Decoy receptor 3 analogous supplement protects steatotic rat liver from ischemia-reperfusion injury.
BACKGROUND
For steatotic livers, pharmacological approaches to minimize the hepatic neutrophil and macrophage infiltration, and cytokine and chemokine release in ischemia-reperfusion (IR) injury are still limited. Tumor necrosis factor (TNF)-α superfamily-stimulated pathogenic cascades and M1 macrophage/Kupffer cells (KC) polarization from Th1 cytokines are important in the pathogenesis of IR liver injury with hepatic steatosis (HS). Conversely, anti-inflammatory M2 macrophages produce Th2 cytokine (interleukin-4), which reciprocally enhances M2 polarization. Toll-like receptor 4-activated KCs can release proinflammatory mediators, skew M1 polarization and escalate liver IR injury. Decoy receptor 3 (DcR3) could be potential agents simultaneously blocking the IR liver injury-related pathogenic changes and extend the survival of steatotic graft.


METHODS
Rats were fed with methionine and choline-deficient high-fat diet (MCD HFD) for 6 weeks to induce HS. Preliminary experiments with HS group and IR group were conducted, and either immunoglobulin G Fc protein or DcR3 analogue was treated for 14 days in all groups to evaluate the severity. In the Zucker rat-focused experiments, various serum and hepatic substances, M1 polarization, and hepatic microcirculation were assessed.


RESULTS
We found that serum/hepatic DcR3levels were lower in nonalcoholic fatty liver disease patients with HS. DcR3a protected Zucker rats with HS from IR liver injury. The beneficial effects of DcR3a supplement were mediated by inhibiting hepatic M1 polarization of KCs, decreasing serum/hepatic TNFα, nitric oxide, nitrotyrosine, soluble TNF-like cytokine 1A, Fas ligand, and interferon-γ levels, neutrophil infiltration, and improving hepatic microcirculatory failure among rats with IR-injured steatotic livers. Additionally, downregulated hepatic TNF-like cytokine 1A/Fas-ligand and toll-like receptor 4/nuclear factor-κB signals were found to mediate the DcR3a-related protective effects of steatotic livers from IR injury.


CONCLUSIONS
Using multimodal in vivo and in vitro approaches, we found that DcR3a analogue was a potential agent to protect steatotic liver against IR injury by simultaneous blockade of the multiple IR injury-related pathogenic changes.
Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chiayi Branch, Taichung Veteran General Hospital, Chiayi, Taiwan, ROC; Institute of Clinical Medicine, Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Tzu-Hao
TH
Li
Division of Allergy, Immunology and Rheumatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC.
Chih-Wei
CW
Liu
Division of Gastroenterology and Hepatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Pei-Chang
PC
Lee
Division of Clinical Skills Training, Taipei Veteran General Hospital, Taipei, Taiwan, ROC; Division of General Medicine, Department of Medicine, Taipei Veteran General Hospital, Taipei, Taiwan, ROC.
Chia-Chang
CC
Huang
Division of Gastroenterology and Hepatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Kuei-Chuan
KC
Lee
Division of Gastroenterology and Hepatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Yun-Cheng
YC
Hsieh
Institute of Clinical Medicine, Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Division of Allergy, Immunology and Rheumatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC; Division of Gastroenterology and Hepatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Division of General Medicine, Department of Medicine, Taipei Veteran General Hospital, Taipei, Taiwan, ROC. Electronic address: yangyy@vghtpe.gov.tw.
Ying-Ying
YY
Yang
Institute of Clinical Medicine, Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC.
Shie-Liang
SL
Hsieh
Division of Gastroenterology and Hepatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Han-Chieh
HC
Lin
Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chiayi Branch, Taichung Veteran General Hospital, Chiayi, Taiwan, ROC; Department of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Chang-Youh
CY
Tsai
D000818:Animals; D017209:Apoptosis; D019587:Dietary Supplements; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy*; D051381:Rats; D011924:Rats, Zucker; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000008:administration & dosage* / Q000097:blood; D015427:Reperfusion Injury / Q000517:prevention & control*; D051197:Toll-Like Receptor 4 / Q000502:physiology
D016328:NF-kappa B; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D051197:Toll-Like Receptor 4
Kupffer cells; Toll-like receptor 4; hepatic steatosis; ischemia–reperfusion injury