Intermittent fasting ameliorates MAFLD by downregulating Lrg1: insights from bulk RNA sequencing and functional...

Area of Science:

• Hepatology
• Metabolic Disorders
• Genomics

Background:

• Metabolic dysfunction-associated fatty liver disease (MAFLD) prevalence is rising globally.
• Current MAFLD treatments have limitations.
• Investigating intermittent fasting (IF) as a potential therapeutic strategy for MAFLD.

Purpose of the Study:

• To investigate the effects of intermittent fasting (IF) on MAFLD.
• To elucidate the underlying molecular mechanisms of IF in MAFLD.

Main Methods:

• Bulk RNA sequencing of liver tissues from mice under different dietary and fasting conditions.
• Differential gene expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA).
• Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, and RT-qPCR for key gene validation.

Main Results:

• IF significantly improved metabolic abnormalities and reduced hepatic lipid deposition in MAFLD mice.
• Transcriptome analysis identified differentially expressed genes (DEGs) enriched in fatty acid metabolism and inflammatory response pathways.
• Lrg1 was identified as a key gene; its knockdown inhibited lipogenic gene expression (Srebf1, Scd1, Fasn) via the PI3K-AKT pathway, slowing MAFLD progression.

Conclusions:

• Intermittent fasting ameliorates MAFLD by modulating fatty acid metabolism and inflammatory pathways.
• Key genes, including Lrg1, play crucial roles in IF's therapeutic effects on MAFLD.
• Targeting Lrg1 presents a potential therapeutic strategy for slowing MAFLD progression.