Protectin DX ameliorates palmitate‐induced hepatic insulin resistance through AMPK/SIRT1‐mediated modulation of fetuin‐A and SeP expression. (21st July 2019)

• Record Type: Journal Article
• Authors: Jung, Tae Woo; Ahn, Sung Ho; Shin, Jong Wook; Kim, Hyoung‐Chun; Park, Eon Sub; Abd El‐Aty, A. M.; Hacımüftüoğlu, Ahmet; Song, Ki Hak; Jeong, Ji Hoon
• Is Part Of: Clinical and experimental pharmacology and physiology. Volume 46:Number 10(2019)
• Page Start: 898
• Page End: 909
• Publication Date: 2019-07-21
• Subjects: AMPK -- fetuin‐A -- hepatocytes -- protectin DX -- selenoprotein P -- SIRT1; Clinical pharmacology -- Periodicals; Pharmacology, Experimental -- Periodicals; Physiology, Experimental -- Periodicals; Physiology, Pathological -- Periodicals; 615.1
• DOI: 10.1111/1440-1681.13131
• Languages: English
• ISSNs: 0305-1870

Abstract

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.