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 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.

Insulin resistance and cardiovascular disease

“…On the other hand, fetuin-A levels have been shown to be significantly lower in the setting of ischemic cardiomyopathy, as compared with that of dilated cardiomyopathy, potentially providing fetuin-A with a discriminative power between these different types of HF. 88 Results of different studies regarding fetuin-A confirm its contribution to the pathogenesis of IR; it seemingly impedes the maturation of β cells in the pancreatic islets, 89 enhances apoptosis and damages pancreatic β cells when oversecreted, 90 and is overexpressed at the initiation of a high-fat diet, concurrent with IR, in murine models. 91 Additionally, fetuin-A along with a Western lifestyle are held accountable for the development of IR, vascular inflammation and atherosclerosis, 92 as well as for the development of T2D in people of Pakistani origin.…”

Metformin and Dapagliflozin Decrease Fetuin A, Hepatic & Pancreatic Fat and Hepatic Fibrosis in Asian Indians with Type 2 diabetes

“…It is an endogenous inhibitor of the insulin-stimulated insulin receptor tyrosine kinase, and insulin resistance substrate-1. Elevated Fetuin A levels in pancreatic beta cells increase macrophagesmigration and cause beta cell in ammation (12).Experimental studies have suggested critical role of circulatory fetuin-A and β-cell secreted fetuin-A in β-cell dysfunction and apoptosis (13). Clinical studies have shown it to be an independent risk factor for T2D (14).…”

The structure, biosynthesis, and biological roles of fetuin-A: A review

“…Pancreatic β-cells treated with fetuin-A and FFA (palmitate) have been associated with beta cell failure and apoptosis, which is suggested to be mediated through the TLR4-signaling pathway (Shen et al, 2015). Consistently, a follow-up study by Mukhuty et al (2022) unveiled that fetuin-A plays a critical role in triggering FFA-mediated beta cell inflammation, beta-cell dysfunction, and apoptosis by inducing lipotoxicity and activating the TLR4-NF-κB pathway in hyperlipidemic conditions. More interestingly, the apoptosisinducing activity of fetuin-A has also been observed in cancer cell lines, such as mouse P388 leukemia and PC-3 prostate cancer models, with no effect on normal cell lines, suggesting its potential use as a selective anticancer agent.…”

“…Fetuin-A also aggravates IR by inducing fetuin-A secretion from pancreatic beta cells, which promotes macrophages migration and transformation into the M1 phenotype in islets, elicits beta cell inflammation, and impairs their function. ( Agarwal et al, 2017 ; Mukhuty et al, 2017 ; Mukhuty et al, 2021a ; Mukhuty et al, 2022 ). This fetuin-A-mediated chronic beta cell inflammation occurs in hyperlipidemic conditions and is linked with beta cell apoptosis, mass reduction, and dysfunction, leading to decreased insulin secretion and worsening of IR ( Hennige et al, 2008 ; Shen et al, 2015 ).…”