Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK/SIRT1-mediated modulation of fetuin-A and SeP expression


Jung T. W., Ahn S. H., Shin J. W., Kim H., Park E. S., Abd El-Aty A. M., ...More

Clinical and Experimental Pharmacology and Physiology, vol.46, no.10, pp.898-909, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 46 Issue: 10
  • Publication Date: 2019
  • Doi Number: 10.1111/1440-1681.13131
  • Journal Name: Clinical and Experimental Pharmacology and Physiology
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.898-909
  • Keywords: AMPK, fetuin-A, hepatocytes, protectin DX, selenoprotein P, SIRT1, ACTIVATED PROTEIN-KINASE, NF-KAPPA-B, SELENOPROTEIN-P, SKELETAL-MUSCLE, AMPK, EXERCISE, LIVER, INFLAMMATION, SENSITIVITY, RESVERATROL
  • Ataturk University Affiliated: Yes

Abstract

© 2019 John Wiley & Sons Australia, LtdThe 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.