Tzu-Hao Li1,2,3,4, Ying-Ying Yang5,6,2,3, Chia-Chang Huang6,2,3, Chih-Wei Liu1,2,3, Hung-Cheng Tsai1,6,7,3, Ming-Wei Lin8,3, Chang-Youh Tsai1,7,3, Shiang-Fen Huang9,2,3, Ying-Wen Wang10,7,3, Tzung-Yan Lee3,11, Yi-Hsiang Huang10,7,2,3, Ming-Chih Hou10,7,3, Han-Chieh Lin5,7,3. 1. Division of Allergy and Immunology, Taipei Veterans General Hospital, Taipei, Taiwan. 2. Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. 3. Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. 4. Division of Allergy and Immunology, Department of Medicine, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan. 5. Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan yangyy@vghtpe.gov.tw hclin@vghtpe.gov.tw. 6. Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 7. Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 8. Institute of Public Health, National Yang-Ming University School of Medicine, Taipei, Taiwan. 9. Division of Infection, Taipei Veterans General Hospital, Taipei, Taiwan. 10. Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan. 11. Graduate Institute of Traditional Chinese Medicine, Chang Guang Menorial Hospital, Linkou, Taiwan.
Abstract
Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.
Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.