Sun YQ, Wu Y, Li MR, Wei YY, Guo M, Zhang ZL. Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function. World J Gastroenterol 2024; 30(43): 4660-4668 [PMID: 39575408 DOI: 10.3748/wjg.v30.i43.4660]
Corresponding Author of This Article
Zi-Li Zhang, MD, PhD, Professor, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Nanjing 210023, Jiangsu Province, China. zilizhang@njucm.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Letter to the Editor
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Nov 21, 2024; 30(43): 4660-4668 Published online Nov 21, 2024. doi: 10.3748/wjg.v30.i43.4660
Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function
Yu-Qi Sun, Yang Wu, Meng-Ran Li, Yu-Yao Wei, Mei Guo, Zi-Li Zhang
Yu-Qi Sun, Yang Wu, Meng-Ran Li, Yu-Yao Wei, Mei Guo, Zi-Li Zhang, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Co-corresponding authors: Mei Guo and Zi-Li Zhang.
Author contributions: Sun YQ, Li MR, Wei YY, Guo M, and Zhang ZL contributed to this paper; Zhang ZL designed the overall concept and outline of the manuscript; Guo M and Sun YQ contributed to the discussion and design of the manuscript; Sun YQ, Wu Y, Li MR, and Wei YY contributed to the writing, and editing the manuscript, illustrations, and review of literature; Guo M and Zhang ZL contributed equally to this work as co-corresponding authors; and all authors have read and approved the final manuscript.
Supported bythe National Natural Science Foundation of China, No. 82474164, No. 82305046, and No. 82000572; Natural Science Foundation of Jiangsu Province, No. BK20220467; Major Project of the Natural Science Research of Jiangsu Higher Education Institutions, No. 22KJB310013; and Science and Technology Project of Jiangsu Province, No. BK20200840.
Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zi-Li Zhang, MD, PhD, Professor, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Nanjing 210023, Jiangsu Province, China. zilizhang@njucm.edu.cn
Received: July 26, 2024 Revised: September 29, 2024 Accepted: October 18, 2024 Published online: November 21, 2024 Processing time: 97 Days and 7.6 Hours
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.
Core Tip: Peroxisome proliferator-activated receptor (PPAR) can inhibit the pathological process of alcohol-related liver disease (ALD). However, the dual PPARα/δ agonist elafibranor has been studied mainly in metabolic dysfunction-associated steatohepatitis and primary cholangitis, and its role in ALD and its mechanism need to be further explored.
