Fetuin-A excess expression amplifies lipid induced apoptosis and β-cell damage.

Abstract

Fetuin-A, a hepato-adipokine, is associated with lipid-mediated islet inflammation and inflicts β-cell death but the underlying mechanisms are still unclear. In an earlier report, it was shownthat fetuin-A promotes lipid-induced insulin resistance by acting as an endogenous ligand of toll like receptor 4. Recently, we have also reported that β-cells secrete fetuin-A on stimulation by palmitate causing β-cell dysfunction. The aim of this study was twofold: (a) screening the role of fetuin-A in survival of murine β-cells, and (b) to validate the effect of fetuin-A release and lipid induced apoptosis in mouse insulinoma cell line MIN6. Excess of lipid and fetuin-A in circulation induced significant deterioration of islet histoarchitecture and impeded insulin secretion by 2.7 ± 0.5-folds in 20 weeks high fat diet mice. Administration of fetuin-A (0.7 mg/g) along with 4 weeks of HFD produced similar results as20 weeks of high fat feeding. Treating high doses of palmitate alone (0.50 mM) as well as in combination with fetuin-A (100 µg/ml) for 24 h inflicted apoptosis in MIN6 through the mitochondrial pathway. Knockdown of fetuin-A gene partially inhibited palmitate inflicted apoptosis in MIN6 by 1.83 ± 0.25 times, however, fetuin-A when added in the medium caused re-emergence of apoptosis. Notably, apoptosis induced by palmitate conditioned media from MIN6, 3T3L1, and HepG2, was partially inhibited in fetuin-A KD MIN6. These results confirmed the critical role of circulatory fetuin-A and β-cell secreted fetuin-A in β-cell dysfunction and apoptosis under hyperlipidemic conditions.