Role of trans-10, cis-12 conjugated linoleic acid and unconventional prefoldin RPB5 interactor 1 protein in non-alcoholic fatty liver disease
| dc.contributor.author | Cordero-Monroy, Luis | |
| dc.contributor.examiningcommittee | Suh, Miyoung (Food and Human Nutritional Sciences) | en_US |
| dc.contributor.examiningcommittee | McManus, Kirk (Biochemistry and Medical Genetics) | en_US |
| dc.contributor.supervisor | Taylor, Carla | |
| dc.contributor.supervisor | Zahradka, Peter | |
| dc.date.accessioned | 2022-09-16T14:01:56Z | |
| dc.date.available | 2022-09-16T14:01:56Z | |
| dc.date.copyright | 2022-09-14 | |
| dc.date.issued | 2022-09-14 | |
| dc.date.submitted | 2022-09-14T18:22:29Z | en_US |
| dc.degree.discipline | Food and Human Nutritional Sciences | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| dc.description.abstract | Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Due to its high prevalence, and its link to hepatocellular carcinoma (HCC), studying the pathogenesis of NAFLD is crucial. Unconventional prefoldin RPB5 interactor 1 (URI1) belongs to the prefoldin family of proteins that have been shown to coordinate nutrient availability by transcriptional regulation of genes involved in glucose and lipid metabolism. URI1 has been shown to be elevated in mouse liver after induction of NAFLD by a high fat diet and contributes to the development of HCC. Trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA) is marketed as a weight loss supplement and feeding t10,c12 CLA to mice results in hepatic steatosis (the earliest stage of NAFLD characterized by hepatic lipid accumulation). In this thesis, it is hypothesized that t10,c12 CLA feeding of lean and obese db/db mice facilitates hepatic steatosis through upregulation of URI1 protein expression. The validity of this hypothesis was assessed using in vivo (mouse) and in vitro (H4IIE cell line) experimental models, which included heterozygous and homozygous Uri1 knock out (KO) H4IIE cell lines, which were generated using the CRISPR/Cas9 system. T10,c12 CLA feeding promoted hepatic steatosis in both lean and db/db mice, compared to mice fed the control diet, by upregulating hepatic de novo lipogenesis and fatty acid uptake which, potentially, may occur by t10,c12 CLA-mediated activation of the mammalian target of rapamycin pathway. Obesity- and t10,c12 CLA-induced hepatic steatosis also resulted in i increased hepatic URI1 levels. In parallel, URI1 protein levels and neutral lipid accumulation in vitro were both elevated the most after 24 hours of oleic acid (OA) treatment. Lastly, in comparison to wild type H4IIE cells, Uri1 KO H4IIE cells exhibited fewer lipid droplets in response to OA treatment, suggesting a role for URI1 in hepatic lipid accumulation. In conclusion, t10,c12 CLA may promote hepatic steatosis by upregulating hepatic URI1 expression since t10,c12 CLA feeding resulted in increased hepatic URI1 protein levels and URI1 facilitates hepatic lipid accumulation. This study identifies URI1 as a potential novel promoter of hepatic steatosis which may also contribute to the progression of NAFLD to HCC. | en_US |
| dc.description.note | October 2022 | en_US |
| dc.description.sponsorship | Natural Sciences and Engineering Research Council | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/36913 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Non-alcoholic fatty liver disease | en_US |
| dc.subject | trans-10, cis-12 conjugated linoleic acid | en_US |
| dc.subject | Unconventional prefoldin RPB5 interacting 1 protein | en_US |
| dc.subject | Lipid droplets | en_US |
| dc.subject | hepatocytes | en_US |
| dc.subject | CRISPR/Cas9 | en_US |
| dc.subject | lipid | en_US |
| dc.title | Role of trans-10, cis-12 conjugated linoleic acid and unconventional prefoldin RPB5 interactor 1 protein in non-alcoholic fatty liver disease | en_US |
| dc.type | master thesis | en_US |
| local.subject.manitoba | no | en_US |
| oaire.awardTitle | University Collaborative Research Grant | en_US |
| oaire.awardURI | https://umanitoba.ca/research/ors/media/UCRP_Guidelines_2021.pdf | en_US |
| project.funder.identifier | http://dx.doi.org/10.13039/100010318 | en_US |
| project.funder.name | University of Manitoba | en_US |