Trimethylamine N-oxide induces non-alcoholic fatty liver disease by activating the PERK

Area of Science:

• Hepatology and Gastroenterology
• Metabolic Disorders
• Microbiome Research

Background:

• Nonalcoholic fatty liver disease (NAFLD) involves progressive liver pathology.
• Gut microbiota metabolite Trimethylamine N-oxide (TMAO) activates the PERK pathway.
• Previous studies suggest TMAO's association with NAFLD, but direct causation and mechanisms are unclear.

Purpose of the Study:

• To determine if TMAO consumption directly induces NAFLD.
• To elucidate the underlying molecular mechanisms of TMAO-induced NAFLD.

Main Methods:

• Adult male zebrafish were fed diets containing 1% or 3% TMAO for 20 weeks.
• Liver pathology, including lipid accumulation, inflammation, injury, and fibrosis, was assessed.
• Activation of the PERK signaling pathway was examined in zebrafish livers, HepG2 cells, and hepatic stellate cells.

Main Results:

• TMAO administration led to significant lipid accumulation, inflammatory infiltration, liver injury, and fibrosis in zebrafish.
• The PERK signaling pathway was notably activated in the livers of TMAO-fed zebrafish.
• These findings were corroborated in cellular models (HepG2 and hepatic stellate cells).

Conclusions:

• TMAO directly induces NAFLD-like pathological changes in zebrafish.
• Activation of the PERK pathway is a key mechanism underlying TMAO's direct role in NAFLD.
• This research offers potential diagnostic and therapeutic strategies for NAFLD.