Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity. (5th September 2015)

• Record Type: Journal Article
• Authors: Shen, Ximei; Yang, Liyong; Yan, Sunjie; Zheng, Huanhuan; Liang, Liyu; Cai, Xiuhui; Liao, Meng
• Is Part Of: Molecular and cellular endocrinology. Volume 412(2015)
• Page Start: 1
• Page End: 11
• Publication Date: 2015-09-05
• Subjects: Fetuin A -- Palmitic acid -- Toll-like receptor 4 -- JNK -- Apoptosis -- G-protein-coupled receptor 40; ERS endoplasmic reticulum stress -- FetA Fetuin A -- FFA free fatty acids -- GPR40 G-protein-coupled receptor 40 -- GSIS glucose-stimulated insulin secretion -- HFD high-fat diet -- IPGTT intraperitoneal glucose tolerance test -- IR insulin resistance -- ITT insulin tolerance test -- JNK c-Jun NH2-terminal kinase -- KRBB Krebs–Ringer bicarbonate buffer -- LPS lipopolysaccharide -- NF-κB nuclear factor κ-B -- PA palmitic acid -- PDX-1 pancreatic duodenal homeobox-1 -- PIO pioglitazone -- p-JNK phosphorylated c-Jun NH2-terminal kinase -- PPARγ peroxisome proliferator-activated receptor γ -- SD Sprague–Dawley -- TLR4 toll-like receptor 4; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.05.014
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: FetA dose-dependently aggravated PA-induced βTC6 cell lipotoxicity. Only PA combined with FetA could upregulate TLR4 expression. Inhibition TLR4/JNK/NF-κB could prevent the enhanced effect of FetA. PIO could ameliorate lipotoxicity in vitro and in vivo . Fetuin A was directly proportional to the β cell lipotoxicity in vivo . Abstract: Objective: Fetuin A (FetA), a secreted glycoprotein, is known to affect inflammation and insulin resistance (IR) in obese humans and animals. Lipotoxicity from chronic hyperlipidemia damages pancreatic β cells, hastening the onset of diabetes. We sought to determine whether FetA promotes lipotoxicity through modulation of the toll-like receptor 4 (TLR4) inflammatory signaling pathway as well as the protective effect of pioglitazone(PIO) on lipotoxicity. Methods: βTC6, a glucose-sensitive mouse pancreatic β cell line, and Sprague–Dawley rats with diet-induced obesity, were used to investigate FetA-mediated lipotoxicity. Protein expression/activation were measured by Western blotting. Small interfering (si)RNAs for TLR4 were used. Cell apoptosis was quantified by TUNEL analysis or flow cytometry, respectively. Insulin release was assessed with an insulin ELISA. Results: FetA dose-dependently aggravated palmitic acid (PA)-induced βTC6 cell apoptosis, insulin secretion impairment, and inhibition of the expression of G-protein-coupled receptor 40 (GPR40) and pancreatic duodenal homeobox-1(PDX-1). Combined FetA + PA induced TLR4 expression, and subsequent inhibition of TLR4 signaling or expression was shown to prevent the strengthening effect of FetA on PA-induced lipotoxicity in βTC6 cells. FetA + PA induced p-JNK and nuclear factor-κB (NF-κB) subunit P65 expression, and inhibition of this activity reduced PA+ FetA lipotoxicity in βTC6 cells. PIO could ameliorate PA+ FetA-induced damage to βTC6 cells. Similarly, PIO improved insulin secretion disorder, reduced apoptosis, decreased FetA, TLR4, p-JNK, NF-κB subunit P65 and cleaved caspase 3 expression, and increased GPR40 and PDX-1 expression in islet β cells of diet-induced obese rats. The correlative bivariate analysis showed that increases in Fetuin A were directly proportional to the development of β cell injury. Conclusions: FetA can promote lipotoxicity in β cells through the TLR4-JNK-NF-κB signaling pathway. The protective effects of PIO on lipotoxicity in β cells may involve the inhibition of the activation of the FetA and TLR4 signaling pathway.