L-Carnitine protects human hepatocytes from oxidative stress-induced toxicity through Akt-mediated activation of Nrf2 signaling pathway

Canadian Journal of Physiology and Pharmacology

Volumn 94, Issue 5, 2016, Pages 517-525

  Li, Jinlian ^a,b   Zhang, Yanli ^b   Luan, Haiyun ^b   Chen, Xuehong ^a   Han, Yantao ^a   Wang, Chunbo ^a  

^a QINGDAO UNIVERSITY   (China)

^b BINZHOU MEDICAL UNIVERSITY   (China)

Author keywords

Akt; Hepatocyte; Hydrogen peroxide; L carnitine; NFE2 related factor 2

Indexed keywords

CARNITINE; HEME OXYGENASE 1; HYDROGEN PEROXIDE; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; SMALL INTERFERING RNA; TRANSCRIPTION FACTOR NRF2; 5233705 COMPOUND; ANTIOXIDANT; BENZIMIDAZOLE DERIVATIVE; BENZOTHIAZOLE DERIVATIVE; HMOX1 PROTEIN, HUMAN; NFE2L2 PROTEIN, HUMAN; OXIDIZING AGENT; PROTEIN KINASE INHIBITOR;

ARTICLE; BINDING AFFINITY; CELL NUCLEUS; CELL PROTECTION; CONTROLLED STUDY; DNA BINDING; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; LIVER CELL; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; ACTIVE TRANSPORT; ADVERSE EFFECTS; AGONISTS; ANTAGONISTS AND INHIBITORS; CELL LINE; CELL SURVIVAL; CHEMISTRY; DIETARY SUPPLEMENT; DRUG EFFECTS; GEL MOBILITY SHIFT ASSAY; GENETICS; METABOLISM; PHOSPHORYLATION; PROTEIN PROCESSING; RNA INTERFERENCE;

ACTIVE TRANSPORT, CELL NUCLEUS; ANTIOXIDANTS; BENZIMIDAZOLES; BENZOTHIAZOLES; CARNITINE; CELL LINE; CELL SURVIVAL; DIETARY SUPPLEMENTS; ELECTROPHORETIC MOBILITY SHIFT ASSAY; ENZYME ACTIVATION; HEME OXYGENASE-1; HEPATOCYTES; HUMANS; HYDROGEN PEROXIDE; NF-E2-RELATED FACTOR 2; OXIDANTS; OXIDATIVE STRESS; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTO-ONCOGENE PROTEINS C-AKT; RNA INTERFERENCE; SIGNAL TRANSDUCTION;

EID: 84964884159     PISSN: 00084212     EISSN: 12057541     Source Type: Journal    
DOI: 10.1139/cjpp-2015-0305     Document Type: Article

References (40)

1. Bakhautdin, B., Das, D., Mandal, P., Roychowdhury, S., Danner, J., Bush, K., et al. 2014. Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice. J. Hepatol. 61(5): 1029-1037. doi:10.1016/j.jhep.2014.06.007. PMID:24946281
2. Bykov, I., Jarvelainen, H., and Lindros, K. 2003. L-carnitine alleviates alcoholinduced liver damage in rats: role of tumour necrosis factor-alpha. Alcohol Alcohol. 38(5): 400-406. doi:10.1093/alcalc/agg109. PMID:12915513
3. Cao, Y., Li, X., Wang, C.J., Li, P., Yang, B., Wang, C.B., et al. 2015. Role of NF-E2-related factor 2 in neuroprotective effect of L-carnitine against high glucoseinduced oxidative stress in the retinal ganglion cells. Biomed. Pharmacother. 69: 345-348. doi:10.1016/j.biopha.2014.12.030. PMID:25661380
4. Chan, K., Han, X.D., and Kan, Y.W. 2001. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc. Natl. Acad. Sci. U.S.A. 98(8): 4611-4616. doi:10.1073/pnas.081082098. PMID:11287661
5. Chapple, S.J., Siow, R.C., and Mann, G.E. 2012. Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int. J. Biochem. Cell Biol. 44(8): 1315-1320. doi:10.1016/j.biocel.2012.04.021. PMID:22575091
6. Chen, L., Xu, B., Liu, L., Luo, Y., Yin, J., Zhou, H., et al. 2010. Hydrogen peroxide inhibits mTOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells. Lab. Invest. 90(5): 762-773. doi:10.1038/labinvest.2010.36. PMID:20142804
7. Dokmeci, D., Akpolat, M., Aydogdu, N., Doganay, L., and Turan, F.N. 2005. L-carnitine inhibits ethanol-induced gastric mucosal injury in rats. Pharmacol. Rep. 57(4): 481-488. PMID:16129915
8. Enomoto, A., Itoh, K., Nagayoshi, E., Haruta, J., Kimura, T., O’Connor, T., et al. 2001. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol. Sci. 59(1): 169-177. doi:10.1093/toxsci/59.1.169. PMID:11134556
9. Ferrari, R., Merli, E., Cicchitelli, G., Mele, D., Fucili, A., and Ceconi, C. 2004. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann. N. Y. Acad. Sci. 1033: 79-91. doi:10.1196/annals.1320.007. PMID:15591005
10. Gan, N., Mi, L., Sun, X., Dai, G., Chung, F.L., and Song, L. 2010. Sulforaphane protects Microcystin-LR-induced toxicity through activation of the Nrf2- mediated defensive response. Toxicol. Appl. Pharmacol. 247(2): 129-137. doi:10.1016/j.taap.2010.06.005. PMID:20600217
11. Gülçin, I. 2006. Antioxidant and antiradical activities of L-carnitine. Life Sci. 78(8): 803-811. doi:10.1016/j.lfs.2005.05.103. PMID:16253281
12. Gupte, A.A., Lyon, C.J., and Hsueh, W.A. 2013. Nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2), a key regulator of the antioxidant response to protect against atherosclerosis and nonalcoholic steatohepatitis. Curr. Diab. Rep. 13(3): 362-371. doi:10.1007/s11892-013-0372-1. PMID:23475581
13. Hinds, T.D., Jr., Sodhi, K., Meadows, C., Fedorova, L., Puri, N., Kim, D.H., et al. 2014. Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Obesity (Silver Spring), 22(3): 705-712. doi:10.1002/oby.20559. PMID:23839791
14. Hsu, J.T., Kan, W.H., Hsieh, C.H., Choudhry, M.A., Schwacha, M.G., Bland, K.I., et al. 2007. Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation. J. Leukoc. Biol. 82(4): 1019-1026. doi:10.1189/jlb.0607355. PMID:17656650
15. Hu, Z., Chen, J., Wei, Q., and Xia, Y. 2008. Bidirectional actions of hydrogen peroxide on endothelial nitric-oxide synthase phosphorylation and function: co-commitment and interplay of Akt and AMPK. J. Biol. Chem. 283(37): 25256-25263. doi:10.1074/jbc.M802455200. PMID:18617528
16. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., et al. 1997. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236(2): 313-322. doi:10.1006/bbrc.1997.6943. PMID:9240432.I
17. zgüt-Uysal, V.N., Agac, A., and Derin, N. 2003. Effect of L-carnitine on carrageenan-induced inflammation in aged rats. Gerontology, 49(5): 287-292. doi:10.1159/000071709. PMID:12920348
18. Jeong, W.S., Jun, M., and Kong, A.N. 2006. Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Antioxid. Redox Signal. 8(1-2): 99-106. doi:10.1089/ars.2006.8.99. PMID:16487042
19. Ke, B., Shen, X.D., Gao, F., Qiao, B., Ji, H., Busuttil, R.W., et al. 2009. Small interfering RNA targeting heme oxygenase-1 (HO-1) reinforces liver apoptosis induced by ischemia-reperfusion injury in mice: HO-1 is necessary for cytoprotection. Hum. Gene Ther. 20(10): 1133-1142. doi:10.1089/hum.2009.049. PMID:19534599
20. Kudoh, K., Uchinami, H., Yoshioka, M., Seki, E., and Yamamoto, Y. 2014. Nrf2 activation protects the liver from ischemia/reperfusion injury in mice. Ann. Surg. 260(1): 118-127. doi:10.1097/SLA.0000000000000287. PMID:24368646
21. Lee, I.C., Kim, S.H., Baek, H.S., Moon, C., Kang, S.S., Kim, S.H., et al. 2014. The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory response in rats. Food Chem. Toxicol. 63: 174-185. doi:10.1016/j.fct.2013.11.006. PMID: 24246655
22. Lheureux, P.E., and Hantson, P. 2009. Carnitine in the treatment of valproic acid-induced toxicity. Clin. Toxicol. (Phila.), 47(2): 101-111. doi:10.1080/15563650902752376. PMID:19280426
23. Li, J.L., Wang, Q.Y., Luan, H.Y., Kang, Z.C., and Wang, C.B. 2012. Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha. J. Biomed. Sci. 19: 32. doi:10.1186/1423-0127-19-32. PMID:22435679
24. Liu, C.M., Zheng, G.H., Ming, Q.L., Sun, J.M., and Cheng, C. 2013. Protective effect of quercetin on lead-induced oxidative stress and endoplasmic reticulum stress in rat liver via the IRE1/JNK and PI3K/Akt pathway. Free Radic. Res. 47(3): 192-201. doi:10.3109/10715762.2012.760198. PMID:23249147
25. Ma, Q. 2013. Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 53: 401-426. doi:10.1146/annurev-pharmtox-011112-140320. PMID: 23294312
26. Morse, D., and Choi, A.M. 2002. Heme oxygenase-1: the “emerging molecule” has arrived. Am. J. Respir. Cell Mol. Biol. 27(1): 8-16. doi:10.1165/ajrcmb.27.1.4862. PMID:12091240
27. Muriel, P. 2009. Role of free radicals in liver diseases. Hepatol. Int. 3(4): 526-536. doi:10.1007/s12072-009-9158-6. PMID:19941170
28. Nakaso, K., Yano, H., Fukuhara, Y., Takeshima, T., Wada-Isoe, K., and Nakashima, K. 2003. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 546(2-3): 181-184. doi:10.1016/S0014-5793(03)00517-9. PMID:12832036
29. Onem, G., Aral, E., Enli, Y., Oguz, E.O., Coskun, E., Aybek, H., et al. 2006. Neuroprotective effects of L-carnitine and vitamin E alone or in combination against ischemia-reperfusion injury in rats. J. Surg. Res. 131(1): 124-130. doi: 10.1016/j.jss.2005.12.017. PMID:16457849
30. Prawan, A., Keum, Y.S., Khor, T.O., Yu, S., Nair, S., Li, W., et al. 2008. Structural influence of isothiocyanates on the antioxidant response element (ARE)- mediated heme oxygenase-1 (HO-1) expression. Pharm. Res. 25(4): 836-844. doi:10.1007/s11095-007-9370-9. PMID:17657593
31. Rebouche, C.J. 2004. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann. N. Y. Acad. Sci. 1033: 30-41. doi:10.1196/annals.1320.003. PMID:15591001
32. Salinas, M., Wang, J., de Rosa, S.M., Martin, D., Rojo, A.I., Martin-Perez, J., et al. 2004. Protein kinase Akt/PKB phosphorylates heme oxygenase-1 in vitro and in vivo. FEBS Lett. 578(1-2): 90-94. doi:10.1016/j.febslet.2004.10.077. PMID: 15581622
33. Shin, S.M., Yang, J.H., and Ki, S.H. 2013. Role of the Nrf2-ARE pathway in liver diseases. Oxid. Med. Cell. Longev. 2013: 763257. doi:10.1155/2013/763257. PMID:23766860
34. Silva-Gomes, S., Santos, A.G., Caldas, C., Silva, C.M., Neves, J.V., Lopes, J., et al. 2014. Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death. J. Hepatol. 60(2): 354-361. doi:10.1016/j.jhep.2013.09.004. PMID:24021424
35. Tseng, H.L., Li, C.J., Huang, L.H., Chen, C.Y., Tsai, C.H., Lin, C.N., et al. 2012. Quercetin 3-O-methyl ether protects FL83B cells from copper induced oxidative stress through the PI3K/Akt and MAPK/Erk pathway. Toxicol. Appl. Pharmacol. 264(1): 104-113. doi:10.1016/j.taap.2012.07.022. PMID:22842013
36. Wang, L., Chen, Y., Sternberg, P., and Cai, J. 2008. Essential roles of the PI3 kinase/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Invest. Ophthalmol. Vis. Sci. 49(4): 1671-1678. doi:10.1167/iovs.07-1099. PMID:18385090
37. Weng, C.J., Chen, M.J., Yeh, C.T., and Yen, G.C. 2011. Hepatoprotection of quercetin against oxidative stress by induction of metallothionein expression through activating MAPK and PI3K pathways and enhancing Nrf2 DNAbinding activity. N. Biotechnol. 28(6): 767-777. doi:10.1016/j.nbt.2011.05.003. PMID:21624509
38. Yang, X., Qin, L., Liu, J., Tian, L., and Qian, H. 2012. 17beta-Estradiol protects the liver against cold ischemia/reperfusion injury through the Akt kinase pathway. J. Surg. Res. 178(2): 996-1002. doi:10.1016/j.jss.2012.07.007. PMID:22835949
39. Zhang, Y.K., Yeager, R.L., Tanaka, Y., and Klaassen, C.D. 2010a. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet. Toxicol. Appl. Pharmacol. 245(3): 326-334. doi:10.1016/j.taap.2010.03.016. PMID:20350562
40. Zhang, Z.F., Lu, J., Zheng, Y.L., Hu, B., Fan, S.H., Wu, D.M., et al. 2010b. Purple sweet potato color protects mouse liver against d-galactose-induced apoptosis via inhibiting caspase-3 activation and enhancing PI3K/Akt pathway. Food Chem. Toxicol. 48(89): 2500-2507. doi:10.1016/j.fct.2010.06.023. PMID:20600541