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Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury.
Toxicol Appl Pharmacol. 2019 09 15; 379:114665.TA

Abstract

Ferroptosis is the non-apoptotic form of cell death caused by small molecules or conditions that inhibit glutathione biosynthesis or resulting in iron-dependent accumulation of lipid peroxidation by lipid reactive oxygen species (ROS). Sestrin2 (Sesn2), a conserved antioxidant protein, is responsive to various stresses including genotoxic, metabolic, and oxidative stresses and acts to restore homeostatic balance. Sesn2 expression was reported to be regulated via stress-responsive transcription factors including p53, Nrf2, and HIF-1α. However, the role of Sesn2 in regulating ferroptosis is not known. In the current study, we investigated whether ferroptosis inducing compounds including erastin, sorafenib, and buthionine sulfoximine affect Sesn2 expression and the role of Sesn2 in cytoprotection against ferroptosis-mediated cell death. Our data demonstrate that ferroptosis inducers significantly increased Sesn2 in hepatocytes in a dose- and time-dependent manner. Treatment with erastin upregulated Sesn2 mRNA levels and luciferase reporter gene activity, and erastin-mediated Sesn2 induction was transcriptionally regulated by NF-E2-related factor 2 (Nrf2). Furthermore, deletion of the antioxidant response element (ARE) in the Sesn2 promoter or Nrf2 knockout or knockdown abolished erastin-induced Sesn2 expression. In cells expressing Sesn2, erastin-induced cell death, ROS formation, and glutathione depletion were almost completely inhibited compared to that in control cells. Treatment with phenylhydrazine in mice, well-reported iron overload liver injury model, increased ALT and AST levels and altered histological features, which were almost completely inhibited by adenoviral Sesn2 infection. Collectively, our results suggest that ferroptosis-mediated Sesn2 induction is dependent on Nrf2 and plays a protective role against iron overload and ferroptosis-induced liver injury.

Authors+Show Affiliations

College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea; National Development Institute of Korean Medicine, Jangheung, Jeollanam-do 59338, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea; College of Korean Medicine, Dongshin University, Naju, Jeollanam-do 58245, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Woosuk University, Wanju, Jeonbuk 55338, Republic of Korea.Department of Pharmacology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.HCLD-RC, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.HCLD-RC, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea. Electronic address: shki@chosun.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31323261

Citation

Park, Su Jung, et al. "Protective Effect of Sestrin2 Against Iron Overload and Ferroptosis-induced Liver Injury." Toxicology and Applied Pharmacology, vol. 379, 2019, p. 114665.
Park SJ, Cho SS, Kim KM, et al. Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicol Appl Pharmacol. 2019;379:114665.
Park, S. J., Cho, S. S., Kim, K. M., Yang, J. H., Kim, J. H., Jeong, E. H., Yang, J. W., Han, C. Y., Ku, S. K., Cho, I. J., & Ki, S. H. (2019). Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicology and Applied Pharmacology, 379, 114665. https://doi.org/10.1016/j.taap.2019.114665
Park SJ, et al. Protective Effect of Sestrin2 Against Iron Overload and Ferroptosis-induced Liver Injury. Toxicol Appl Pharmacol. 2019 09 15;379:114665. PubMed PMID: 31323261.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. AU - Park,Su Jung, AU - Cho,Sam Seok, AU - Kim,Kyu Min, AU - Yang,Ji Hye, AU - Kim,Jae Hoon, AU - Jeong,Eun Hee, AU - Yang,Jin Won, AU - Han,Chang Yeob, AU - Ku,Sae Kwang, AU - Cho,Il Je, AU - Ki,Sung Hwan, Y1 - 2019/07/16/ PY - 2019/03/29/received PY - 2019/07/10/revised PY - 2019/07/14/accepted PY - 2019/7/20/pubmed PY - 2020/6/2/medline PY - 2019/7/20/entrez KW - Ferroptosis KW - Hepatocytes KW - Liver injury KW - Nrf2 KW - Sestrin2 SP - 114665 EP - 114665 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 379 N2 - Ferroptosis is the non-apoptotic form of cell death caused by small molecules or conditions that inhibit glutathione biosynthesis or resulting in iron-dependent accumulation of lipid peroxidation by lipid reactive oxygen species (ROS). Sestrin2 (Sesn2), a conserved antioxidant protein, is responsive to various stresses including genotoxic, metabolic, and oxidative stresses and acts to restore homeostatic balance. Sesn2 expression was reported to be regulated via stress-responsive transcription factors including p53, Nrf2, and HIF-1α. However, the role of Sesn2 in regulating ferroptosis is not known. In the current study, we investigated whether ferroptosis inducing compounds including erastin, sorafenib, and buthionine sulfoximine affect Sesn2 expression and the role of Sesn2 in cytoprotection against ferroptosis-mediated cell death. Our data demonstrate that ferroptosis inducers significantly increased Sesn2 in hepatocytes in a dose- and time-dependent manner. Treatment with erastin upregulated Sesn2 mRNA levels and luciferase reporter gene activity, and erastin-mediated Sesn2 induction was transcriptionally regulated by NF-E2-related factor 2 (Nrf2). Furthermore, deletion of the antioxidant response element (ARE) in the Sesn2 promoter or Nrf2 knockout or knockdown abolished erastin-induced Sesn2 expression. In cells expressing Sesn2, erastin-induced cell death, ROS formation, and glutathione depletion were almost completely inhibited compared to that in control cells. Treatment with phenylhydrazine in mice, well-reported iron overload liver injury model, increased ALT and AST levels and altered histological features, which were almost completely inhibited by adenoviral Sesn2 infection. Collectively, our results suggest that ferroptosis-mediated Sesn2 induction is dependent on Nrf2 and plays a protective role against iron overload and ferroptosis-induced liver injury. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/31323261/Protective_effect_of_sestrin2_against_iron_overload_and_ferroptosis_induced_liver_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(19)30273-X DB - PRIME DP - Unbound Medicine ER -