title: l-carnitine protects human hepatocytes from oxidative stress-induced toxicity through Akt-mediated activation of Nrf2 signaling pathway.
abstract: In our previous study, l-carnitine was shown to have cytoprotective effect against hydrogen peroxide (H2O2)-induced injury in human normal HL7702 hepatocytes. The aim of this study was to investigate whether the protective effect of l-carnitine was associated with the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) pathway. Our results showed that pretreatment with l-carnitine augmented Nrf2 nuclear translocation, DNA binding activity and heme oxygenase-1 (HO-1) expression in H2O2-treated HL7702 cells, although l-carnitine treatment alone had no effect on them. Analysis using Nrf2 siRNA demonstrated that Nrf2 activation was involved in l-carnitine-induced HO-1 expression. In addition, l-carnitine-mediated protection against H2O2 toxicity was abrogated by Nrf2 siRNA, indicating the important role of Nrf2 in l-carnitine-induced cytoprotection. Further experiments revealed that l-carnitine pretreatment enhanced the phosphorylation of Akt in H2O2-treated cells. Blocking Akt pathway with inhibitor partly abrogated the protective effect of l-carnitine. Moreover, our finding demonstrated that the induction of Nrf2 translocation and HO-1 expression by l-carnitine directly correlated with the Akt pathway because Akt inhibitor showed inhibitory effects on the Nrf2 translocation and HO-1 expression. Altogether, these results demonstrate that l-carnitine protects HL7702 cells against H2O2-induced cell damage through Akt-mediated activation of Nrf2 signaling pathway.
authors.affiliation: a Medical College, Qingdao University, 308 Ningxia Road, Qingdao 266071, China.|b Binzhou Medical University, 346 Guanhai Road, Yantai 264003, China.
authors.forename: Jinlian
authors.initials: J
authors.lastname: Li
authors.affiliation: b Binzhou Medical University, 346 Guanhai Road, Yantai 264003, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: b Binzhou Medical University, 346 Guanhai Road, Yantai 264003, China.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Luan
authors.affiliation: c Department of Pharmacology, Medical College, Qingdao University, 308 Ningxia Road, Qingdao 266071, China.
authors.forename: Xuehong
authors.initials: X
authors.lastname: Chen
authors.affiliation: c Department of Pharmacology, Medical College, Qingdao University, 308 Ningxia Road, Qingdao 266071, China.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Han
authors.affiliation: c Department of Pharmacology, Medical College, Qingdao University, 308 Ningxia Road, Qingdao 266071, China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000975:Antioxidants / Q000009:adverse effects / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D002331:Carnitine / Q000009:adverse effects / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019587:Dietary Supplements / Q000009:adverse effects; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000737:chemistry / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000604115:5233705 compound; D000975:Antioxidants; D001562:Benzimidazoles; D052160:Benzothiazoles; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D002331:Carnitine
keywords: Akt; NFE2-related factor 2; facteur Nrf2; hepatocyte; hydrogen peroxide; hépatocyte; l-carnitine; peroxyde d’hydrogène