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. 2024 Nov 21;30(43):4660-4668.
doi: 10.3748/wjg.v30.i43.4660.

Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function

Yu-Qi Sun  1 , Yang Wu  1 , Meng-Ran Li  1 , Yu-Yao Wei  1 , Mei Guo  1 , Zi-Li Zhang  2
Affiliations

Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function

Yu-Qi Sun et al. World J Gastroenterol. .

Abstract

We discuss the article by Koizumi et al published in the World Journal of Gastroenterology. Our focus is on the therapeutic targets for fibrosis associated with alcohol-related liver disease (ALD) and the mechanism of action of elafibranor (EFN), a dual agonist of peroxisome proliferator-activated receptor α (PPARα) and peroxisome PPAR δ (PPARδ). EFN is currently in phase III clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis. ALD progresses from alcoholic fatty liver to alcoholic steatohepatitis (ASH), with chronic ASH eventually leading to fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. The pathogenesis of ALD is driven by hepatic steatosis, oxidative stress, and acetaldehyde toxicity. Alcohol consumption disrupts lipid metabolism by inactivating PPARα, exacerbating the progression of ALD. EFN primarily activates PPARα, promoting lipolysis and β-oxidation in ethanol-stimulated HepG2 cells, which significantly reduces hepatic steatosis, apoptosis, and fibrosis in an ALD mouse model. Additionally, alcohol disrupts the gut-liver axis at several interconnected levels, contributing to a proinflammatory environment in the liver. EFN helps alleviate intestinal hyperpermeability by restoring tight junction protein expression and autophagy, inhibiting apoptosis and inflammatory responses, and enhancing intestinal barrier function through PPARδ activation.

Keywords: Apoptosis; Autophagy; Ethanol; Gut barrier function; Liver fibrosis; Peroxisome proliferator-activated receptor.

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Conflict of interest statement

Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose.

Figures

Figure 1
Figure 1
Effects of elafibranor on alcohol-associated liver disease in mice. Elafibranor (EFN) activates peroxisome proliferator-activated receptor α (PPARα), inhibiting liver fibrosis in alcoholic liver disease through four primary mechanisms. First, it increases the expression of phospholipase A2 and cyclooxygenase-2, promoting lipid breakdown and fatty acid oxidation. Second, it enhances hepatocyte autophagy and increases antioxidant activity, specifically, superoxide dismutase 1 and catalase, thereby preventing hepatocyte apoptosis. Third, EFN reduces extracellular matrix production by regulating the activity of matrix metalloproteinases and tissue inhibitors of metalloproteinases. Finally, it suppresses macrophage activation by inhibiting the lipopolysaccharide/Toll-like receptor 4 signaling pathway. Moreover, PPARδ activation improves intestinal permeability by preventing intestinal epithelial cell apoptosis and promoting M2 macrophage polarization. It also enhances intestinal barrier integrity by upregulating tight junction proteins, such as zonula occludens-1, occludin, and claudin-2. PPAR: Peroxisome proliferator-activated receptor; ALD: Alcoholic liver disease; PLA2: Phospholipase A2; COX2: Cyclooxygenase-2; SOD1: Superoxide dismutase 1; CAT: Catalase; MMPs: Matrix metalloproteinases; TIMP-1: Tissue inhibitors of metalloproteinases; LPS: Lipopolysaccharides; TLR4: Toll-like receptor 4; TJPs: Tight junction proteins; ZO-1: Zonula occludens-1.
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