Please wait a minute...
Journal of Integrative Agriculture
Advanced Online Publication | Current Issue | Archive | Adv Search
Dietary sulforaphane modulates hepatic anti-oxidative genes via REV-ERBα and histone modifications in pigs

Yi-Ting Wang1, Shicheng Li1, Yufei Kan1, Yanli Zhu1, Kaiqi Li1 , Hao-Yu Liu1,2, Tadelle Dessie Alemayehu3, In Ho Kim4, Mohammad D. Obeidat5, Rui Zhang6,  Zhaojian Li1*,  Demin Cai1,2* 

1 Laboratory of Animal Physiology and Molecular Nutrition, Jiangsu Key Laboratory of Animal Genetic Breeding and Molecular Design, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China

2 International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement

3 Livestock Research Institute (ILRI)P.O. Box 5689, Addis Ababa

4 Dankook University 119, Dandae-ro, Cheonan, 31116, South Korea

5 Department of Animal Production, Jordan University of Science and Technology (JUST), P.O. Box 3030, 22110, Irbid JORDAN

6 Meat Processing Key Laboratory of Sichuan Province, College of Food and Biological Engineering, Chengdu University. Chengdu 610106, China

Download:  PDF in ScienceDirect  
Export:  BibTeX | EndNote (RIS)      
摘要  

萝卜硫素(SFN)是一种在十字花科蔬菜中天然存在的异硫氰酸酯,其在体内的抗炎和抗氧化效应而受到广泛关注。尽管SFN的健康益处已被广泛认可,但其在动物饲料中添加对猪肝脏健康的影响及其作用机制尚未完全明了。为了探究这一问题,本研究在猪的饲粮中添加了1g kg-1SFN,并在50天的饲养周期后对猪的肝脏和血清样本进行了深入分析。研究发现萝卜硫素的添加显著提升了猪的生长性能和肝细胞的增殖能力。此外,SFN还显示出对肝脏健康具有积极影响,它降低了肝脏和血清中的丙二醛(MDA)水平,这是氧化应激的一个重要生物标志物。同时,SFN还增加了肝脏中谷胱甘肽过氧化物酶(GSH-PX)的活性,这是一种关键的抗氧化酶。转录组和蛋白质组学研究表明,SFN下调了包括氧化磷酸化、炎症反应、IL-6-JAK-STAT3信号传导和通过NFκBTNFα信号传导在内的多个途径。这些途径的下调有助于减轻炎症和氧化应激。同时,它上调了NRF2/GPX4/HO-1的表达,并减少了IL-6TNFα的表达。这些都是与炎症和氧化应激相关的关键分子。机制研究进一步揭示SFN可能通过影响NR1D1NRF2这两个转录因子来调节肝脏中GPX4HO-1基因的表达。这些基因与抗氧化防御机制密切相关。此外,代谢组分析显示,SFN给药后血清中β-羟丁酸水平下降,这可能与SFN增强了肝脏中赖氨酸β-羟丁酰化(Kbhb)这种表观遗传修饰有关。Kbhb是一种新型的蛋白质修饰方式,其在调控代谢和炎症反应中的作用逐渐受到重视。综上所述,SFN在抵御肝脏炎症和氧化损伤中发挥着保护作用,而且可能通过NRF2NR1D1的协同作用以及促进肝脏Kbhb的形成来实现这些效果。这些发现为SFN在动物营养和健康领域的应用提供了新的科学依据,但SFN如何促进肝脏Kbhb的形成及其具体机制仍需进一步的研究和探索。



Abstract  

Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, is known for its anti-inflammatory and antioxidant effects in the body. However, whether its dietary addition impact porcine liver health, and if so, by which mechanims remains unclear. In this study, the diet of growing pigs was supplemented with 1 g kg-1 SFN and was found to improve growth performance and hepatocellular proliferation. Further analyses revealed that SFN decreased hepatic and serum malondialdehyde levels, while increasing glutathione peroxidase (GSH-PX) activity in the liver. Transcriptomic and proteomic studies demonstrated that SFN down-regulated multiple pathways, including oxidative phosphorylation, inflammatory responses, IL-6-JAK-STAT3 signaling, and TNFα signaling via NFκB. Meanwhile, it upregulated NRF2/GPX4/HO-1 expression and reduced IL-6 and TNFα expression. Mechanistic studies identified potential NR1D1 and NRF2 binding elements in the promoters of the GPX4 and HO-1 genes in the liver. Furthermore, Metabolomic profiling revealed a decline in serum β-hydroxybutyrate levels after the administration of SFN, while further analysis confirmed that SFN enhanced a type of epigenetic modification in the liver, lysine β-hydroxybutyrylation (Kbhb).  These results highlight SFN protective roles against liver inflammation and oxidative damage and propose a novel mechanism involving NRF2 and NR1D1 synergy, with SFN’s promotion of hepatic Kbhb necessitating further exploration.

Keywords:  Sulforaphane       Anti-oxidative       NR1D1       Lysine β-hydroxybutyrylatio  
Online: 17 February 2025  
Fund: 

This work was funded by the National Key R&D Program of China (2023YFD1301200, 2021YFD1300205), Jiangsu Provincial Double-Innovation Team Program (JSSCTD202147), Natural Science Foundation of Jiangsu Province (BK20220582, BK20210812), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Open Project Program of the International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement.

Cite this article: 

Yi-Ting Wang , Shicheng Li, Yufei Kan, Yanli Zhu, Kaiqi Li, Hao-Yu Liu, Tadelle Dessie Alemayehu, In Ho Kim, Mohammad D. Obeidat, Rui Zhang, Zhaojian Li, Demin Cai . 2025. Dietary sulforaphane modulates hepatic anti-oxidative genes via REV-ERBα and histone modifications in pigs. Journal of Integrative Agriculture, Doi:10.1016/j.jia.2025.02.019

Abdulkhaleq, L. A., M. A. Assi, R. Abdullah, M. Zamri-Saad, Y. H. Taufiq-Yap, and M. N. M. Hezmee. 2018. The crucial roles of inflammatory mediators in inflammation: A review. Vet World. 11(5), 627-635.

Adlanmerini, M., H. C. Nguyen, B. M. Krusen, C. W. Teng, C. E. Geisler, L. C. Peed, B. J. Carpenter, M. R. Hayes, and M. A. Lazar. 2021. Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice. J Clin Invest. 131(1).

Al Olayan, Ebtesam M., Abeer S. Aloufi, Ohoud D. AlAmri, Ola H. El-Habit, and Ahmed E. Abdel Moneim. 2020. Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: Role of oxidative stress, inflammation and apoptosis. Science of The Total Environment. 723137969.

Allameh, A., R. Niayesh-Mehr, A. Aliarab, G. Sebastiani, and K. Pantopoulos. 2023. Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants (Basel). 12(9).

Amir, Mohammed, Sweena Chaudhari, Ran Wang, Sean Campbell, Sarah A. Mosure, Laura B. Chopp, Qun Lu, Jinsai Shang, Oliver B. Pelletier, Yuanjun He, Christelle Doebelin, Michael D. Cameron, Douglas J. Kojetin, Theodore M. Kamenecka, and Laura A. Solt. 2018. REV-ERBα Regulates TH17 Cell Development and Autoimmunity. Cell Reports. 25(13).

Bellezza, I., I. Giambanco, A. Minelli, and R. Donato. 2018. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 1865(5), 721-733.

Blas-García, A., and N. Apostolova. 2023. Novel Therapeutic Approaches to Liver Fibrosis Based on Targeting Oxidative Stress. Antioxidants (Basel). 12(8).

Buonacera, Agata, Benedetta Stancanelli, Michele Colaci, and Lorenzo Malatino. 2022. Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases. International Journal of Molecular Sciences. 23(7).

Chang, C., C. S. Loo, X. Zhao, L. A. Solt, Y. Liang, S. P. Bapat, H. Cho, T. M. Kamenecka, M. Leblanc, A. R. Atkins, R. T. Yu, M. Downes, T. P. Burris, R. M. Evans, and Y. Zheng. 2019. The nuclear receptor REV-ERBalpha modulates Th17 cell-mediated autoimmune disease. Proc Natl Acad Sci U S A. 116(37), 18528-18536.

Chartoumpekis, Dionysios V., Panos G. Ziros, Jian-Guo Chen, John D. Groopman, Thomas W. Kensler, and Gerasimos P. Sykiotis. 2019. Broccoli sprout beverage is safe for thyroid hormonal and autoimmune status: Results of a 12-week randomized trial. Food and Chemical Toxicology : an International Journal Published For the British Industrial Biological Research Association. 1261-6.

Chen, Q. M., and A. J. Maltagliati. 2018. Nrf2 at the heart of oxidative stress and cardiac protection. Physiol Genomics. 50(2), 77-97.

Clark, G. M., L. G. Dressler, M. A. Owens, G. Pounds, T. Oldaker, and W. L. McGuire. 1989. Prediction of relapse or survival in patients with node-negative breast cancer by DNA flow cytometry. The New England Journal of Medicine. 320(10), 627-633.

Dasgupta, S., D. M. Lonard, and B. W. O'Malley. 2014. Nuclear receptor coactivators: master regulators of human health and disease. Annu Rev Med. 65279-92.

Dinkova-Kostova, A. T., and R. V. Kostov. 2012. Glucosinolates and isothiocyanates in health and disease. Trends Mol Med. 18(6), 337-47.

Dong, Z., H. Shang, Y. Q. Chen, L. L. Pan, M. Bhatia, and J. Sun. 2016. Sulforaphane Protects Pancreatic Acinar Cell Injury by Modulating Nrf2-Mediated Oxidative Stress and NLRP3 Inflammatory Pathway. Oxid Med Cell Longev. 20167864150.

Duez, H., J. N. van der Veen, C. Duhem, B. Pourcet, T. Touvier, C. Fontaine, B. Derudas, E. Baugé, R. Havinga, V. W. Bloks, H. Wolters, F. H. van der Sluijs, B. Vennström, F. Kuipers, and B. Staels. 2008. Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha. Gastroenterology. 135(2), 689-98.

Etemadi, Y., J. Y. Akakpo, A. Ramachandran, and H. Jaeschke. 2023. Nrf2 as a therapeutic target in acetaminophen hepatotoxicity: A case study with sulforaphane. J Biochem Mol Toxicol. 37(12), e23505.

Feng, J., J. Wang, Y. Wang, X. Huang, T. Shao, X. Deng, Y. Cao, M. Zhou, and C. Zhao. 2022. Oxidative Stress and Lipid Peroxidation: Prospective Associations Between Ferroptosis and Delayed Wound Healing in Diabetic Ulcers. Front Cell Dev Biol. 10898657.

Ford, H. R., and M. Bionaz. 2024. The Experimental and In Silico-Based Evaluation of NRF2 Modulators, Sulforaphane and Brusatol, on the Transcriptome of Immortalized Bovine Mammary Alveolar Cells. Int J Mol Sci. 25(8).

Forrester, S. J., D. S. Kikuchi, M. S. Hernandes, Q. Xu, and K. K. Griendling. 2018. Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circ Res. 122(6), 877-902.

Gilad, Y., D. M. Lonard, and B. W. O'Malley. 2022. Steroid receptor coactivators - their role in immunity. Front Immunol. 131079011.

Gurevich, I., A. M. Flores, and B. J. Aneskievich. 2007. Corepressors of agonist-bound nuclear receptors. Toxicol Appl Pharmacol. 223(3), 288-98.

Hao, Y., M. Xing, and X. Gu. 2021. Research Progress on Oxidative Stress and Its Nutritional Regulation Strategies in Pigs. Animals (Basel). 11(5).

He, F., X. Ru, and T. Wen. 2020. NRF2, a Transcription Factor for Stress Response and Beyond. Int J Mol Sci. 21(13).

He, Y., X. Cheng, T. Zhou, D. Li, J. Peng, Y. Xu, and W. Huang. 2023. β-Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications. Heliyon. 9(11), e21098.

Hiraki, M. 1994. Intracellular DNA and RNA in the course of tumor cell growth. The Kurume Medical Journal. 41(1).

Holman, J., M. Hurd, P. L. Moses, G. M. Mawe, T. Zhang, S. L. Ishaq, and Y. Li. 2023. Interplay of broccoli/broccoli sprout bioactives with gut microbiota in reducing inflammation in inflammatory bowel diseases. J Nutr Biochem. 113109238.

Hong, T., Y. Chen, X. Li, and Y. Lu. 2021. The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD. Oxid Med Cell Longev. 20216889533.

Huang, H., D. Zhang, Y. Weng, K. Delaney, Z. Tang, C. Yan, S. Qi, C. Peng, P. A. Cole, R. G. Roeder, and Y. Zhao. 2021. The regulatory enzymes and protein substrates for the lysine β-hydroxybutyrylation pathway. Sci Adv. 7(9).

Inc., Thermo Fisher Scientific 2016 TRIzol™ Reagent user guide.

Kong, Y., W. Zhou, and Z. Sun. 2020. Nuclear receptor corepressors in intellectual disability and autism. Mol Psychiatry. 25(10), 2220-2236.

Koronowski, K. B., C. M. Greco, H. Huang, J. K. Kim, J. L. Fribourgh, P. Crosby, L. Mathur, X. Ren, C. L. Partch, C. Jang, F. Qiao, Y. Zhao, and P. Sassone-Corsi. 2021. Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation. Cell Rep. 36(5), 109487.

Kowluru, R. A. 2023. Cross Talks between Oxidative Stress, Inflammation and Epigenetics in Diabetic Retinopathy. Cells. 12(2).

Kumar, N., L. A. Solt, Y. Wang, P. M. Rogers, G. Bhattacharyya, T. M. Kamenecka, K. R. Stayrook, C. Crumbley, Z. E. Floyd, J. M. Gimble, P. R. Griffin, and T. P. Burris. 2010. Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology. 151(7), 3015-25.

Li, Q., S. Yang, F. Chen, W. Guan, and S. Zhang. 2022. Nutritional strategies to alleviate oxidative stress in sows. Anim Nutr. 960-73.

Ligasová, Anna, and Karel Koberna. 2021. DNA Dyes-Highly Sensitive Reporters of Cell Quantification: Comparison with Other Cell Quantification Methods. Molecules (Basel, Switzerland). 26(18).

Ma, C., C. Gu, P. Lian, J. Wazir, R. Lu, B. Ruan, L. Wei, L. Li, W. Pu, Z. Peng, W. Wang, Y. Zong, Z. Huang, H. Wang, Y. Lu, and Z. Su. 2023. Sulforaphane alleviates psoriasis by enhancing antioxidant defense through KEAP1-NRF2 Pathway activation and attenuating inflammatory signaling. Cell Death Dis. 14(11), 768.

Migita, H., J. Morser, and K. Kawai. 2004. Rev-erbalpha upregulates NF-kappaB-responsive genes in vascular smooth muscle cells. FEBS Lett. 561(1-3), 69-74.

Nestle, M. 1998. Broccoli sprouts in cancer prevention. Nutr Rev. 56(4 Pt 1), 127-30.

Perissi, V., K. Jepsen, C. K. Glass, and M. G. Rosenfeld. 2010. Deconstructing repression: evolving models of co-repressor action. Nat Rev Genet. 11(2), 109-23.

Puchalska, P., and P. A. Crawford. 2021. Metabolic and Signaling Roles of Ketone Bodies in Health and Disease. Annu Rev Nutr. 4149-77.

Rao, Z. X., M. D. Tokach, J. C. Woodworth, J. M. DeRouchey, R. D. Goodband, and J. T. Gebhardt. 2023. Effects of Various Feed Additives on Finishing Pig Growth Performance and Carcass Characteristics: A Review. Animals (Basel). 13(2).

Saha, S., B. Buttari, E. Panieri, E. Profumo, and L. Saso. 2020. An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation. Molecules. 25(22).

Sajadimajd, S., and M. Khazaei. 2018. Oxidative Stress and Cancer: The Role of Nrf2. Curr Cancer Drug Targets. 18(6), 538-557.

Saleh, D. O., D. F. Mansour, I. M. Hashad, and R. M. Bakeer. 2019. Effects of sulforaphane on D-galactose-induced liver aging in rats: Role of keap-1/nrf-2 pathway. Eur J Pharmacol. 85540-49.

Sherman, Brad T., Ming Hao, Ju Qiu, Xiaoli Jiao, Michael W. Baseler, H. Clifford Lane, Tomozumi Imamichi, and Weizhong Chang. 2022. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Research. 50(W1), W216-W221.

Socała, Katarzyna, Dorota Nieoczym, Edyta Kowalczuk-Vasilev, Elżbieta Wyska, and Piotr Wlaź. 2017. Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice. Toxicology and Applied Pharmacology. 32643-53.

Tian, Y., Y. Wu, and B. Ni. 2015. Signaling Pathways and Epigenetic Regulations in the Control of RORγt Expression in T Helper 17 Cells. Int Rev Immunol. 34(4), 305-17.

Tossetta, G., and D. Marzioni. 2022. Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway. Pharmacol Res. 183106365.

van der Pol, A., W. H. van Gilst, A. A. Voors, and P. van der Meer. 2019. Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail. 21(4), 425-435.

Wang, H., B. Wang, J. Wei, Z. Zheng, J. Su, C. Bian, Y. Xin, and X. Jiang. 2022. Sulforaphane regulates Nrf2-mediated antioxidant activity and downregulates TGF-β1/Smad pathways to prevent radiation-induced muscle fibrosis. Life Sci. 311(Pt B), 121197.

Wolter, B. F., M. Ellis, B. P. Corrigan, J. M. DeDecker, S. E. Curtis, E. N. Parr, and D. M. Webel. 2003. Impact of early postweaning growth rate as affected by diet complexity and space allocation on subsequent growth performance of pigs in a wean-to-finish production system. J Anim Sci. 81(2), 353-9.

Wu, Y. K., Z. N. Ren, S. L. Zhu, Y. Z. Wu, G. Wang, H. Zhang, W. Chen, Z. He, X. L. Ye, and Q. X. Zhai. 2022. Sulforaphane ameliorates non-alcoholic fatty liver disease in mice by promoting FGF21/FGFR1 signaling pathway. Acta Pharmacol Sin. 43(6), 1473-1483.

Xu, Y., X. Huang, B. Huangfu, Y. Hu, J. Xu, R. Gao, K. Huang, and X. He. 2023. Sulforaphane Ameliorates Nonalcoholic Fatty Liver Disease Induced by High-Fat and High-Fructose Diet via LPS/TLR4 in the Gut-Liver Axis. Nutrients. 15(3).

Yagishita, Y., J. W. Fahey, A. T. Dinkova-Kostova, and T. W. Kensler. 2019. Broccoli or Sulforaphane: Is It the Source or Dose That Matters? Molecules. 24(19).

Yang, G., C. J. Wright, M. D. Hinson, A. P. Fernando, S. Sengupta, C. Biswas, P. La, and P. A. Dennery. 2014. Oxidative stress and inflammation modulate Rev-erbα signaling in the neonatal lung and affect circadian rhythmicity. Antioxid Redox Signal. 21(1), 17-32.

Yi, T., X. Li, E. Wang, Y. Zhang, Y. Fu, J. Li, and T. Jiang. 2018. Activation of the Nuclear Erythroid 2-Related Factor 2 Antioxidant Responsive Element (Nrf2-ARE) Signaling Pathway Alleviates Acute Graft-Versus-Host Disease by Reducing Oxidative Stress and Inhibiting Infiltration of Inflammatory Cells in an Allogeneic Stem Cell Transplantation Mouse Model. Med Sci Monit. 245973-5979.

Zaghlool, S. S., N. Abdelaal, E. A. M. El-Shoura, N. I. Mahmoud, and Y. M. Ahmed. 2023. Restoring glomerular filtration rate by sulforaphane modulates ERK1/2/JNK/p38MAPK, IRF3/iNOS, Nrf2/HO-1 signaling pathways against folic acid-induced acute renal injury in rats. Int Immunopharmacol. 123110777.

Zhang, D., Z. Tang, H. Huang, G. Zhou, C. Cui, Y. Weng, W. Liu, S. Kim, S. Lee, M. Perez-Neut, J. Ding, D. Czyz, R. Hu, Z. Ye, M. He, Y. G. Zheng, H. A. Shuman, L. Dai, B. Ren, R. G. Roeder, L. Becker, and Y. Zhao. 2019. Metabolic regulation of gene expression by histone lactylation. Nature. 574(7779), 575-580.

Zhang, H., K. Tang, J. Ma, L. Zhou, J. Liu, L. Zeng, L. Zhu, P. Xu, J. Chen, K. Wei, X. Liang, J. Lv, J. Xie, Y. Liu, Y. Wan, and B. Huang. 2020. Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8(+) T-cell memory development. Nat Cell Biol. 22(1), 18-25.

Zhang, S. 2023. From Challenge to Opportunity: Addressing Oxidative Stress in Animal Husbandry. Antioxidants (Basel). 12(8).

Zhang, Y. Q., C. X. Shi, D. M. Zhang, L. Y. Zhang, L. W. Wang, and Z. J. Gong. 2023. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 21(5), 464-473.

Zhang, Y., Q. Wu, J. Liu, Z. Zhang, X. Ma, Y. Zhang, J. Zhu, R. W. Thring, M. Wu, Y. Gao, and H. Tong. 2022. Sulforaphane alleviates high fat diet-induced insulin resistance via AMPK/Nrf2/GPx4 axis. Biomed Pharmacother. 152113273.

Zhou, Tingting, Xi Cheng, Yanqiu He, Yumei Xie, Fangyuan Xu, Yong Xu, and Wei Huang. 2022. Function and mechanism of histone β-hydroxybutyrylation in health and disease. Frontiers in Immunology. 13981285.

 

No related articles found!
No Suggested Reading articles found!