NF-κB mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance

Abstract

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.

Association of Insulin Resistance, β-Cell Function Impairment and Calcium, Magnesium, and Fetuin-A Concentrations in Women with Type 2 Diabetes Mellitus

“…In both genders, fetuin-A is positively correlated with IR (18). Therefore, fetuin-A may play an important role in the pathophysiology of T2DM (19). Our results are consistent with those described in previous studies (20,21).…”

Cardiac Autonomic Functions in Obese Children - Original Article

“…Although it is unclear which factors regulate fetuin-A production, it was reported that free fat acids (FFAs) and hyperglycemia increase fetuin-A expression and induce insulin resistance (22). Ix et al (23) conducted a study to investigate the relationship between metabolic syndrome and fetuin-A on 711 patients with coronary artery disease having non-diabetic metabolic syndrome and found that the increase in fetuin-A level was associated to each component of metabolic syndrome.…”

Fetuin-A (AHSG) and its usefulness in clinical practice. Review of the literature

“…Besides the induction of insulin resistance, fetuin-A promotes cytokine expression in human monocytes and reduces the expression of the atheroprotective adipokine-adiponectin in animals 8,9,46 . Moreover fetuin-A deteriorates free fatty acid uptake and storage in adipocytes 10 . A decrease in adiponectin levels that usually enhances oxidation of free fatty acids, observed in patients with coronary artery disease or with at high risk for CVD, may increase free fatty acid levels and lead to worsening atherosclerosis 12,24,28 .…”

“…It also accumulates in bones and teeth as a major fraction of noncollagenous bone proteins and regulates bone remodeling and calcium metabolism being an important inhibitor of calcium salt precipitation and calcification in vivo 2,7 . Fetuin-A has adipogenic properties, reduces expression of the atheroprotective adipokine-adiponectin and deteriorates free fatty acid uptake and storage in adipocytes 3,8,10 . Therefore fat accumulation in the liver may be associated with higher levels of fetuin-A (ref.…”