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

ApoA-I overexpression alleviated MASLD in a gut microbiota-dependent manner.

• The contribution of the gut microbiota was evaluated using faecal microbiota transplantation (FMT) and antibiotic cocktail (ABX)-mediated depletion.
• ApoA-I overexpression restored microbial homeostasis in MASLD models.
• Microbial composition was assessed via 16S rRNA sequencing.
• The protective effect of apoA-I against hepatic lipid accumulation and inflammation was dependent on an intact gut microbiota.

ApoA-I overexpression elevated propionic acid (PPA) levels in association with restored gut microbial homeostasis.

• Short-chain fatty acid (SCFA) concentrations were quantified alongside microbial composition analysis.
• PPA was identified as a key gut microbiota-derived metabolite mediating the effects of apoA-I on MASLD.
• ApoA-I overexpression was associated with increased PPA levels compared to controls.
• The apoA-I-microbiota-PPA axis was identified as a novel therapeutic target for MASLD intervention.

PPA supplementation improved MASLD phenotypes in both in vivo and in vitro models.

• PPA treatment reduced hepatic lipid accumulation characteristic of MASLD.
• Both in vivo animal models and in vitro cell models were used to examine the effects of PPA on MASLD.
• PPA supplementation recapitulated the beneficial effects observed with apoA-I overexpression on MASLD phenotypes.

PPA mediates its effects on MASLD through activation of the GPR43-Ca2+-CAMKII-ATGL hepatic lipolysis pathway.

• PPA treatment was associated with activation of GPR43, a G-protein coupled receptor for short-chain fatty acids.
• The signaling cascade proceeds through increased intracellular calcium (Ca2+) and activation of CAMKII (calcium/calmodulin-dependent protein kinase II).
• Downstream activation of ATGL (adipose triglyceride lipase) stimulates hepatic lipolysis.
• PPA treatment also enhanced mitochondrial β-oxidation in addition to stimulating hepatic lipolysis.

ApoA-I, the principal structural component of HDL, has a previously unclear function in MASLD that this study sought to elucidate.

• ApoA-I is described as 'the principal structural component of high-density lipoprotein (HDL)' and is linked to various metabolic disorders.
• Prior to this study, the function of apoA-I in MASLD had 'not yet been clearly elucidated.'
• MASLD is characterized by hepatic lipid accumulation and inflammation.
• The study focused on the possible role of the gut microbiota and propionic acid in mediating apoA-I's effects.