Short-term L-arabinose administration alleviates MASLD by remodeling gut microbiota and activating hepatic ATF5-dependent mitochondrial unfolded protein response

Abstract

Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) involves gut microbial dysbiosis and mitochondrial stress, yet the molecular link between these processes remains unclear. This study explored whether short-term L-arabinose (LA) supplementation mitigates MASLD by modulating the gut-liver axis and mitochondrial adaptive signaling.

Methods: A murine early-stage fatty liver model was established and treated orally with LA for four weeks. Gut microbial changes were assessed by 16S ribosomal RNA gene (16S rRNA) sequencing and functional prediction, while hepatic mechanisms were examined through activating transcription factor 5 (ATF5) gain- and loss-of-function experiments both in vivo and in vitro.

Results: Short-term LA administration significantly reshaped gut microbiota, enriching short-chain fatty acid-producing taxa and improving hepatic lipid metabolism. Mechanistically, LA enhanced hepatic expression of ATF5, leading to the upregulation of mitochondrial chaperone heat shock protein 60 (HSP60) and protease Lon protease 1 (LONP1), thereby initiating the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restored mitochondrial integrity, reduced oxidative stress, and attenuated hepatic lipid deposition. Silencing ATF5 abolished these protective effects, confirming its central regulatory role.

Conclusion: Short-term LA treatment alleviates MASLD by reprogramming gut microbiota and activating hepatic ATF5-mediated UPRmt signaling. These findings reveal a novel gut–mitochondrial regulatory pathway that links microbial metabolism to hepatic mitochondrial proteostasis, providing new mechanistic insight and therapeutic potential for metabolic liver disease.

Keywords

MASLD / lipid deposition / mitochondrial unfolded protein response / gut microbiota / ATF5