背景:胰岛长期暴露于脂肪酸(FA),常见于肥胖症,代谢综合征,和2型糖尿病,导致代偿性多动,然后炎症,凋亡,功能失调的β细胞,并导致患者的胰岛素依赖性。限制胰岛β细胞的脂肪摄取可以保护它们免受脂毒性。
目的:胰岛β细胞表达脂肪酸结合蛋白3(FABP3)以结合FAs并协调脂质信号。基于此,我们调查了FABP3是否通过Fabp3沉默下调,可能减缓脂质代谢并防止胰岛素分泌细胞的脂毒性。
结果:Fabp3均未沉默,在没有FA的情况下,也没有过表达会影响葡萄糖刺激的胰岛素分泌。Fabp3沉默降低FA摄取,脂滴形成,和脂质积累调节基因Dgat1在Ins1E细胞中的表达。它通过NF-κB的失活减少FA诱导的炎症,这与IκBα的上调和NF-κBp65核易位的失活有关,和细胞因子ILl-6,IL-1β的下调,和TNFα。如通过包括DNA降解和切割的半胱天冬酶-3免疫印迹的不同参数评估的,Ins1E细胞被保护免受FA诱导的凋亡。此外,FABP3沉默提高了生存能力,Pdx1基因表达,以及长期用棕榈酸培养的细胞的胰岛素分泌功能。通过FABP3过表达所产生的相反作用证实了所有结果。
结论:目前的数据表明,可以通过抑制FA摄取来保护胰腺β细胞免受脂毒性,细胞内利用和积累。FABP3抑制,因此,可能是治疗肥胖症的一种有用的药物方法,代谢综合征,和2型糖尿病。
BACKGROUND: Long-term exposure of pancreatic islets to fatty acids (FAs), common in obesity, metabolic syndrome, and type 2 diabetes, leads to a compensatory hyperactivity followed by inflammation, apoptosis, dysfunctional beta cells, and results in insulin dependence of the patient. Restriction of fatty uptake by islet beta cells may protect them from lipotoxicity.
OBJECTIVE: Pancreatic islet beta cells express the fatty acid binding protein 3 (FABP3) to bind FAs and to orchestrate lipid signals. Based on this, we investigated whether downregulation of FABP3, by Fabp3 silencing, might slow lipid metabolism and protect against lipotoxicity in insulin-secreting cells.
RESULTS: Neither Fabp3 silencing, nor overexpression affected the glucose-stimulated insulin secretion in absence of FAs. Fabp3 silencing decreased FA-uptake, lipid droplets formation, and the expression of the lipid accumulation-regulating gene Dgat1 in Ins1E cells. It reduced FA-induced inflammation by deactivation of NF-κB, which was associated with upregulation of IκBα and deactivation of the NF-κB p65 nuclear translocation, and the downregulation of the cytokines ILl-6, IL-1β, and TNFα. Ins1E cells were protected from the FA-induced apoptosis as assessed by different parameters including DNA degradation and cleaved caspase-3 immunoblotting. Furthermore, FABP3 silencing improved the viability, Pdx1 gene expression, and the insulin-secreting function in cells long-term cultured with palmitic acid. All results were confirmed by the opposite action rendered by FABP3 overexpression.
CONCLUSIONS: The present data reveals that pancreatic beta cells can be protected from lipotoxicity by inhibition of FA-uptake, intracellular utilization and accumulation. FABP3 inhibition, hence, may be a useful pharmaceutical approach in obesity, metabolic syndrome, and type 2 diabetes.