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Luteolin prevents liver from tunicamycin-induced endoplasmic reticulum stress via nuclear factor erythroid 2-related factor 2-dependent sestrin 2 induction.
Toxicol Appl Pharmacol. 2020 07 15; 399:115036.TA

Abstract

Endoplasmic reticulum (ER) stress designates a cellular response to the accumulation of misfolded proteins, which is related to disease progression in the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found frequently in medicinal herbs. Although luteolin has been reported to possess the therapeutic potential to prevent diverse stage of liver diseases, its role in hepatic ER stress has not been established. Thus, the present study aimed to determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to identify the relevant mechanisms involved in its hepatoprotective effects. In hepatocyte-derived cells and primary hepatocytes, luteolin significantly decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) expression. In addition, luteolin reduced the activation of three canonical signaling pathways related to the unfolded protein response, and decreased mRNA levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 (SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. Deletion of the antioxidant response element in the human SESN2 promoter inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a critical transcription factor for luteolin-dependent SESN2 expression. In a Tm-mediated liver injury model, luteolin decreased serum alanine aminotransferase and aspartate aminotransferase activities, prevented degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin may be an effective phytochemical to manage ER stress-related liver injury.

Authors+Show Affiliations

College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.Hani Bio Co., Ltd, 142 Yulam-ro, Daegu 41059, 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, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea. Electronic address: skek023@dhu.ac.kr.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea. Electronic address: sckim@dhu.ac.kr.

Pub Type(s)

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

Language

eng

PubMed ID

32407927

Citation

Jegal, Kyung Hwan, et al. "Luteolin Prevents Liver From Tunicamycin-induced Endoplasmic Reticulum Stress Via Nuclear Factor Erythroid 2-related Factor 2-dependent Sestrin 2 Induction." Toxicology and Applied Pharmacology, vol. 399, 2020, p. 115036.
Jegal KH, Kim EO, Kim JK, et al. Luteolin prevents liver from tunicamycin-induced endoplasmic reticulum stress via nuclear factor erythroid 2-related factor 2-dependent sestrin 2 induction. Toxicol Appl Pharmacol. 2020;399:115036.
Jegal, K. H., Kim, E. O., Kim, J. K., Park, S. M., Jung, D. H., Lee, G. H., Ki, S. H., Byun, S. H., Ku, S. K., Cho, I. J., & Kim, S. C. (2020). Luteolin prevents liver from tunicamycin-induced endoplasmic reticulum stress via nuclear factor erythroid 2-related factor 2-dependent sestrin 2 induction. Toxicology and Applied Pharmacology, 399, 115036. https://doi.org/10.1016/j.taap.2020.115036
Jegal KH, et al. Luteolin Prevents Liver From Tunicamycin-induced Endoplasmic Reticulum Stress Via Nuclear Factor Erythroid 2-related Factor 2-dependent Sestrin 2 Induction. Toxicol Appl Pharmacol. 2020 07 15;399:115036. PubMed PMID: 32407927.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Luteolin prevents liver from tunicamycin-induced endoplasmic reticulum stress via nuclear factor erythroid 2-related factor 2-dependent sestrin 2 induction. AU - Jegal,Kyung Hwan, AU - Kim,Eun Ok, AU - Kim,Jae Kwang, AU - Park,Sang Mi, AU - Jung,Dae Hwa, AU - Lee,Gum Hwa, AU - Ki,Sung Hwan, AU - Byun,Sung Hui, AU - Ku,Sae Kwang, AU - Cho,Il Je, AU - Kim,Sang Chan, Y1 - 2020/05/11/ PY - 2020/02/20/received PY - 2020/05/07/revised PY - 2020/05/08/accepted PY - 2020/5/15/pubmed PY - 2020/8/19/medline PY - 2020/5/15/entrez KW - Endoplasmic reticulum (ER) stress KW - Liver KW - Luteolin KW - Nuclear factor erythroid 2-related factor 2 (Nrf2) KW - Sestrin 2 (SESN2) SP - 115036 EP - 115036 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 399 N2 - Endoplasmic reticulum (ER) stress designates a cellular response to the accumulation of misfolded proteins, which is related to disease progression in the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found frequently in medicinal herbs. Although luteolin has been reported to possess the therapeutic potential to prevent diverse stage of liver diseases, its role in hepatic ER stress has not been established. Thus, the present study aimed to determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to identify the relevant mechanisms involved in its hepatoprotective effects. In hepatocyte-derived cells and primary hepatocytes, luteolin significantly decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) expression. In addition, luteolin reduced the activation of three canonical signaling pathways related to the unfolded protein response, and decreased mRNA levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 (SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. Deletion of the antioxidant response element in the human SESN2 promoter inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a critical transcription factor for luteolin-dependent SESN2 expression. In a Tm-mediated liver injury model, luteolin decreased serum alanine aminotransferase and aspartate aminotransferase activities, prevented degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin may be an effective phytochemical to manage ER stress-related liver injury. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/32407927/Luteolin_prevents_liver_from_tunicamycin_induced_endoplasmic_reticulum_stress_via_nuclear_factor_erythroid_2_related_factor_2_dependent_sestrin_2_induction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(20)30160-5 DB - PRIME DP - Unbound Medicine ER -