Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of abnormal liver function in countries with western-style high fat, high cholesterol diets. Liver damage associated with NAFLD may lead to liver cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Additionally, recent data suggest that nonalcoholic steatohepatitis (NASH), the inflammatory phase of NAFLD, is linked to increased cardiovascular risk independent of the broad spectrum of risk factors of metabolic syndrome. Therefore, novel therapies are needed to inhibit the inflammatory liver damage that drives NAFLD. Hepatic macrophages (HMΦ’s), which include resident Kupffer cells and monocyte-derived macrophages, are the primary drivers of liver inflammation in both human and mouse models. In macrophages, chronic lipid exposure promotes pro-inflammatory polarization and the activation of pyroptosis via the NLRP3 inflammasome. While the role of the canonical pyroptosis pathway has been studied in NAFLD, the role of the newly discovered noncanonical (caspase-11/-Gasdermin-Ddependent) pathway has not been defined. Diet-induced NAFLD promoted hepatic steatosis and lobular inflammation in male WT mice. Caspase-11 deficiency decreases macrovesicular steatosis and total NAFLD Activity Score (NAS). High fat feeding promoted recruitment and activation of HMΦ in both Caspase-11 deficient (Casp11KO) and WT male mice, however, noncanonical pyroptosis (caspase-11 activity, surface Gasdermin-D, expression, liver IL-1β secretion) was ablated in HMΦs from Casp11KO mice. Bone marrow transplantation restored capacity for noncanonical pyroptosis in Casp11KO mice. RNAseq and microarray analysis revealed that lipid peroxidation and trained immunity mediate noncanonical pyroptosis in diet induced NALFD. / Biomedical Sciences / Accompanied by 1 PDF file: DrummerIV_temple_0225E_171/CED
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/7659 |
| Date | January 2022 |
| Creators | Drummer, Charles, 0000-0001-9059-1454 |
| Contributors | Yang, Xiao-Feng, Wang, Hong, 1956 September 19-, Khan, Mohsin, Hu, Wenhui, Zhang, Yanqiao |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 120 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/7631, Theses and Dissertations |
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