NF-kappaB mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance.
Fetuin-A, a hepatic secretory protein, has recently been implicated in insulin resistance and Type 2 diabetes. It is an endogenous inhibitor of insulin receptor tyrosine kinase. However, regulation of fetuin-A synthesis in relation to insulin resistance is unclear. In the present paper, we report that both non-esterified ('free') fatty acids and fetuin-A coexist at high levels in the serum of db/db mice, indicating an association between them. For an in-depth study, we incubated palmitate with HepG2 cells and rat primary hepatocytes, and found enhanced fetuin-A secretion to more than 4-fold over the control. Interestingly, cell lysates from these incubations showed overexpression and activity of NF-kappaB (nuclear factor kappaB). In NF-kappaB-knockout HepG2 cells, palmitate failed to increase fetuin-A secretion, whereas forced expression of NF-kappaB released fetuin-A massively in the absence of palmitate. Moreover, palmitate stimulated NF-kappaB binding to the fetuin-A promoter resulting in increased reporter activity. These results suggest NF-kappaB to be the mediator of the palmitate effect. Palmitate-induced robust expression of fetuin-A indicates the occurrence of additional targets, and we found that fetuin-A severely impaired adipocyte function leading to insulin resistance. Our results reveal a new dimension of lipid-induced insulin resistance and open another contemporary target for therapeutic intervention in Type 2 diabetes.
Dasgupta
Suman
S
Department of Zoology, Visva-Bharati, A Central University, Santiniketan, India.
Bhattacharya
Sushmita
S
Biswas
Anindita
A
Majumdar
Subeer S
SS
Mukhopadhyay
Satinath
S
Ray
Sukanta
S
Bhattacharya
Samir
S
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008055:Lipids / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D008055:Lipids; D016328:NF-kappa B; D000509:alpha-Fetoproteins