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

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP−/−) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP−/− mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP−/− mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

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Inflammation and Cell Death During Cholestasis: The Evolving Role of Bile Acids

Gene Expression ◽

10.3727/105221619x15614873062730 ◽

2019 ◽

Vol 19 (3) ◽

pp. 215-228 ◽

Cited By ~ 11

Author(s):

Benjamin L. Woolbright ◽

Hartmut Jaeschke

Keyword(s):

Cell Death ◽

Liver Injury ◽

Bile Acids ◽

Primary Role ◽

Drug Induced ◽

Chronic Cholestasis ◽

Biliary Tracts ◽

Acute Retention ◽

Cholestatic Liver Injury

Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.

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Chlorpromazine-induced perturbations of bile acids and free fatty acids in cholestatic liver injury prevented by the Chinese herbal compound Yin-Chen-Hao-Tang

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-015-0627-2 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 14

Author(s):

Qiaoling Yang ◽

Fan Yang ◽

Xiaowen Tang ◽

Lili Ding ◽

Ying Xu ◽

...

Keyword(s):

Fatty Acids ◽

Liver Injury ◽

Free Fatty Acids ◽

Bile Acids ◽

Chinese Herbal ◽

Herbal Compound ◽

Chinese Herbal Compound ◽

Cholestatic Liver Injury

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The Role of Inflammation in the Mechanisms of Bile Acid-Induced Liver Damage

Digestive Diseases ◽

10.1159/000450916 ◽

2017 ◽

Vol 35 (3) ◽

pp. 232-234 ◽

Cited By ~ 11

Author(s):

Shi-Ying Cai ◽

James L. Boyer

Keyword(s):

Bile Acid ◽

Liver Injury ◽

Inflammatory Response ◽

Bile Acids ◽

Liver Damage ◽

Inflammatory Cytokine ◽

Early Time ◽

Liver Cells ◽

Wild Type Littermate

Background: The mechanism by which bile acids induce liver injury in cholestasis remains controversial. Although high levels of bile acids are toxic when applied to liver cells, the level of toxic bile acids in the liver of most cholestatic animals and patients is <10 μM, indicating there must be alternative mechanisms. Recent studies suggest that the inflammatory response may play an important role in bile acid-induced liver injury, as pro-inflammatory cytokine expression is stimulated by bile acids in mouse hepatocyte cultures. To elucidate the mechanisms of bile acid-induced liver injury, we assessed signs of liver damage and gene expression in Abcb4-/- mice, a well-known model for cholestasis. Key Messages: Elevated plasma levels of bile acids were detected as early as 10 days after birth and at all later ages in Abcb4-/- mice compared to their wild-type littermate controls. Parallel increases in expression of Tnfα, Ccl2, Cxcl1, and Cxcl2 mRNA occurred at these early time points and throughout 12 weeks in Abcb4-/- livers. Marked hepatic neutrophil infiltration was first detected in 3-week mice, whereas histological evidence of liver injury was not detected until 6-weeks of age. Subsequent in vitro studies demonstrated that normal hepatocytes but not other non-parenchymal liver cells responded to bile acids with inflammatory cytokine induction. Conclusion: Bile acids induce the expression of pro-inflammatory cytokines in hepatocytes in Abcb4-/- mice that initiates an inflammatory response. This inflammatory response plays an important role in the development of cholestatic liver injury in this and other cholestatic conditions. Furthermore, understanding of these inflammatory mechanisms should lead to new therapeutic approaches for cholestatic liver diseases.

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