Gut microbiota-derived indole-3-propionic acid alleviates endoplasmic reticulum stress by regulating FMO2 in MASLD

Area of Science:

• Hepatology
• Microbiome Research
• Metabolic Diseases

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern with no approved treatments.
• The role of gut microbiota metabolites, like Indole-3-propionic acid (IPA), in MASLD pathogenesis is not fully understood.
• Investigating IPA's molecular mechanisms is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying the effects of Indole-3-propionic acid (IPA) in the development of metabolic dysfunction-associated steatotic liver disease (MASLD).
• To evaluate the therapeutic potential of IPA in a mouse model of MASLD.

Main Methods:

• Comparative metabolomic analysis of serum and fecal samples from MASLD and normal mice.
• In vivo studies using a MASLD mouse model and in vitro studies using cell models to assess IPA's effects.
• Transcriptome analysis, flow cytometry, western blotting, RNA interference, and immunoprecipitation for mechanistic validation.

Main Results:

• Serum and fecal IPA levels were significantly reduced in MASLD mice.
• IPA supplementation ameliorated hepatic lipid accumulation, insulin resistance, liver damage, and steatosis, while restoring gut microbiota balance.
• Mechanistically, IPA promotes FMO2 expression, which inhibits the PERK/eIF2α/ATF4/CHOP pathway, reducing endoplasmic reticulum stress, hepatocyte apoptosis, and reactive oxygen species.

Conclusions:

• IPA enhances FMO2 expression, leading to FMO2-PERK binding in hepatocytes, inhibiting PERK phosphorylation and subsequent ER stress.
• This mechanism reduces hepatocyte apoptosis and oxidative stress, offering a novel therapeutic approach for MASLD.
• The IPA/FMO2/PERK axis represents a potential therapeutic target for managing ER stress in MASLD.