Effects of Modulating Hepatic Nrf1 and Nrf2 Activity on Obesity-linked Metabolic Associated Steatohepatitis
Date
2024-12-04
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0001-8062-3985
Type
Thesis
Degree Level
Doctoral
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.
Description
Keywords
MASLD, MASH
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Anatomy, Physiology, and Pharmacology
Program
Anatomy, Physiology, and Pharmacology