Pei-Chang Lee1,2,3, Ling-Yu Yang4, Ying-Wen Wang2,5, Shiang-Fen Huang2,6, Kuei-Chuan Lee2,5, Yun-Cheng Hsieh1,2,5, Ying-Ying Yang2,4,7,8, Shie-Liang Hsieh8,9, Ming-Chih Hou2,5, Han-Chieh Lin2,5, Fa-Yuah Lee2,5, Shou-Dong Lee10. 1. Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. 2. Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan. 3. Division of Gastroenterology and Hepatology, Department of Medicine, Yuanshan Branch, Taipei Veterans General Hospital, Yilan, Taiwan. 4. Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan. 5. Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan. 6. Division of Infection, Taipei Veterans General Hospital, Taipei, Taiwan. 7. Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 8. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. 9. Genomics Research Center, Academia Sinica, Taipei, Taiwan. 10. Cheng Hsin General Hospital, Taipei, Taiwan.
Abstract
AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice. METHODS: Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated. RESULTS: Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress. CONCLUSION: The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH.
AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice. METHODS:Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated. RESULTS: Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress. CONCLUSION: The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH.
Authors: David Sacerdoti; Shailendra P Singh; Joseph Schragenheim; Lars Bellner; Luca Vanella; Marco Raffaele; Aliza Meissner; Ilana Grant; Gaia Favero; Rita Rezzani; Luigi F Rodella; David Bamshad; Edward Lebovics; Nader G Abraham Journal: Int J Hepatol Date: 2018-07-02