Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response

Cai, Shi‐Ying; Ouyang, Xinshou; Chen, Yonglin; Soroka, Carol J.; Wang, Juxian; Mennone, Albert; Wang, Yucheng; Mehal, Wajahat Z.; Jain, Dhanpat; Boyer, James L.

doi:10.1172/jci.insight.90780

Cited by 192 publications

(215 citation statements)

References 38 publications

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“…Once accumulated in the cell, bile acid caused ER stress and mitochondrial damage, as has been previously reported (23–27). However, there was no evidence of caspase 3 cleavage in these cells, in agreement with the findings of others that apoptosis is not playing a role (10–12, 18). …”

Section: Cholestatic Hepatocytes Initiate Inflammatory Response Bysupporting

confidence: 92%

“…Of note, MyD88 and Trif are downstream molecules in Tlr9 signaling pathway. Reduced liver injury was also found in Tlr9 −/− mouse liver after BDL (18, 29). However, Tlr9 normally resides on the endoplasmic reticulum and endosomes so that the mechanism of activation remains unclear.…”

Section: Cholestatic Hepatocytes Initiate Inflammatory Response Bymentioning

confidence: 83%

“…However, Tlr9 normally resides on the endoplasmic reticulum and endosomes so that the mechanism of activation remains unclear. One possibility is that injured mitochondria undergo autophagy/mitophagy and present mitochondrial DNA to Tlr9 (30) Bile acid induction of cytokines are reduced in mouse hepatocytes when mitochondria are protected by cyclosporine A or norursodeoxycholic acid, (18). Norursodeoxycholic acid also improves liver function in several cholestatic rodent models and in patients with sclerosing cholanagitis in a recent phase II trial (31–33).…”

Section: Cholestatic Hepatocytes Initiate Inflammatory Response Bymentioning

confidence: 99%

“…Rather, it is the infiltration of neutrophils that best correlates with liver injury in cholestasis (16–18). Altogether, these concerns suggest that under pathophysiological conditions, bile acids must injure the liver by alternative mechanisms rather than by their intrinsic toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

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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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Section: Cholestatic Hepatocytes Initiate Inflammatory Response Bysupporting

confidence: 92%

Section: Cholestatic Hepatocytes Initiate Inflammatory Response Bymentioning

confidence: 83%

Section: Cholestatic Hepatocytes Initiate Inflammatory Response Bymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

Self Cite

193

120

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show abstract

“…A high concentration of bile acids, especially the hydrophobic bile acids, is particularly toxic and promotes hepatocyte damage, liver fibrosis, cirrhosis and hepatocellular carcinoma under cholestatic conditions (29,30). Notably, the reduced flow of bile acids into the small intestine facilitates the movement of flora and bacterial endotoxins from the portal vein into the liver and causes disruption of the intestinal epithelial barrier (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Heme Oxygenase-1 against Intestinal Barrier Dysfunction in Cholestatic Liver Injury Is Associated with NF-κB Inhibition

Zhang

Liu

et al. 2017

Mol Med

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Heme oxygenase-1 (HO-1) is reported to protect against liver injury, but little is known about its effect on the intestinal barrier in cholestatic liver injury. In this study, we investigated the effects of HO-1 and its enzymatic by-product on intestinal barrier dysfunction in bile duct ligation (BDL) rats and explored the possible mechanism. The HO-1 inducer cobalt protoporphyrin (CoPP) and carbon monoxide-releasing molecule-2 (CORM-2) were used; the expression levels of tight junction (TJ) proteins, intestinal inflammation and NF-κB p65 were measured. For an in vitro experiment, stable Caco-2 cell lines were constructed, one overexpressed the HO-1 gene and another with that gene knocked down, and the specific NF-κB inhibitor JSH-23 was used. CoPP and CORM-2 treatment alleviated liver and intestinal mucosa injury in BDL rats; improved ZO-1, claudin-1 and PCNA expression; and reduced cell apoptosis and intestinal interleukin-6 (IL-6) expression. In vitro studies confirmed that HO-1, ZO-1 and occludin were overexpressed in HO-1-transfected Caco-2 cells, while decreased in the short hairpin HO (sh-HO-1) group. JSH-23 significantly increased occludin expression in both the HO-1 overexpression and sh-HO-1 groups, compared with their respective controls. HO-1 overexpression also inhibited the nuclear translocation of NF-κB p65 after lipopolysaccharide (LPS) treatment. Additionally, phospho-p65 expression in sh-HO-1 cells was significantly increased compared with that of the HO-1 overexpression group. In conclusion, HO-1 and CORM-2 improved intestinal epithelial barrier function in BDL-induced cholestatic liver injury mainly by restoring TJ, reducing cell apoptosis and intestinal inflammation. HO-1 exerts a protective effect, which is partially correlated with the regulation of NF-κB.

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FXR controls CHOP expression in steatohepatitis

et al. 2017

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The farnesoid X receptor (FXR) and C/EBP homologous protein (CHOP) have critical functions in hepatic lipid metabolism. Here, we aimed to explore a potential relationship between FXR and CHOP. We fed wild‐type (WT) and FXR KO mice a MCD diet (model of steatohepatitis) and found that Chop mRNA expression is upregulated in WT but not FXR KO mice. The absence of FXR aggravates hepatic inflammation after MCD feeding. In HepG2 cells, we found that Chop expression is regulated in a FXR/Retinoid X receptor (RXR)‐dependent manner. We identified a FXR/RXR‐binding site in the human CHOP promoter, demonstrating a highly conserved regulatory pathway. Our study shows that FXR/RXR regulates Chop expression in a mouse model of steatohepatitis, providing novel insights into pathogenesis of this disorder.

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Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response

Cited by 192 publications

References 38 publications

Mechanisms of bile acid mediated inflammation in the liver

Mechanisms of bile acid mediated inflammation in the liver

The Protective Effect of Heme Oxygenase-1 against Intestinal Barrier Dysfunction in Cholestatic Liver Injury Is Associated with NF-κB Inhibition

FXR controls CHOP expression in steatohepatitis

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