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Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK/SIRT1-mediated modulation of fetuin-A and SeP expression.
Clin Exp Pharmacol Physiol. 2019 10; 46(10):898-909.CE

Abstract

The role as well as the molecular mechanisms of protectin DX (PDX) in the prevention of hepatic insulin resistance, a hallmark of type 2 diabetes, remains unknown. Therefore, the present study was designed to explore the direct impact of PDX on insulin resistance and to investigate the expression of fetuin-A and selenoprotein P (SeP), hepatokines that are involved in insulin signalling, in hepatocytes. Human serum levels of PDX as well as fetuin-A and SeP were determined by high-performance liquid chromatography (HPLC). Human primary hepatocytes were treated with palmitate and PDX. NF-κB phosphorylation as well as expression of insulin signalling associated genes and hepatokines were determined by Western blotting analysis. FOXO1 binding levels were measured by quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si) RNA-mediated gene suppression. Serum PDX levels were significantly (P < 0.05) downregulated, whereas serum fetuin-A and SeP levels were increased (P < 0.05) in obese subjects compared with healthy subjects. In in vitro experiments, PDX treatment increased AMP-activated protein kinase (AMPK) phosphorylation and SIRT1 expression and attenuated palmitate-induced fetuin-A and SeP expression and insulin resistance in hepatocytes. AMPK or SIRT1 siRNA mitigated the suppressive effects of PDX on palmitate-induced fetuin-A through NF-κB and SeP expression linked to FOXO1 and insulin resistance. Recombinant fetuin-A and SeP reversed the suppressive effects of fetuin-A and SeP expression on palmitate-mediated impairment of insulin signalling. The current finding provides novel insight into the underlying mechanism linking hepatokines to the pathogenesis of hepatic insulin resistance.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea.Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Korea.Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Korea.Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Korea.Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt. Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey.Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey.Department of Urology, College of Medicine, Chungnam National University, Daejeon, Korea.Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea.

Pub Type(s)

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

Language

eng

PubMed ID

31246318

Citation

Jung, Tae Woo, et al. "Protectin DX Ameliorates Palmitate-induced Hepatic Insulin Resistance Through AMPK/SIRT1-mediated Modulation of fetuin-A and SeP Expression." Clinical and Experimental Pharmacology & Physiology, vol. 46, no. 10, 2019, pp. 898-909.
Jung TW, Ahn SH, Shin JW, et al. Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK/SIRT1-mediated modulation of fetuin-A and SeP expression. Clin Exp Pharmacol Physiol. 2019;46(10):898-909.
Jung, T. W., Ahn, S. H., Shin, J. W., Kim, H. C., Park, E. S., Abd El-Aty, A. M., Hacımüftüoğlu, A., Song, K. H., & Jeong, J. H. (2019). Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK/SIRT1-mediated modulation of fetuin-A and SeP expression. Clinical and Experimental Pharmacology & Physiology, 46(10), 898-909. https://doi.org/10.1111/1440-1681.13131
Jung TW, et al. Protectin DX Ameliorates Palmitate-induced Hepatic Insulin Resistance Through AMPK/SIRT1-mediated Modulation of fetuin-A and SeP Expression. Clin Exp Pharmacol Physiol. 2019;46(10):898-909. PubMed PMID: 31246318.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK/SIRT1-mediated modulation of fetuin-A and SeP expression. AU - Jung,Tae Woo, AU - Ahn,Sung Ho, AU - Shin,Jong Wook, AU - Kim,Hyoung-Chun, AU - Park,Eon Sub, AU - Abd El-Aty,A M, AU - Hacımüftüoğlu,Ahmet, AU - Song,Ki Hak, AU - Jeong,Ji Hoon, Y1 - 2019/07/21/ PY - 2019/03/15/received PY - 2019/05/08/revised PY - 2019/06/21/accepted PY - 2019/6/28/pubmed PY - 2020/9/9/medline PY - 2019/6/28/entrez KW - AMPK KW - SIRT1 KW - fetuin-A KW - hepatocytes KW - protectin DX KW - selenoprotein P SP - 898 EP - 909 JF - Clinical and experimental pharmacology & physiology JO - Clin Exp Pharmacol Physiol VL - 46 IS - 10 N2 - The role as well as the molecular mechanisms of protectin DX (PDX) in the prevention of hepatic insulin resistance, a hallmark of type 2 diabetes, remains unknown. Therefore, the present study was designed to explore the direct impact of PDX on insulin resistance and to investigate the expression of fetuin-A and selenoprotein P (SeP), hepatokines that are involved in insulin signalling, in hepatocytes. Human serum levels of PDX as well as fetuin-A and SeP were determined by high-performance liquid chromatography (HPLC). Human primary hepatocytes were treated with palmitate and PDX. NF-κB phosphorylation as well as expression of insulin signalling associated genes and hepatokines were determined by Western blotting analysis. FOXO1 binding levels were measured by quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si) RNA-mediated gene suppression. Serum PDX levels were significantly (P < 0.05) downregulated, whereas serum fetuin-A and SeP levels were increased (P < 0.05) in obese subjects compared with healthy subjects. In in vitro experiments, PDX treatment increased AMP-activated protein kinase (AMPK) phosphorylation and SIRT1 expression and attenuated palmitate-induced fetuin-A and SeP expression and insulin resistance in hepatocytes. AMPK or SIRT1 siRNA mitigated the suppressive effects of PDX on palmitate-induced fetuin-A through NF-κB and SeP expression linked to FOXO1 and insulin resistance. Recombinant fetuin-A and SeP reversed the suppressive effects of fetuin-A and SeP expression on palmitate-mediated impairment of insulin signalling. The current finding provides novel insight into the underlying mechanism linking hepatokines to the pathogenesis of hepatic insulin resistance. SN - 1440-1681 UR - https://www.unboundmedicine.com/medline/citation/31246318/Protectin_DX_ameliorates_palmitate_induced_hepatic_insulin_resistance_through_AMPK/SIRT1_mediated_modulation_of_fetuin_A_and_SeP_expression_ L2 - https://doi.org/10.1111/1440-1681.13131 DB - PRIME DP - Unbound Medicine ER -