Effects of Modulating Hepatic Nrf1 and Nrf2 Activity on Obesity-linked Metabolic Associated Steatohepatitis
| dc.contributor.advisor | Widenmaier, Scott B | |
| dc.contributor.committeeMember | Unniappan, Suraj | |
| dc.contributor.committeeMember | Campanucci, Veronica | |
| dc.contributor.committeeMember | Bekar, Lane | |
| dc.contributor.committeeMember | Xiao, Changting | |
| dc.contributor.committeeMember | Schertzer, Jonathan D | |
| dc.creator | Akl, May G | |
| dc.creator.orcid | 0000-0001-8062-3985 | |
| dc.date.accessioned | 2024-12-04T20:24:53Z | |
| dc.date.available | 2024-12-04T20:24:53Z | |
| dc.date.copyright | 2024 | |
| dc.date.created | 2024-09 | |
| dc.date.issued | 2024-12-04 | |
| dc.date.submitted | September 2024 | |
| dc.date.updated | 2024-12-04T20:24:53Z | |
| dc.description.abstract | Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease. MASLD’s early steatotic asymptomatic stage is liable to progress to a more severe form known as metabolic dysfunction-associated steatohepatitis (MASH), with advanced complications such as cirrhosis and cancer. Such detrimental outcomes, besides a lack of effective therapeutic options, necessitate an adequate understanding of the mechanisms underpinning disease development and progression. Hepatocyte lipotoxicity, oxidative damage, and organelle dysfunction are main events when it comes to MASH progression. The stress defense transcription factors, nuclear factor erythroid 2 related factor-1 (Nrf1) and 2 (Nrf2) are two homologous transcription factors known for their cytoprotective role. They can also influence cholesterol, triglyceride, and glucose metabolism. Altogether, this led us to postulate that hepatocyte Nrf1 and Nrf2 exert a potential role in MASH development and progression and that enhancing their functions can be protective. In the current thesis, we found that Nrf1 and Nrf2 complementarily regulate genes regulating bile acid and cholesterol homeostasis. Their combined hepatocyte-specific deficiency accelerated MASH development after short-term MASH-promoting diet intake. Short-term hepatocyte Nrf1 deficiency was associated with mild steatosis and led to lower fasting and postprandial glycemia, while hepatocyte Nrf2 deficiency did not induce any evident effects. On the other hand, enhancing Nrf2 functions for 1-8 weeks, by injecting bardoxolone, effectively reduced lipid accumulation, inflammation, and fibrosis in MASH and in fibrosis mouse models. Combining Nrf2 induction with hepatocyte-specific overexpression of NRF1 augmented these effects to some extent. Moreover, long-term Nrf1 deficiency was accompanied by enhanced incidence of MASH-related hepatocarcinogenesis, and neither combined Nrf1 & Nrf2 nor Nrf2 deficiency alone showed similar effect. In summary, evidence in this thesis reveals that Nrf1 and Nrf2 are two stress defenders safeguarding against cell stress during MASH development. Both factors’ distinct and synergistic functions guard against MASH, liver fibrosis, and tumorigenesis. Nrf1 has another distinct regulatory role over glycemic homeostasis, requiring in-depth exploration. Importantly, these defense factors may be a beneficial therapeutic target in preventing MASH development and progression. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | https://hdl.handle.net/10388/16305 | |
| dc.language.iso | en | |
| dc.subject | MASLD | |
| dc.subject | MASH | |
| dc.title | Effects of Modulating Hepatic Nrf1 and Nrf2 Activity on Obesity-linked Metabolic Associated Steatohepatitis | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Anatomy, Physiology, and Pharmacology | |
| thesis.degree.discipline | Anatomy, Physiology, and Pharmacology | |
| thesis.degree.grantor | University of Saskatchewan | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |