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TGR5 deficiency aggravates hepatic ischemic/reperfusion injury via inhibiting SIRT3/FOXO3/HIF-1? pathway.

ABSTRACT: Ischemia/reperfusion (I/R) injury is responsible for liver injury during hepatic resection and liver transplantation. The plasma membrane-bound G protein-coupled bile acid receptor (TGR5) could regulate immune response in multiple liver diseases. Nevertheless, the underlying role of TGR5 in hepatic I/R injury remains largely unknown. This study aimed to investigate the potential mechanism of TGR5 in hepatic I/R injury. Wild-type (WT) and TGR5 knockout (TGR5KO) mice were used to perform hepatic I/R, and macrophages were isolated from mice for in vitro experiments. The results demonstrated that knockout of TGR5 in mice significantly exacerbated liver injury and inflammatory response. TGR5KO mice infused with WT macrophages showed relieved liver injury. Further study revealed that TGR5 knockout inhibited sirtuin 3 (SIRT3) and forkhead box O3 (FOXO3) expression. In vitro experiments indicated that SIRT3 inhibited acetylation, ubiquitination and degradation of FOXO3. FOXO3 inhibited HIF-1? transcription by binding to its promoter. TGR5 knockout inhibited SIRT3 expression, thus promoted the acetylation, ubiquitination, and degradation of FOXO3, which resulted in increased HIF-1? transcription and macrophages proinflammatory response. Collectively, TGR5 plays a critical protective role in hepatic I/R injury. FOXO3 deacetylation mediated by SIRT3 can attenuate hepatic I/R injury. TGR5 deficiency aggravates hepatic I/R injury via inhibiting SIRT3/FOXO3/HIF-1? pathway.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7604280 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TGR5 deficiency aggravates hepatic ischemic/reperfusion injury via inhibiting SIRT3/FOXO3/HIF-1ɑ pathway.

Wang Qi Q Wei Song S Li Lei L Qiu Jiannan J Zhou Shun S Shi Chengyu C Shi Yong Y Zhou Haoming H Lu Ling L

Cell death discovery 20201101 1

Ischemia/reperfusion (I/R) injury is responsible for liver injury during hepatic resection and liver transplantation. The plasma membrane-bound G protein-coupled bile acid receptor (TGR5) could regulate immune response in multiple liver diseases. Nevertheless, the underlying role of TGR5 in hepatic I/R injury remains largely unknown. This study aimed to investigate the potential mechanism of TGR5 in hepatic I/R injury. Wild-type (WT) and TGR5 knockout (TGR5KO) mice were used to perform hepatic I ...[more]

PMID: 33298860

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Project description:Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn(-/-) mice compared with wild-type (Wt) mice after I-R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn(-/-) mice versus Wt mice after I-R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn(-/-) mice versus Wt mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.

Dataset Information

TGR5 deficiency aggravates hepatic ischemic/reperfusion injury via inhibiting SIRT3/FOXO3/HIF-1? pathway.

Publications

TGR5 deficiency aggravates hepatic ischemic/reperfusion injury via inhibiting SIRT3/FOXO3/HIF-1ɑ pathway.

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