Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress.
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.
Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea.
Tae Woo
TW
Jung
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea.
Hyung-Chun
HC
Kim
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.
A M
AM
Abd El-Aty
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea. Electronic address: jhjeong3@cau.ac.kr.
Ji Hoon
JH
Jeong
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005943:Gluconeogenesis / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010168:Palmitates / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C000591716:10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010168:Palmitates; D034741:RNA, Small Interfering; D004281:Docosahexaenoic Acids; D051547:Heme Oxygenase-1; D055372:AMP-Activated Protein Kinases
AMP-activated protein kinase; Endoplasmic reticulum stress; Gluconeogenesis; Heme oxygenase 1; Protectin DX