FUNCTION AND REGULATION OF FATTY ACID BINDING PROTEINS

长链脂肪酸在细胞浆中的转运 膜和通过细胞质以及它们的 随后用于能量生产和甘油脂质 合成可能部分取决于它们与脂肪酸相互作用 酸结合蛋白（FABP）存在于两种细胞血浆中 膜和细胞质。 虽然只有一种分子形式的 膜相关FABP已在肝脏中表征（LPM-1）。 FABP; 40 dDa），三种不同的14-15 kDa细胞质FABP具有 分别从肝（L-FABP）、肠（I-FABP）、肝（L-FABP）和肠（I-FABP）中分离纯化得到L-FABP。 FABP）和心肌（M-FABP）。 细胞质FABP可能 在脂肪酸转运中发挥特殊功能， 在这些不同的组织中使用。 精确的性质 然而，FABP的功能仍然没有定义。 L-FABP，in 此外，在肝细胞中并不均匀表达， 在小叶I区（门静脉周围）肝细胞中占优势。 然而，在这方面， 肝细胞L- FABP与脂肪酸代谢的特定途径 与肝细胞抵抗 长链脂肪酸的潜在毒性作用是未知的。 这项建议的目的是作为其广泛的目标，阐明 细胞FABP的功能，并将：（1）确定 L-FABP丰度与长链脂肪酸的关系 （a）从区域分离的肝细胞中的利用和毒性 丰富（门静脉周围肝细胞）和稀疏（静脉周围 肝细胞）在其L-FABP表达中的作用，以及（B） 肝细胞单层培养后的L- 通过脂质体介导注射抗-L-FABP测定FABP池大小 IgG或纯L-FABP 1（2）确定比较机制 L-FABP和M-FABP对线粒体和微粒体 长链酰基辅酶A的合成，并确定是否 放射性标记的L-FABP和M-FABP以特异性方式结合至 微粒体和线粒体膜;（3）定义推定的 LPM-FABP在膜脂肪酸转运中的作用 鉴定和表征肝质膜蛋白 用光反应性长链脂肪酸探针标记， 开发用于纯化LPM-FABP的改进方法， 测定其脂肪酸转运功能， 脂质体。 总体而言，拟议的研究将提供 关于我们所知甚少的 细胞FABP的功能及其在细胞转运中的作用 和调节脂肪酸代谢。

The transport of long chain fatty acids across the cell plasma membrane and through the cell cytoplasm as well as their subsequent utilization for energy production and glycerolipid synthesis may depend, in part, upon their interaction with fatty acid binding proteins (FABP) present in both the cell plasma membrane and cytoplasm. Although only one molecular form of membrane-associated FABP has been characterized in liver (LPM- FABP; 40 dDa), three distinct 14-15 kDa cytoplamic FABP have been purified, respectively, from liver (L-FABP), intestine (I- FABP), and heart muscle (M-FABP). The cytoplasmic FABP may perform specialized functions in fatty acid transport and utilization in these different tissues. The nature of the precise functions of the FABP, however, remains undefined. L-FABP, in addition, is not uniformly expressed in liver cells, but predominates in lobular zone I (periportal) hepatocytes. However, the significance of the differential hepatocellular expression of L- FABP in relation to specific pathways of fatty acid metabolism and in relation to the ability of hepatocytes to withstand potentially toxic effects of long chain fatty acids is unknown. The aims of this proposal have as their broad goal, the elucidation of the function of the cellular FABP and are to: (1) determine the relationship between L-FABP abundance and long chain fatty acid utilization and toxicity in (a) hepatocytes isolated from zones abundant (periportal hepatocytes) and sparse (perivenous hepatocytes) in their expression of L-FABP, as well as in (b) hepatocyte monolayer cultures following alteration of the L- FABP pool size by liposome-mediated injection of anti-L-FABP IgG or pure L-FABPl (2) determine the comparative mechanisms of L-FABP and M-FABP effects on mitochondrial and microsomal long chain acyl-CoA synthesis and to determine whether radiolabeled L-FABP and M-FABP bind in a specific manner to microsomal and mitochondrial membranes; (3) define the putative function of LPM-FABP in membrane fatty acid translocation by identifying and characterizing liver plasma membrane proteins labeled with photoreactive long chain fatty acid probes and by developing improved methods for purifying LPM-FABP in order to determined its fatty acid transport function reconstituted in liposomes. Collectively, the proposed studies will provide important new information regarding the poorly understood function of cellular FABP and their role in the cellular transport and regulation of fatty acid metabolism.