Published online Jul 28, 2024. doi: 10.3748/wjg.v30.i28.3428
Revised: May 31, 2024
Accepted: June 20, 2024
Published online: July 28, 2024
Processing time: 148 Days and 18.6 Hours
Alcohol-associated liver disease (ALD) is a leading cause of liver-related mor
To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.
ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histo
The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation.
EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.
Core Tip: Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to alcohol-associated liver disease (ALD) pathogenesis. This study elucidates the preventive effect of elafibranor, a dual PPARα/δ agonist from ALD-related liver fibrosis induced by ethanol plus carbon tetrachloride in mice. This effect is involved in multifaceted regulatory functions: (1) Suppression of lipid accumulation and improvement of autophagy in hepatocytes, which reduced apoptosis and enhanced antioxidant activities; and (2) Inhibition of toll like receptor 4 pathway with blockade of hepatic influx of lipopolysaccharide by repairing intestinal barrier integrity. This regimen represents a potential strategy against ALD-related liver fibrosis.