHR and AMPK were applied to explore the regulatory mechanism of IPA on lipid deposition. In vivo, C57BL/6J mice on a high-fat diet received 50 mg/kg IPA for 16 weeks, followed by histopathological evaluation and assessment of AHR/AMPK pathway activation. Results showed that IPA dose-dependently reduced lipid deposition in HepG2 cells. IPA inhibited lipid synthesis by activating AHR (inducing CYP1A1 expression and nuclear translocation) and promoting AMPK phosphorylation, thereby downregulating SREBP-1c and FAS expression. Pharmacological experiments demonstrated that IPA-induced AMPK activation was dependent on AHR nuclear translocation. Moreover, phosphorylated AMPK further promoted AHR nuclear translocation, indicating the existence of a potential bidirectional crosstalk between AHR and AMPK. In animal studies, IPA mitigated HFD-induced hepatic steatosis through activation of the AHR/AMPK signaling pathways. In conclusion, indole-3-propionic acid may alleviate MAFLD by ameliorating high-fat diet-induced hepatic lipid deposition through AHR/AMPK signaling activation.