Identification of a Potential Biomarker for FABP4 Inhibition: The Power of Lipidomics in Preclinical Drug Testing
Identification of a Potential Biomarker for FABP4 Inhibition: The Power of Lipidomics in Preclinical Drug Testing
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DOI：
10.1177/1087057111402200
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发表时间：
2011-06-01
影响因子：
--
通讯作者：
Augustin, Robert
中科院分区：
文献类型：
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作者：
Suhre, Karsten;Roemisch-Margl, Werner;Augustin, Robert
脂肪酸结合蛋白4（FABP 4）属于脂质伴侣蛋白家族，其控制细胞内通量和其各自配体的区室化（例如，胞内转运）。例如，在一个实施例中，脂肪酸）。FABP 4几乎只在脂肪细胞和巨噬细胞中表达，有助于小鼠胰岛素抵抗和动脉粥样硬化的发展。缺乏FABP 4可以防止小鼠发生与遗传或饮食诱导的肥胖相关的胰岛素抵抗。此外，总的或巨噬细胞特异性FABP 4缺乏对载脂蛋白E缺乏小鼠的动脉粥样硬化具有保护作用。FABP 4小分子抑制剂BMS 309403已在2型糖尿病和动脉粥样硬化的小鼠模型中显示出疗效，其表型类似于FABP 4缺陷小鼠。然而，尽管FABP 4抑制具有治疗上有吸引力的长期效果，但缺乏药物作用的急性生物标志物。作者将质谱脂质组学分析应用于抑制剂治疗后的体外和体内（血浆和脂肪组织）样本。他们报告了急性体内FABP 4抑制的潜在生物标志物的鉴定，该生物标志物适用于进一步研究，并且可以在简单和快速流动注射质谱分析中实施。此外，这种方法可以被认为是一种原理验证研究，可以应用于其他脂质通路靶向机制。（Journal of Biomolecular Screening 2011; 16：467-475）
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. (Journal of Biomolecular Screening 2011; 16: 467-475)