Fetuin‐A excess expression  amplifies lipid induced apoptosis and β‐cell damage. Issue 1 (5th July 2021)

• Record Type: Journal Article
• Authors: Mukhuty, Alpana; Fouzder, Chandrani; Kundu, Rakesh
• Is Part Of: Journal of cellular physiology. Volume 237:Issue 1(2022)
• Page Start: 532
• Page End: 550
• Publication Date: 2021-07-05
• Subjects: apoptosis -- fetuin‐A -- MIN6 -- pancreatic β‐cell -- TLR4 -- type 2 diabetes; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30499
• Languages: English
• ISSNs: 0021-9541

Abstract

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 shown that 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 as 20 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.