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Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress.
Cell Signal. 2017 06; 34:133-140.CS

Abstract

Several studies have shown that protectins, which are ω-3 fatty acid-derived proresolution mediators, may improve insulin resistance. Recently, protectin DX (PDX) was documented to attenuate insulin resistance by stimulating IL-6 expression in skeletal muscle, thereby regulating hepatic gluconeogenesis. These findings made us investigate the direct effects of PDX on hepatic glucose metabolism in the context of diabetes. In the current study, we show that PDX regulates hepatic gluconeogenesis in a manner distinct from its indirect glucoregulatory activity via IL-6. We found that PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation, thereby inducing heme oxygenase 1 (HO-1) expression. This induction blocked hepatic gluconeogenesis by suppressing endoplasmic reticulum (ER) stress in hepatocytes under hyperlipidemic conditions. These effects were significantly dampened by silencing AMPK or HO-1 expression with small interfering RNA (siRNA). We also demonstrated that administration of PDX to high fat diet (HFD)-fed mice resulted in increased hepatic AMPK phosphorylation and HO-1 expression, whereas hepatic ER stress was substantially attenuated. Furthermore, PDX treatment suppressed the expression of gluconeogenic genes, thereby decreasing blood glucose levels in HFD-fed mice. In conclusion, our findings suggest that PDX inhibits hepatic gluconeogenesis via AMPK-HO-1-dependent suppression of ER stress. Thus, PDX may be an effective therapeutic target for the treatment of insulin resistance and type 2 diabetes through the regulation of hepatic gluconeogenesis.

Authors+Show Affiliations

Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea.Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea.Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211-Giza, Egypt; Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea.Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea. Electronic address: jhjeong3@cau.ac.kr.

Pub Type(s)

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

Language

eng

PubMed ID

28342842

Citation

Jung, Tae Woo, et al. "Protectin DX Suppresses Hepatic Gluconeogenesis Through AMPK-HO-1-mediated Inhibition of ER Stress." Cellular Signalling, vol. 34, 2017, pp. 133-140.
Jung TW, Kim HC, Abd El-Aty AM, et al. Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress. Cell Signal. 2017;34:133-140.
Jung, T. W., Kim, H. C., Abd El-Aty, A. M., & Jeong, J. H. (2017). Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress. Cellular Signalling, 34, 133-140. https://doi.org/10.1016/j.cellsig.2017.03.013
Jung TW, et al. Protectin DX Suppresses Hepatic Gluconeogenesis Through AMPK-HO-1-mediated Inhibition of ER Stress. Cell Signal. 2017;34:133-140. PubMed PMID: 28342842.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress. AU - Jung,Tae Woo, AU - Kim,Hyung-Chun, AU - Abd El-Aty,A M, AU - Jeong,Ji Hoon, Y1 - 2017/03/22/ PY - 2017/01/27/received PY - 2017/03/11/revised PY - 2017/03/19/accepted PY - 2017/3/28/pubmed PY - 2018/1/20/medline PY - 2017/3/27/entrez KW - AMP-activated protein kinase KW - Endoplasmic reticulum stress KW - Gluconeogenesis KW - Heme oxygenase 1 KW - Protectin DX SP - 133 EP - 140 JF - Cellular signalling JO - Cell Signal VL - 34 N2 - Several studies have shown that protectins, which are ω-3 fatty acid-derived proresolution mediators, may improve insulin resistance. Recently, protectin DX (PDX) was documented to attenuate insulin resistance by stimulating IL-6 expression in skeletal muscle, thereby regulating hepatic gluconeogenesis. These findings made us investigate the direct effects of PDX on hepatic glucose metabolism in the context of diabetes. In the current study, we show that PDX regulates hepatic gluconeogenesis in a manner distinct from its indirect glucoregulatory activity via IL-6. We found that PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation, thereby inducing heme oxygenase 1 (HO-1) expression. This induction blocked hepatic gluconeogenesis by suppressing endoplasmic reticulum (ER) stress in hepatocytes under hyperlipidemic conditions. These effects were significantly dampened by silencing AMPK or HO-1 expression with small interfering RNA (siRNA). We also demonstrated that administration of PDX to high fat diet (HFD)-fed mice resulted in increased hepatic AMPK phosphorylation and HO-1 expression, whereas hepatic ER stress was substantially attenuated. Furthermore, PDX treatment suppressed the expression of gluconeogenic genes, thereby decreasing blood glucose levels in HFD-fed mice. In conclusion, our findings suggest that PDX inhibits hepatic gluconeogenesis via AMPK-HO-1-dependent suppression of ER stress. Thus, PDX may be an effective therapeutic target for the treatment of insulin resistance and type 2 diabetes through the regulation of hepatic gluconeogenesis. SN - 1873-3913 UR - https://www.unboundmedicine.com/medline/citation/28342842/Protectin_DX_suppresses_hepatic_gluconeogenesis_through_AMPK_HO_1_mediated_inhibition_of_ER_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(17)30082-7 DB - PRIME DP - Unbound Medicine ER -