Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity
Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity
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DOI：
10.1016/j.bbrc.2015.08.055
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发表时间：
2015-09-25
影响因子：
3.1
通讯作者：
DiRusso, Concetta C.
中科院分区：
文献类型：
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作者：
Saini, Nipun;Black, Paul N.;DiRusso, Concetta C.
抑制脂肪酸摄取到非脂肪组织中为预防导致肥胖相关的非酒精性脂肪性肝病和2型糖尿病的脂毒性提供了有吸引力的靶点。脂肪酸转运蛋白（FATPs）是一种双功能蛋白质，参与脂肪酸的摄取和活化。在这里，我们的特点Grassofermata/CB 5，以前确定为脂肪酸摄取抑制剂针对HsFATP 2。该化合物在低微摩尔范围内（IC 50 8-11 μ M）有效抑制脂肪酸的摄取，并防止作为肠、肝、肌肉和胰腺模型的细胞系中棕榈酸酯介导的脂质积聚和细胞死亡。在脂肪细胞中，摄取抑制作用不太有效（IC 50 58 μ M）。抑制是特定的长链脂肪酸和无效的中链脂肪酸，这是通过扩散运输。Grassofermata依赖的FA转运抑制动力学分析验证了非竞争性机制。通过与Grassofermata比较，几种以前被认为是FA摄取抑制剂的非典型抗精神病药物无效。在小鼠中，Grassofermata降低了C-13-油酸酯的吸收，表明其作为治疗剂的潜力。(C)2015 Elsevier Inc. All rights reserved.
The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC50 8-11 mu M) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC50 58 mu M). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of C-13-oleate demonstrating its potential as a therapeutic agent. (C) 2015 Elsevier Inc. All rights reserved.