# Gut Microbiota-Derived Propionic Acid Mediates ApoA-I-Induced Amelioration of MASLD via Activation of GPR43–Ca2+–CAMKII–ATGL Hepatic Lipolysis

## TL;DR

This study shows that apoA-I helps reduce liver disease by boosting gut microbes that produce propionic acid, which activates a pathway to break down liver fat.

## Contribution

The study identifies a novel apoA-I–microbiota–PPA axis that mediates hepatic lipolysis via GPR43–Ca2+–CAMKII–ATGL signaling to ameliorate MASLD.

## Key findings

- ApoA-I overexpression reduces MASLD by restoring gut microbiota balance and increasing propionic acid levels.
- Propionic acid activates the GPR43–Ca2+–CAMKII–ATGL pathway to stimulate hepatic lipolysis and mitochondrial β-oxidation.
- PPA supplementation alone improves MASLD symptoms, suggesting therapeutic potential.

## Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread hepatic condition characterised by hepatic lipid accumulation and inflammation. Emerging research highlights the contribution of the intestinal microbiota and its metabolic byproducts to the pathogenesis of MASLD through the gut–liver axis. Apolipoprotein A-I (apoA-I), the principal structural component of high-density lipoprotein (HDL), is linked to various metabolic disorders; however, its function in MASLD has not yet been clearly elucidated. This study sought to examine whether apoA-I protects against MASLD, with a focus on the possible role of the gut microbiota and propionic acid (PPA). The contribution of the gut microbiota was evaluated using faecal microbiota transplantation (FMT) and antibiotic cocktail (ABX)-mediated depletion. Microbial composition was assessed via 16S rRNA sequencing, and concentrations of short-chain fatty acids (SCFAs) were quantified. The effects of PPA on MASLD were examined using in vivo and in vitro models. The results showed that apoA-I overexpression alleviated MASLD in a gut microbiota-dependent manner, restored microbial homeostasis, and elevated PPA levels. PPA supplementation improved MASLD phenotypes. Mechanistically, PPA treatment was associated with the activation of the GPR43–Ca2+–CAMKII–ATGL pathway, suggesting that PPA plays a role in stimulating hepatic lipolysis and enhancing mitochondrial β-oxidation. These findings reveal a novel pathway through which apoA-I ameliorates MASLD by modulating the gut microbiota and increasing PPA levels, which activate a hepatic lipolysis cascade. The apoA-I–microbiota–PPA axis represents a promising therapeutic target for MASLD intervention.