Mechanisms of bile acid mediated inflammation in the liver

Li, Man; Cai, Shi‐Ying; Boyer, James L.

doi:10.1016/j.mam.2017.06.001

Cited by 193 publications

(130 citation statements)

References 112 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…89 It is well known that inflammation plays major roles in cholestasis. 90 In BDL-induced obstructive cholestasis, neutrophil infiltration, proinflammatory cytokine over production and oxidative stress are correlated with the severity of cholestatic liver injury. 91,92 Bile acids and/or triterpenoids overdose-mediated inflammation in the biliary tree may contribute to cholestatic liver injury.…”

Section: Tgr5 Activation In Oa Hepatoprotection and Hepatotoxicitymentioning

confidence: 99%

“…91,92 Bile acids and/or triterpenoids overdose-mediated inflammation in the biliary tree may contribute to cholestatic liver injury. 18,19,90 In this regards, chenodeoxycholic acid produced cholestasis by activating the NLRP3 inflammasome through TGR5 downstream signalling F I G U R E 3 The Nrf2/ARE activation in OA-mediated hepatoprotection and hepatotoxicity. Induction of Nrf2 (1) promotes GSH biosynthesis and GSH conjugation; (2) increases in Nqo1 and HO-1 detoxify electrophiles; (3) increases in Phase-2 detoxification conjugation; and (4) increases in the Mrp efflux pumps to eliminate toxic bile acids out of hepatocytes.…”

Section: Tgr5 Activation In Oa Hepatoprotection and Hepatotoxicitymentioning

confidence: 99%

See 1 more Smart Citation

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

Liu

Lü

et al. 2018

Liver International

View full text Add to dashboard Cite

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.

show abstract

Section: Tgr5 Activation In Oa Hepatoprotection and Hepatotoxicitymentioning

confidence: 99%

Section: Tgr5 Activation In Oa Hepatoprotection and Hepatotoxicitymentioning

confidence: 99%

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

Liu

Lü

et al. 2018

Liver International

View full text Add to dashboard Cite

show abstract

“…Given the liver involvement in their synthesis and transport, the liver is exposed to very high concentrations of bile acids. While their detergent‐like properties help with digestion, leakage and accumulation of bile acids in hepatocytes at higher concentrations may lead to activation of cholangiocytes, causing chronic inflammation, proliferation, apoptosis and subsequently fibrosis . Bile acids are thought to play a key role in the progression of both PBC and PSC.…”

Section: Bile Acid Homoeostasis Signalling Pathways and Targets For mentioning

confidence: 99%

Novel and emerging therapies for cholestatic liver diseases

Goldstein

Levy

2018

Liver International

View full text Add to dashboard Cite

While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

show abstract

“…Neutrophils express myeloperoxidase, which catalyzes the production of large amounts of hypochlorous acid, which kills liver cells by strong oxidation. Immunohistochemistry confirmed that 3-chlorotyrosine-protein complex staining was positive in hepatic necrotic tissue during cholestasis, indicating that neutrophils in the hepatic necrosis area release highly toxic hypochlorous acid, leading to hepatocyte death (14).…”

Section: The Role Of Neutrophils In Cholestasismentioning

confidence: 76%

Anti-inflammatory, anti-oxidative stress and novel therapeutic targets for cholestatic liver injury

Zhang

et al. 2019

BST

View full text Add to dashboard Cite

Cholestasis is a pathological process in which bile drainage is poor for a variety of reasons. Many studies have shown that cholestatic liver injury is a neutrophil-mediated inflammatory response, and oxidative stress induced by neutrophils is the main mechanism of liver cell death. The literature summarizes the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the oxidative stress damage produced by neutrophil activation, summarizes the latest research progress. Sphingosine-1-phosphate receptor (S1PR) is a potential therapeutic target for cholestasis that reduces neutrophil aggregation without inhibiting systemic immune status. Early growth response factor 1 (Egr-1) may play a central role in the inflammation induced by cholestasis, and it is also a potential therapeutic target to inhibit the inflammation induced by cholestasis. Strengthening the antioxidant system of hepatocytes to cope with oxidative stress of neutrophils is a feasible treatment for cholestatic liver injury.

show abstract

Mechanisms of bile acid mediated inflammation in the liver

Cited by 193 publications

References 112 publications

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

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

Novel and emerging therapies for cholestatic liver diseases

Anti-inflammatory, anti-oxidative stress and novel therapeutic targets for cholestatic liver injury

Contact Info

Product

Resources

About