Gut-derived Danger Signals Contribute to Hepatocellular Injury and Inflammation during Non-alcoholic Fatty Liver Disease

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dc.contributor.advisorEksteen, Bertus
dc.contributor.advisorReimer, Raylene
dc.contributor.authorReid, Danielle
dc.contributor.committeememberMadsen, Karen
dc.contributor.committeemembervon der Weid, Pierre-Yves
dc.contributor.committeememberBeck, Paul
dc.contributor.committeememberMcKay, Derek
dc.contributor.committeememberJenne, Craig
dc.date.accessioned2016-10-05T19:05:05Z
dc.date.available2016-10-05T19:05:05Z
dc.date.issued2016
dc.date.submitted2016en
dc.description.abstractNon-alcoholic fatty liver disease (NAFLD) has become the leading liver disease in North America. Associated with the obesity epidemic, it is estimated that NAFLD currently affects over seven million Canadians. In certain cases, individuals with NAFLD may develop a progressive, inflammatory liver disease known as non-alcoholic steatohepatitis (NASH) that may lead to cirrhosis or hepatocellular carcinoma. Currently, the etiology of NASH remains unclear and there are no treatment strategies available beyond intensive dietary and lifestyle modification. The goal of this dissertation was to examine if the activation of liver-resident macrophages, Kupffer cells, by gut-derived metabolites contributes to the release of pro-inflammatory mediators and the recruitment of effector immune cells to promote inflammation and hepatocellular damage in experimental NASH. We found that Kupffer cells are critical for initiating inflammation during NASH while the absence of KCs limits the recruitment of leukocytes into the liver and protects against inflammation. Moreover, we identified unique transcriptional differences in resident and recruited macrophage populations that reflect the dynamic changes we characterized in Kupffer cells and infiltrating monocyte-derived macrophages during NASH. It has been suggested that compromised gut barrier function associated with obesity may result in the translocation of microbial by-products into the liver and contribute to hepatocellular injury and inflammation observed in NASH. We strengthen this link between the gut and the liver through the identification of novel, gut-derived volatile organic compounds (VOCs) in portal circulation in mice with NASH that have the potential to directly disrupt cellular processes in KCs and result in the secretion of proinflammatory cytokines. Once in the liver, microbial by-products such as VOCs may be detected by KCs through innate pattern recognition receptors such as the NLRP3 inflammasome, lead to the activation of KCs and contribute to inflammation in the liver. We found that the expression of the NLRP3 inflammasome within KCs has a dual proinflammatory and protective role during the development of experimental steatohepatitis. These studies provide evidence that gut-liver crosstalk influencing the activation of Kupffer cells is central in the development of experimental NASH and should be a major target for the development of novel treatment strategies.en_US
dc.identifier.citationReid, D. (2016). Gut-derived Danger Signals Contribute to Hepatocellular Injury and Inflammation during Non-alcoholic Fatty Liver Disease (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26334en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/26334
dc.identifier.urihttp://hdl.handle.net/11023/3410
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectImmunology
dc.subject.classificationFatty liver diseaseen_US
dc.subject.classificationGut-liver axisen_US
dc.subject.classificationMacrophagesen_US
dc.titleGut-derived Danger Signals Contribute to Hepatocellular Injury and Inflammation during Non-alcoholic Fatty Liver Disease
dc.typedoctoral thesis
thesis.degree.disciplineImmunology
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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