PMID- 33169298 OWN - NLM STAT- MEDLINE DCOM- 20211208 LR - 20240226 IS - 1573-2576 (Electronic) IS - 0360-3997 (Linking) VI - 44 IP - 3 DP - 2021 Jun TI - TGR5 Attenuated Liver Ischemia-Reperfusion Injury by Activating the Keap1-Nrf2 Signaling Pathway in Mice. PG - 859-872 LID - 10.1007/s10753-020-01382-y [doi] AB - Hepatic ischemia/reperfusion injury (IRI) still remains an unavoidable problem in hepatectomy. The inflammatory response plays an important role in its pathogenesis. The plasma membrane-bound G protein-coupled bile acid receptor (TGR5), as one of G protein-coupled receptor (GPCR) families, has been proved to serve a protective role in several liver diseases. However, the exact function of TGR5 in modulating IRI remains obscure. We injected wild mice with a small interfering RNA of TGR5 (si-TGR5) or TGR5 agonist (INT-777) and established liver partial warm ischemia/reperfusion model. The results showed that knockdown of TGR5 significantly aggravated hepatic tissue injury, but treatment with INT-777 could reverse it, as evidenced by serum ALT and AST tests, liver histological injury, cytokines expressions, liver immunohistochemical analysis, and TUNEL staining. The apoptosis-associated proteins were evaluated after reperfusion. Moreover, we used primary bone marrow-derived macrophages (BMDMs) to establish hypoxia/reoxygenation (H/R) model to verify the anti-inflammation effect of TGR5. In in vivo experiments, we used TGR5-siRNA and TGR5 agonist (INT-777) to determine that TGR5 significantly attenuated liver damage after IRI through activating the Keap1-Nrf2 pathway. In addition, we found that overexpression of INT-777-activated TGR5 could reduce oxidative stress and inflammatory response in H/R-induced BMDMs through regulation of Keap1-Nef2 pathway during in vitro experiment. Importantly, these results were completely reversed in si-TGR5 BMDMs. In conclusion, the results indicated that TGR5 could effectively alleviated inflammation response via accelerating the activation of Keap1-Nrf2 signaling pathway during hepatic IRI, which may be meaningful in reducing related inflammatory molecules and adjusting inherent immunity. FAU - Zhuang, Lin AU - Zhuang L AUID- ORCID: 0000-0002-8107-9085 AD - Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, China. FAU - Ding, Wenbin AU - Ding W AD - The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Naval Medical University, Shanghai, 200438, China. FAU - Zhang, Qi AU - Zhang Q AD - Department of Intensive Care Unit, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical College of Xuzhou Medical University, Changzhou, 213000, China. FAU - Ding, Wei AU - Ding W AD - Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, China. FAU - Xu, Xuezhong AU - Xu X AD - Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, China. FAU - Yu, Xiaolong AU - Yu X AD - Department of Ultrasound, Wujin Affiliated Hospital of Jiangsu University and The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, China. xllxl9999@126.com. FAU - Xi, Dong AU - Xi D AD - Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, China. xi-dong76@hotmail.com. LA - eng GR - Z2019027/Medical research guidance project of Jiangsu Provincial Health Committee/ GR - ZD201719/Major science and technology projects of Changzhou City/ GR - JLY20180084/Clinical Medical Science and Technology Development Foundation of Jiangsu University/ GR - WS201708, WS201808, WS201611/Science and technology development projects of Wujin District/ GR - CZQM2020120/The project funding from Young Talent Development Plan of Changzhou Health Commission/ PT - Journal Article DEP - 20201110 PL - United States TA - Inflammation JT - Inflammation JID - 7600105 RN - 0 (6alpha-ethyl-23(S)-methylcholic acid) RN - 0 (Cholic Acids) RN - 0 (Cytokines) RN - 0 (Gpbar1 protein, mouse) RN - 0 (Keap1 protein, mouse) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Receptors, G-Protein-Coupled) SB - IM MH - Animals MH - Apoptosis MH - Cell Hypoxia MH - Cells, Cultured MH - Cholic Acids/pharmacology MH - Cytokines/genetics/metabolism MH - Disease Models, Animal MH - Kelch-Like ECH-Associated Protein 1/genetics/*metabolism MH - Liver/drug effects/*metabolism/pathology MH - Liver Diseases/genetics/*metabolism/pathology/prevention & control MH - Macrophages/metabolism MH - Male MH - Mice, Inbred C57BL MH - NF-E2-Related Factor 2/genetics/*metabolism MH - Oxidative Stress MH - RNA Interference MH - Receptors, G-Protein-Coupled/agonists/genetics/*metabolism MH - Reperfusion Injury/genetics/*metabolism/pathology/prevention & control MH - Signal Transduction MH - Warm Ischemia MH - Mice OTO - NOTNLM OT - Keap1-Nrf2 pathway OT - TGR5 OT - inflammation OT - ischemia-reperfusion injury EDAT- 2020/11/11 06:00 MHDA- 2021/12/15 06:00 CRDT- 2020/11/10 05:46 PHST- 2020/02/25 00:00 [received] PHST- 2020/11/02 00:00 [accepted] PHST- 2020/09/30 00:00 [revised] PHST- 2020/11/11 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2020/11/10 05:46 [entrez] AID - 10.1007/s10753-020-01382-y [pii] AID - 10.1007/s10753-020-01382-y [doi] PST - ppublish SO - Inflammation. 2021 Jun;44(3):859-872. doi: 10.1007/s10753-020-01382-y. Epub 2020 Nov 10.