scholarly journals Functional Role of the Secretin/Secretin Receptor Signaling During Cholestatic Liver Injury

Hepatology ◽  
2020 ◽  
Vol 72 (6) ◽  
pp. 2219-2227 ◽  
Author(s):  
Nan Wu ◽  
Leonardo Baiocchi ◽  
Tianhao Zhou ◽  
Lindsey Kennedy ◽  
Ludovica Ceci ◽  
...  
Keyword(s):  
Liver Injury ◽  
Functional Role ◽  
Receptor Signaling ◽  
Secretin Receptor ◽  
Cholestatic Liver Injury

473 Functional Role of Definitive Endoderm Marker FOXA2 in Biliary-Committed Progenitor Cells During Cholestatic Liver Injury

2014 ◽  
Vol 146 (5) ◽  
pp. S-912
Author(s):  
Kelly McDaniel ◽  
Yuyan Han ◽  
Shannon Glaser ◽  
Heather L. Francis ◽  
Julie Venter ◽  
...  
Keyword(s):  
Liver Injury ◽  
Progenitor Cells ◽  
Functional Role ◽  
Definitive Endoderm ◽  
Cholestatic Liver Injury

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Gut ◽  
2019 ◽  
Vol 68 (8) ◽  
pp. 1477-1492 ◽  
Author(s):  
Lijun Liao ◽  
Kai Markus Schneider ◽  
Eric J C Galvez ◽  
Mick Frissen ◽  
Hanns-Ulrich Marschall ◽  
...  
Keyword(s):  
Immune Response ◽  
Liver Injury ◽  
Sclerosing Cholangitis ◽  
Functional Role ◽  
Innate Immune ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Intestinal Dysbiosis ◽  
Nlrp3 Inflammasome Activation

ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2−/−) model resembling human primary sclerosing cholangitis (PSC).DesignMale Mdr2−/−, Mdr2−/− crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/−/Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2−/−-associated intestinal dysbiosis was studied by microbiota transfer experiments.ResultsMdr2−/− mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis in Mdr2−/− mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2−/− microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.ConclusionsMDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

scholarly journals The functional role of micro RNA s in alcoholic liver injury

2014 ◽  
Vol 18 (2) ◽  
pp. 197-207 ◽  
Author(s):  
Kelly McDaniel ◽  
Leonardo Herrera ◽  
Tianhao Zhou ◽  
Heather Francis ◽  
Yuyan Han ◽  
...  
Keyword(s):  
Liver Injury ◽  
Functional Role ◽  
Micro Rna ◽  
Alcoholic Liver Injury

scholarly journals Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

2018 ◽  
Vol 314 (3) ◽  
pp. G319-G333 ◽  
Author(s):  
Nadine Gehrke ◽  
Michael Nagel ◽  
Beate K. Straub ◽  
Marcus A. Wörns ◽  
Marcus Schuchmann ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Bile Acids ◽  
Bile Duct Ligation ◽  
Ex Vivo ◽  
Mapk Signaling ◽  
Caspase 8 ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

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.

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

2019 ◽  
Vol 19 (3) ◽  
pp. 215-228 ◽  
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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