Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury

AbstractNuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

Topics

No keywords indexed for this article. Browse by subject →

References

60

[1]

Labiano, I. et al. TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation. J. Hepatol. 77, 991–1004 (2022). 10.1016/j.jhep.2022.05.044

[2]

Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury

Mick Frissen, Lijun Liao, Kai Markus Schneider et al.

Hepatology 2021 10.1002/hep.31494

[3]

Hooda, V., Gahlaut, A., Gothwal, A. & Hooda, V. Bilirubin enzyme biosensor: potentiality and recent advances towards clinical bioanalysis. Biotechnol. Lett. 39, 1453–1462 (2017). 10.1007/s10529-017-2396-0

[4]

Bilirubin and glutathione have complementary antioxidant and cytoprotective roles

Thomas W. Sedlak, Masoumeh Saleh, Daniel S. Higginson et al.

Proceedings of the National Academy of Sciences 2009 10.1073/pnas.0813132106

[5]

Maghzal, G. J., Leck, M. C., Collinson, E., Li, C. & Stocker, R. Limited role for the bilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection by biliverdin reductase. J. Biol. Chem. 284, 29251–29259 (2009). 10.1074/jbc.m109.037119

[6]

McDonagh, A. F. Controversies in bilirubin biochemistry and their clinical relevance. Semin. Fetal Neonatal. Med. 15, 141–147 (2010). 10.1016/j.siny.2009.10.005

[7]

Bilirubin-Induced Neurologic Damage — Mechanisms and Management Approaches

Jon F. Watchko, Claudio Tiribelli

New England Journal of Medicine 2013 10.1056/nejmra1308124

[8]

Novák, P., Jackson, A. O., Zhao, G. J. & Yin, K. Bilirubin in metabolic syndrome and associated inflammatory diseases: New perspectives. Life Sci. 257, 118032 (2020). 10.1016/j.lfs.2020.118032

[9]

Gao, Z. et al. Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2. Int. J. Biol. Sci. 18, 2146–2162 (2022). 10.7150/ijbs.69116

[10]

Rodríguez, M. J. et al. Maresin-1 prevents liver fibrosis by targeting Nrf2 and NF-κB, reducing oxidative stress and inflammation. Cells 10, 3406 (2021). 10.3390/cells10123406

[11]

Weerachayaphorn, J. et al. Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine. Am J. Physiol. Gastrointest. Liver Physiol. 302, G925–G936 (2012). 10.1152/ajpgi.00263.2011

[12]

Wang, G. Y. et al. Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model. PLoS ONE 17, e0269383 (2022). 10.1371/journal.pone.0269383

[13]

Khodayar, M. J., Kalantari, H., Khorsandi, L., Rashno, M. & Zeidooni, L. Upregulation of Nrf2-related cytoprotective genes expression by acetaminophen-induced acute hepatotoxicity in mice and the protective role of betaine. Hum. Exp. Toxicol. 39, 948–959 (2020). 10.1177/0960327120905962

[14]

Dai, C. et al. Inhibition of oxidative stress and ALOX12 and NF-κB pathways contribute to the protective effect of baicalein on carbon tetrachloride-induced acute liver injury. Antioxidants 10, 976 (2021). 10.3390/antiox10060976

[15]

Liu, J. et al. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice. Toxicol. Appl. Pharmacol. 272, 816–824 (2013). 10.1016/j.taap.2013.08.003

[16]

Doré, S. et al. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc. Natl Acad. Sci. USA 96, 2445–2450 (1999). 10.1073/pnas.96.5.2445

[17]

Qaisiya, M., Coda Zabetta, C. D., Bellarosa, C. & Tiribelli, C. Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell Signal 26, 512–520 (2014). 10.1016/j.cellsig.2013.11.029

[18]

Feng, H., Hu, Y., Zhou, S. & Lu, Y. Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice. J. Appl. Toxicol. 42, 1323–1336 (2022). 10.1002/jat.4298

[19]

Wang, Q. M. et al. Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation. World J. Gastroenterol. 19, 2921–2934 (2013). 10.3748/wjg.v19.i19.2921

[20]

Froh, M. et al. Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats. World J. Gastroenterol. 13, 3478–3486 (2007). 10.3748/wjg.v13.i25.3478

[21]

Maresin 1 protects against lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting macrophage pyroptosis and inflammatory response

Wenchang Yang, Kaixiong Tao, Peng Zhang et al.

Biochemical Pharmacology 2022 10.1016/j.bcp.2021.114863

[22]

Yang, W. et al. Immune-responsive gene 1 protects against liver injury caused by concanavalin A via the activation Nrf2/HO-1 pathway and inhibition of ROS activation pathways. Free Radic. Biol. Med. 182, 108–118 (2022). 10.1016/j.freeradbiomed.2022.02.030

[23]

Cai, X. et al. Astaxanthin activated the Nrf2/HO-1 pathway to enhance autophagy and inhibit ferroptosis, ameliorating acetaminophen-induced liver injury. ACS Appl. Mater. Interfaces 14, 42887–42903 (2022). 10.1021/acsami.2c10506

[24]

Kossor, D. C., Meunier, P. C., Handler, J. A., Sozio, R. S. & Goldstein, R. S. Temporal relationship of changes in hepatobiliary function and morphology in rats following alpha-naphthylisothiocyanate (ANIT) administration. Toxicol. Appl. Pharmacol. 119, 108–114 (1993). 10.1006/taap.1993.1049

[25]

Hinds, T. D. Jr. et al. Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα. Am. J. Physiol. Endocrinol. Metab. 312, E244–e252 (2017). 10.1152/ajpendo.00396.2016

[26]

Liu, J. et al. Bilirubin increases insulin sensitivity by regulating cholesterol metabolism, adipokines and PPARγ levels. Sci. Rep. 5, 9886 (2015). 10.1038/srep09886

[27]

Peyer, A. K. et al. Regulation of human liver delta-aminolevulinic acid synthase by bile acids. Hepatology 46, 1960–1970 (2007). 10.1002/hep.21879

[28]

Li, S. et al. Induction of Nrf2 pathway by Dendrobium nobile Lindl. alkaloids protects against carbon tetrachloride induced acute liver injury. Biomed. Pharmacother. 117, 109073 (2019). 10.1016/j.biopha.2019.109073

[29]

Lefere, S. et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J. Hepatol. 73, 757–770 (2020). 10.1016/j.jhep.2020.04.025

[30]

Kamisako, T., Adachi, Y. & Yamamoto, T. Effect of UDP-glucuronic acid depletion by salicylamide on biliary bilirubin excretion in the rat. J. Pharmacol. Exp. Ther. 254, 380–382 (1990).

[31]

Kullak-Ublick, G. A., Beuers, U. & Paumgartner, G. Hepatobiliary transport. J. Hepatol. 32, 3–18 (2000). 10.1016/s0168-8278(00)80411-0

[32]

Chen, H. L. et al. Developmental expression of canalicular transporter genes in human liver. J. Hepatol. 43, 472–477 (2005). 10.1016/j.jhep.2005.02.030

[33]

Wang, S. et al. FOXA2 prevents hyperbilirubinaemia in acute liver failure by maintaining apical MRP2 expression. Gut 72, 549–559 (2023). 10.1136/gutjnl-2022-326987

[34]

Mustafa, M. G., Cowger, M. L. & King, T. E. Effects of bilirubin on mitochondrial reactions. J. Biol. Chem. 244, 6403–6414 (1969). 10.1016/s0021-9258(18)63479-9

[35]

Chen, H. L. et al. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J. Biomed. Sci. 25, 75 (2018). 10.1186/s12929-018-0475-8

[36]

Chang, J. H., Plise, E., Cheong, J., Ho, Q. & Lin, M. Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. Mol. Pharm. 10, 3067–3075 (2013). 10.1021/mp4001348

[37]

KimK, M. & Ki, S. H. Chapter 28 - nrf2: A Key Regulator of Redox Signaling in Liver Diseases (ed. Muriel, P.) (Liver Pathophysiology, Academic Press, 2017). 10.1016/b978-0-12-804274-8.00028-x

[38]

Shearn, C. T. et al. Cholestatic liver disease results increased production of reactive aldehydes and an atypical periportal hepatic antioxidant response. Free Radic. Biol. Med. 143, 101–114 (2019). 10.1016/j.freeradbiomed.2019.07.036

[39]

Vilas-Boas, V., Gijbels, E., Jonckheer, J., De Waele, E. & Vinken, M. Cholestatic liver injury induced by food additives, dietary supplements and parenteral nutrition. Environ. Int. 136, 105422 (2020). 10.1016/j.envint.2019.105422

[40]

Wang, X. et al. Paradoxical effects of emodin on ANIT-induced intrahepatic cholestasis and herb-induced hepatotoxicity in mice. Toxicol. Sci. 168, 264–278 (2019). 10.1093/toxsci/kfy295

[41]

Marschall, H. U. et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129, 476–485 (2005). 10.1016/j.gastro.2005.05.009

[42]

The role of bile acids in cholestatic liver injury

Shi-Ying Cai, James L. Boyer

Annals of Translational Medicine 2021 10.21037/atm-20-5110

[43]

Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis

Ling-Chu Chang, Shih-Kai Chiang, Shuen-Ei Chen et al.

Cancer Letters 2018 10.1016/j.canlet.2017.12.025

[44]

Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism

Cristina Fernández-Mendívil, Enrique Luengo, Paula Trigo-Alonso et al.

Redox Biology 2021 10.1016/j.redox.2020.101789

[45]

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Ruiran Wei, Yueqin Zhao, Juan Wang et al.

International Journal of Biological Sciences 2021 10.7150/ijbs.59404

[46]

Copple, B. L., Jaeschke, H. & Klaassen, C. D. Oxidative stress and the pathogenesis of cholestasis. Semin. Liver Dis. 30, 195–204 (2010). 10.1055/s-0030-1253228

[47]

Okada, K. et al. Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems. Biochem. Biophys. Res. Commun. 389, 431–436 (2009). 10.1016/j.bbrc.2009.08.156

[48]

He, L., Guo, C., Peng, C. & Li, Y. Advances of natural activators for Nrf2 signaling pathway on cholestatic liver injury protection: a review. Eur. J. Pharmacol. 910, 174447 (2021). 10.1016/j.ejphar.2021.174447

[49]

Fu, X. et al. Dendrobium and its active ingredients: emerging role in liver protection. Biomed. Pharmacother. 157, 114043 (2023). 10.1016/j.biopha.2022.114043

[50]

Shi, L. et al. Baicalein and baicalin alleviate acetaminophen-induced liver injury by activating Nrf2 antioxidative pathway: the involvement of ERK1/2 and PKC. Biochem. Pharmacol. 150, 9–23 (2018). 10.1016/j.bcp.2018.01.026

Showing 50 of 60 references

Metrics

35

Citations

60

References

Details

Published: May 23, 2024
Vol/Issue: 7(1)
License: View

Authors

Kunming University

Institute of Agricultural Economics and Development, Chinese Academy of Agricultural Sciences, Beijing 100081, China

Chinese Academy of Sciences

S

Shaoyu Zhou

Cite This Article

Yi Wang, Xiaolong Fu, Li Zeng, et al. (2024). Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury. Communications Biology, 7(1). https://doi.org/10.1038/s42003-024-06243-0

Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury

You May Also Like