Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2024; 30(28): 3428-3446
Published online Jul 28, 2024. doi: 10.3748/wjg.v30.i28.3428
Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease
Aritoshi Koizumi, Kosuke Kaji, Norihisa Nishimura, Shohei Asada, Takuya Matsuda, Misako Tanaka, Nobuyuki Yorioka, Yuki Tsuji, Koh Kitagawa, Shinya Sato, Tadashi Namisaki, Takemi Akahane, Hitoshi Yoshiji
Aritoshi Koizumi, Kosuke Kaji, Norihisa Nishimura, Shohei Asada, Takuya Matsuda, Misako Tanaka, Nobuyuki Yorioka, Yuki Tsuji, Koh Kitagawa, Shinya Sato, Tadashi Namisaki, Takemi Akahane, Hitoshi Yoshiji, Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
Author contributions: Koizumi A and Kaji K contributed to the data curation; Koizumi A, Nishimura N, Asada S, Matsuda T, Tanaka M, Yorioka N, and Tsuji Y were involved in the investigation of this manuscript; Koizumi A, Nishimura N, and Kitagawa K participated in the formal analysis; Koizumi A, Kaji K, and Namisaki T contributed to the methodology of this study; Koizumi A prepared the writing-original draft; Kaji K and Yoshiji H took part in the conceptualization and resources of this article; Koizumi A, Akahane T, and Yoshiji H contributed to the supervision of this manuscript; Kaji K participated in the validation; Kaji K and Kitagawa K were involved in the visualization; Kaji K, Nishimura N, Asada S, Matsuda T, Tanaka M, Yorioka N, Tsuji Y, Kitagawa K, Sato S, Namisaki T, Akahane T, and Yoshiji H contributed to the writing-review and editing of this manuscript; Sato S contributed to the software.
Institutional review board statement: The study was reviewed and approved by the Institutional review board of Nara Medical University, Kashihara, Japan (authorization numbers: 13130).
Institutional animal care and use committee statement: All animal experiments were performed in accordance with the Guide for Care and Use of Laboratory Animals of the National Research Council.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Kosuke Kaji, MD, PhD, Chief, Lecturer, Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara 634-8521, Japan. kajik@naramed-u.ac.jp
Received: February 26, 2024
Revised: May 31, 2024
Accepted: June 20, 2024
Published online: July 28, 2024
Processing time: 148 Days and 18.6 Hours
Abstract
BACKGROUND

Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown.

AIM

To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.

METHODS

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. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays.

RESULTS

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.

CONCLUSION

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.

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

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.