Akl, M.G.; Li, L.; Widenmaier, S.B. Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, Against MASLD Progression. Preprints2024, 2024041036. https://doi.org/10.20944/preprints202404.1036.v1
APA Style
Akl, M.G., Li, L., & Widenmaier, S.B. (2024). Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, Against MASLD Progression. Preprints. https://doi.org/10.20944/preprints202404.1036.v1
Chicago/Turabian Style
Akl, M.G., Lei Li and Scott B Widenmaier. 2024 "Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, Against MASLD Progression" Preprints. https://doi.org/10.20944/preprints202404.1036.v1
Abstract
Background: Progression of metabolic dysfunction associated steatotic liver disease (MASLD) to steatohepatitis (MASH) is driven by stress-inducing lipids that promote liver inflammation and fibrosis. MASH can lead to cirrhosis and hepatocellular carcinoma. We showed coordinated defenses regulated by transcription factors, nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2), protect against hepatic lipid stress. Here, we investigated protective effects of hepatocyte Nrf1 and Nrf2 against MASLD-induced liver fibrosis and tumorigenesis.
Methods: Using mice fed MASH diet for 24-52 weeks, we examined MASLD in mice with hepatocyte specific Nrf1, Nrf2, or combined deletion, and compared this to control. In a separate study, mice received weekly injections of carbon tetrachloride to induce liver fibrosis. From week 16-24, mice were treated with Nrf2 activating drug bardoxolone, hepatocyte overexpression of human NRF1 (hNRF1), or both, and groups were compared to control.
Results: Hepatocyte Nrf2 deficiency had no effect. Hepatocyte Nrf1 and combined deficiency caused MASH but only hepatocyte Nrf1 deficiency in male mice increased tumor number. Bardoxolone reduced liver steatosis, fibrosis, inflammation, and proliferation, and this effect when combined with hNRF1 was greater than bardoxolone alone.
Conclusion: Physiologic Nrf1 delays MASLD progression, Nrf2-induction alleviates MASH, and combined enhancement synergistically protects against steatosis.
Keywords
Nrf2; Nrf1; HCC; liver fibrosis; mash; masld
Subject
Biology and Life Sciences, Endocrinology and Metabolism
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
