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Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression.
J Pharmacol Exp Ther. 2018 06; 365(3):485-493.JP

Abstract

Docosahexaenoic acid (DHA) and its bioactive compounds may have suppressive effects on inflammation, endoplasmic reticulum (ER) stress, and insulin resistance. Protectin DX (PDX), a double lipoxygenase product from DHA has shown a suppressive effect on inflammation and insulin resistance. However, the effects of PDX on ER stress and hepatic steatosis have not been elucidated yet. Herein we report that PDX could stimulate the AMP-activated protein kinase (AMPK) phosphorylation, thereby upregulating oxygen-regulated protein 150 (ORP150) expression in a dose-dependent manner. Treatment of HepG2 cells with PDX attenuated the palmitate-induced triglyceride accumulation through regulation of the sterol regulatory element-binding protein 1 (SREBP1)-mediated pathway. To deal with the pharmacological significance in the protective effects of PDX on hepatic steatosis, we performed in vivo experiments. In a mouse model, the PDX administration would alleviate the high-fat diet-induced hepatic steatosis and trigger the hepatic AMPK phosphorylation and ORP150 expression. PDX improved palmitate-induced and HFD-induced impairment of hepatic lipid metabolism and steatosis through suppression of ER stress via an AMPK-ORP150-dependent pathway.

Authors+Show Affiliations

Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.).Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.).Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.).Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.).Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.).Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.).Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.).Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.) jhjeong3@cau.ac.kr abdelaty44@hotmail.com amabdelaty@atauni.edu.tr.Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea (T.W.J.); Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea (H.-C.K.); Departments of Pharmacology (E.J.K., Y.K.S., J.H.J.) and Pathology (E.S.P.), College of Medicine and College of Pharmacy (S.H.L.), Chung-Ang University, Seoul, Republic of Korea; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey (A.H., A.M.A.E.-A.); and Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt (A.M.A.E.-A.) jhjeong3@cau.ac.kr abdelaty44@hotmail.com amabdelaty@atauni.edu.tr.

Pub Type(s)

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

Language

eng

PubMed ID

29572342

Citation

Jung, Tae Woo, et al. "Protectin DX Ameliorates Hepatic Steatosis By Suppression of Endoplasmic Reticulum Stress Via AMPK-Induced ORP150 Expression." The Journal of Pharmacology and Experimental Therapeutics, vol. 365, no. 3, 2018, pp. 485-493.
Jung TW, Kyung EJ, Kim HC, et al. Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression. J Pharmacol Exp Ther. 2018;365(3):485-493.
Jung, T. W., Kyung, E. J., Kim, H. C., Shin, Y. K., Lee, S. H., Park, E. S., Hacımüftüoğlu, A., Abd El-Aty, A. M., & Jeong, J. H. (2018). Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression. The Journal of Pharmacology and Experimental Therapeutics, 365(3), 485-493. https://doi.org/10.1124/jpet.117.246686
Jung TW, et al. Protectin DX Ameliorates Hepatic Steatosis By Suppression of Endoplasmic Reticulum Stress Via AMPK-Induced ORP150 Expression. J Pharmacol Exp Ther. 2018;365(3):485-493. PubMed PMID: 29572342.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression. AU - Jung,Tae Woo, AU - Kyung,Eun Jung, AU - Kim,Hyoung-Chun, AU - Shin,Yong Kyu, AU - Lee,Sung Hoon, AU - Park,Eon Sub, AU - Hacımüftüoğlu,Ahmet, AU - Abd El-Aty,A M, AU - Jeong,Ji Hoon, Y1 - 2018/03/23/ PY - 2017/11/23/received PY - 2018/03/20/accepted PY - 2018/3/25/pubmed PY - 2019/10/15/medline PY - 2018/3/25/entrez SP - 485 EP - 493 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 365 IS - 3 N2 - Docosahexaenoic acid (DHA) and its bioactive compounds may have suppressive effects on inflammation, endoplasmic reticulum (ER) stress, and insulin resistance. Protectin DX (PDX), a double lipoxygenase product from DHA has shown a suppressive effect on inflammation and insulin resistance. However, the effects of PDX on ER stress and hepatic steatosis have not been elucidated yet. Herein we report that PDX could stimulate the AMP-activated protein kinase (AMPK) phosphorylation, thereby upregulating oxygen-regulated protein 150 (ORP150) expression in a dose-dependent manner. Treatment of HepG2 cells with PDX attenuated the palmitate-induced triglyceride accumulation through regulation of the sterol regulatory element-binding protein 1 (SREBP1)-mediated pathway. To deal with the pharmacological significance in the protective effects of PDX on hepatic steatosis, we performed in vivo experiments. In a mouse model, the PDX administration would alleviate the high-fat diet-induced hepatic steatosis and trigger the hepatic AMPK phosphorylation and ORP150 expression. PDX improved palmitate-induced and HFD-induced impairment of hepatic lipid metabolism and steatosis through suppression of ER stress via an AMPK-ORP150-dependent pathway. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/29572342/Protectin_DX_Ameliorates_Hepatic_Steatosis_by_Suppression_of_Endoplasmic_Reticulum_Stress_via_AMPK_Induced_ORP150_Expression_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=29572342 DB - PRIME DP - Unbound Medicine ER -