Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK/SIRT1-mediated modulation of fetuin-A and SeP expression.
Tae Woo JungSung Ho AhnJong Wook ShinHyoung-Chun KimEon Sub ParkA M Abd El-AtyAhmet HacımüftüoğluKi Hak SongJi Hoon JeongPublished in: Clinical and experimental pharmacology & physiology (2019)
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.
Keyphrases
- insulin resistance
- poor prognosis
- type diabetes
- protein kinase
- adipose tissue
- metabolic syndrome
- binding protein
- skeletal muscle
- oxidative stress
- signaling pathway
- polycystic ovary syndrome
- long non coding rna
- diabetic rats
- glycemic control
- pi k akt
- drug induced
- high glucose
- liver injury
- dna methylation
- immune response
- bariatric surgery
- simultaneous determination
- ischemia reperfusion injury
- copy number
- cell proliferation
- lps induced
- room temperature
- solid phase extraction
- combination therapy