Suhre Karsten, Römisch-Margl Werner, de Angelis Martin Hrabé, Adamski Jerzy, Luippold Gerd, Augustin Robert
1Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
J Biomol Screen. 2011 Jun;16(5):467-75. doi: 10.1177/1087057111402200. Epub 2011 May 4.
The fatty acid binding protein 4 (FABP4) belongs to the family of lipid chaperones that control intracellular fluxes and compartmentalization of their respective ligands (e.g., fatty acids). FABP4, which is almost exclusively expressed in adipocytes and macrophages, contributes to the development of insulin resistance and atherosclerosis in mice. Lack of FABP4 protects against the development of insulin resistance associated with genetic or diet-induced obesity in mice. Furthermore, total or macrophage-specific FABP4 deficiency is protective against atherosclerosis in apolipoprotein E-deficient mice. The FABP4 small-molecule inhibitor BMS309403 has demonstrated efficacy in mouse models for type 2 diabetes mellitus and atherosclerosis, resembling phenotypes of mice with FABP4 deficiency. However, despite the therapeutically attractive long-term effects of FABP4 inhibition, an acute biomarker for drug action is lacking. The authors applied mass spectrometry lipidomics analysis to in vitro and in vivo (plasma and adipose tissue) samples upon inhibitor treatment. They report the identification of a potential biomarker for acute in vivo FABP4 inhibition that is applicable for further investigations and can be implemented in simple and fast-flow injection mass spectrometry assays. In addition, this approach can be considered a proof-of-principle study that can be applied to other lipid-pathway targeting mechanisms.
脂肪酸结合蛋白4（FABP4）属于脂质伴侣家族，可控制细胞内通量及其各自配体（如脂肪酸）的区室化。FABP4几乎只在脂肪细胞和巨噬细胞中表达，它在小鼠胰岛素抵抗和动脉粥样硬化的发展中起作用。缺乏FABP4可预防小鼠因遗传或饮食诱导的肥胖而产生的胰岛素抵抗。此外，FABP4完全缺失或巨噬细胞特异性缺失对载脂蛋白E缺陷小鼠的动脉粥样硬化具有保护作用。FABP4小分子抑制剂BMS309403在2型糖尿病和动脉粥样硬化小鼠模型中已显示出疗效，类似于FABP4缺陷小鼠的表型。然而，尽管抑制FABP4具有诱人的长期治疗效果，但缺乏药物作用的急性生物标志物。作者对抑制剂处理后的体外和体内（血浆和脂肪组织）样本进行了质谱脂质组学分析。他们报告鉴定出一种潜在的急性体内FABP4抑制生物标志物，可用于进一步研究，并可应用于简单快速的流动注射质谱分析。此外，该方法可被视为一项原理验证研究，可应用于其他脂质途径靶向机制。
