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

Sep 30, 2026

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread hepatic disorder marked by lipid accumulation and inflammation. Intestinal microbiota and their metabolic byproducts drive MASLD progression through the gut–liver axis, yet the role of apolipoprotein A-I (apoA-I) in MASLD remains unclear. This study tested whether apoA-I protects against MASLD by using faecal microbiota transplantation, antibiotic depletion, microbiome profiling, and short-chain fatty acid quantification, then assessed propionic acid (PPA) in vivo and in vitro. ApoA-I overexpression alleviated MASLD in a gut microbiota-dependent manner by restoring microbial balance and increasing PPA, while PPA supplementation improved disease phenotypes and activated the GPR43–Ca2+–CAMKII–ATGL hepatic lipolysis pathway.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Introduction

Gut–liver axis and MASLD progression

Short-chain fatty acids and propionic acid

Role of apolipoprotein A-I in metabolic protection

Study rationale and focus on microbiota-derived PPA

Article Gut Microbiota-Derived Propionic Acid Mediates ApoA-I-Induced Amelioration of MASLD via Activation of GPR43–Ca2+–CAMKII–ATGL Hepatic Lipolysis Mengyuan Liu 1,2, Yutong Wang 3,* and Haixia Huang 1,2, * 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; [lmyuan1997@163.com](lmyuan1997@163.com) 2 Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China 3 Department of Cell Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China * [Correspondence: yutongw@ccmu.edu.cn](Correspondence: yutongw@ccmu.edu.cn) (Y.W.); [haixiah@ccmu.edu.cn](haixiah@ccmu.edu.cn) (H.H.) 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 byproductsto 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 apoAI–microbiota–PPA axis represents a promising therapeutic target for MASLD intervention. Academic Editors: Tomomi Kuwahara and Yoshitohi Ogura Received: 24 November 2025 Revised: 26 December 2025 Accepted: 31 December 2025 Published: 1 January 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Keywords: apolipoprotein A-I; gut microbiota; propionic acid; lipolysis; metabolic dysfunction-associated steatotic liver disease 1. Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD), a common chronic liver condition, affects more than 30% of patients worldwide [1] . The disease process starts with pathological accumulation of lipids within hepatocytes and can progress through multiple stages [2], including metabolic dysfunction-associated steatohepatitis (MASH), which is characterised by hepatocellular ballooning and inflammatory infiltration [3,4] . In a substantial subset of patients (12–40%), MASLD progresses to MASH, which, without effective treatment, may lead sequentially to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [3,4] . The “multiple-hit” hypothesis remains the predominant framework for understanding MASLD pathogenesis [5], incorporating factors such as unhealthy dietary patterns, genetic and epigenetic factors [6], insulin resistance [7], and intestinal dysbiosis [8] . Growing evidence underscores the critical influence of the intestinal microbiota and its metabolic by

FAQs

What does the study propose about apoA-I’s role in MASLD?

The study proposes that apoA-I protects against MASLD through a gut microbiota-dependent mechanism, linked to increased propionic acid (PPA).

How did the researchers assess the role of the gut microbiota?

They evaluated the microbiota using faecal microbiota transplantation (FMT) and antibiotic cocktail (ABX)-mediated depletion, alongside 16S rRNA sequencing and short-chain fatty acid measurements.

What mechanism connects PPA to improved MASLD outcomes?

PPA treatment is associated with activation of the GPR43–Ca2+–CAMKII–ATGL pathway, supporting hepatic lipolysis and mitochondrial β-oxidation.

Sep 30, 2026

Uploaded by McQueen