title: Salsalate and Adiponectin Improve Palmitate-Induced Insulin Resistance via Inhibition of Selenoprotein P through the AMPK-FOXO1α Pathway.
abstract: Selenoprotein P (SeP) was recently identified as a hepatokine that induces insulin resistance (IR) in rodents and humans. Recent clinical trials have shown that salsalate, a prodrug of salicylate, significantly lowers blood glucose levels and increases adiponectin concentrations. We examined the effects of salsalate and full length-adiponectin (fAd) on the expression of SeP under hyperlipidemic conditions and explored their regulatory mechanism on SeP. In palmitate-treated HepG2 cells as well as high fat diet (HFD)-fed male Spraque Dawley (SD) rats and male db/db mice, SeP expression and its regulatory pathway, including AMPK-FOXO1α, were evaluated after administration of salsalate and salicylate. Palmitate treatment significantly increased SeP expression and aggravated IR, while knock-down of SeP by siRNA restored these changes in HepG2 cells. Palmitate-induced SeP expression was inhibited by both salsalate and salicylate, which was mediated by AMPK activation, and was blocked by AMPK siRNA or an inhibitor of AMPK. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift (EMSA) assay showed that salsalate suppressed SeP expression by AMPK-mediated phosphorylation of FOXO1α. Moreover, fAd also reduced palmitate-induced SeP expression through the activation of AMPK, which results in improved IR. Both salsalate and salicylate treatment significantly improved glucose intolerance and insulin sensitivity, accompanied by reduced SeP mRNA and protein expression in HFD-fed rats and db/db mice, respectively. Taken together, we found that salsalate and adiponectin ameliorated palmitate-induced IR in hepatocytes via SeP inhibition through the AMPK-FOXO1α pathway. The regulation of SeP might be a novel mechanism mediating the anti-diabetic effects of salsalate and adiponectin.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Jung
authors.forename: Hae Yoon
authors.initials: HY
authors.lastname: Choi
authors.forename: So Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Ho Cheol
authors.initials: HC
authors.lastname: Hong
authors.forename: Sae Jeong
authors.initials: SJ
authors.lastname: Yang
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Yoo
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Youn
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Baik
authors.forename: Kyung Mook
authors.initials: KM
authors.lastname: Choi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052242:Adiponectin / Q000494:pharmacology*; D000293:Adolescent; D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D009419:Nerve Tissue Proteins; D010168:Palmitates / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology*; D051149:Selenoprotein P / Q000037:antagonists & inhibitors*; D000071161:Forkhead Box Protein O1
chemical_list: D055372:AMP-Activated Protein Kinases; D052242:Adiponectin; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D010168:Palmitates; D012459:Salicylates; D051149:Selenoprotein P; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C014182:salicylsalicylic acid