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Indole-3-Propionic Acid Alleviates Metabolic Dysfunction-Associated Fatty Liver Disease via AHR/AMPK Signaling
Yanting Huang1, Meimei Yu1, Jiaxin Lu1
1Department of Nutrition and Food Hygiene, School of Public Health Guangzhou Medical University Guangzhou China.
Abstract:
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.
Insights
Indole-3-propionic acid (IPA) reduces liver fat accumulation in metabolic dysfunction-associated fatty liver disease (MAFLD). IPA activates the AHR/AMPK pathway, inhibiting lipid synthesis and improving fatty liver in mice.
Area of Science:
- Hepatology
- Metabolic Diseases
- Molecular Biology
Background:
- Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing global health concern characterized by excessive liver lipid accumulation.
- Indole-3-propionic acid (IPA) has shown potential in ameliorating MAFLD, but its precise regulatory mechanism on hepatic lipid synthesis needs clarification.
Purpose of the Study:
- To investigate the regulatory mechanism of indole-3-propionic acid (IPA) in modulating hepatic lipid synthesis and deposition.
- To elucidate the role of the AHR/AMPK signaling pathway in IPA's therapeutic effects on MAFLD.
Main Methods:
- In vitro studies utilized FFA-induced HepG2 cells treated with IPA, assessing lipid accumulation via Oil Red O staining.
- RNA-seq and Western blotting analyzed AHR/AMPK signaling activation, with pharmacological inhibitors and agonists used to explore mechanisms.
- In vivo studies involved C57BL/6J mice on a high-fat diet treated with IPA, followed by histopathological evaluation and pathway analysis.
Main Results:
- IPA dose-dependently reduced lipid deposition in HepG2 cells and mitigated high-fat diet-induced hepatic steatosis in mice.
- IPA activated the Aryl hydrocarbon receptor (AHR) and promoted AMPK phosphorylation, downregulating key lipogenic factors (SREBP-1c, FAS).
- AHR nuclear translocation was essential for IPA-induced AMPK activation, and a bidirectional crosstalk between AHR and AMPK was observed.
Conclusions:
- Indole-3-propionic acid alleviates MAFLD by inhibiting hepatic lipid deposition through the activation of the AHR/AMPK signaling pathway.
- The findings highlight IPA as a potential therapeutic agent for MAFLD, mediated by its effects on lipid metabolism via AHR and AMPK.
