GPBAR1/TGR5 Mediates Bile Acid-Induced Cytokine Expression in Murine Kupffer Cells

Lou, Guiyu; Ma, Xiaoxiao; Fu, Xianghui; Meng, Zhipeng; Zhang, Wenyu; Wang, Yan Dong; Ness, Carl Van; Yu, Donna; Xu, Rongzhen; Huang, Wendong

doi:10.1371/journal.pone.0093567

Cited by 67 publications

(53 citation statements)

References 32 publications

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“…S1A in the supplemental material show that as previously reported, TGR5 activation induced the expression of the Il1b and Tnf genes (33). However, it failed to induce Defa20, Reg3b, or Reg3g, thus suggesting that TGR5 is not involved in the regulation of the synthesis of these AMPPs by CDCA.…”

Section: Resultssupporting

confidence: 67%

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

et al. 2017

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In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell ␣-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or ␤-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal Muc2 and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G ϩ and CD68 ϩ cells, while increasing the relative amount of IgG ϩ B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections.

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Section: Resultssupporting

confidence: 67%

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

et al. 2017

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“…Compared with wild-type mice, TGR5-deficient mice have higher AST levels after cholic acid feeding, as well as increased necrotic areas on liver sections 2 or 3 days after BDL, accompanied with significantly higher levels of serum CCL2 (MCP-1), further demonstrating a role for TGR5 in the protection of cholestatic liver injury (54, 56). The anti-inflammatory effect of TGR5 in macrophages is mediated by inhibiting of NF-kB and JNK signaling pathways (50, 91, 92), as well as through inhibition of NLRP3 inflammasome activation as discussed in detail below in Section 6.…”

Section: The Role Of Other Immune Cells In Cholestatic Liver Injurymentioning

confidence: 99%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

192

120

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Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

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“…In addition, OA decreases CYP 2E1 to reduce bioactivation of CC l 4 and acetaminophen and decreases Oatp1b2 to reduce hepatic uptake of phalloidin . OA is a TGR 5 activator to produce proinflammatory cytokines in the biliary tree implicating in cholestasis…”

Section: Mechanisms For Paradoxical Hepatoprotective and Hepatotoxic mentioning

confidence: 99%

Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses

Liu

Lü

et al. 2018

Liver International

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Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. OA is included in some dietary supplements and is used as a complementary and alternative medicine (CAM) in China, India, Asia, the USA and European countries. OA is effective in protecting against various hepatotoxicants, and one of the protective mechanisms is reprogramming the liver to activate the nuclear factor erythroid 2-related factor 2 (Nrf2). OA derivatives, such as CDDO-Im and CDDO-Me, are even more potent Nrf2 activators. OA has recently been shown to also activate the Takeda G-protein-coupled receptor (TGR5). However, whereas a low dose of OA is hepatoprotective, higher doses and long-term use of OA can produce liver injury, characterized by cholestasis. This paradoxical hepatotoxic effect occurs not only for OA, but also for other OA-type triterpenoids. Dose and length of time of OA exposure differentiate the ability of OA to produce hepatoprotection vs hepatotoxicity. Hepatotoxicity produced by herbs is increasingly recognized and is of global concern. Given the appealing nature of OA in dietary supplements and its use as an alternative medicine around the world, as well as the development of OA derivatives (CDDO-Im and CDDO-Me) as therapeutics, it is important to understand not only that they program the liver to protect against hepatotoxic chemicals, but also how they produce hepatotoxicity.

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GPBAR1/TGR5 Mediates Bile Acid-Induced Cytokine Expression in Murine Kupffer Cells

Cited by 67 publications

References 32 publications

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

Mechanisms of bile acid mediated inflammation in the liver

Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses

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