Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle.

Fatty acids (FAs) are the major substrate for energy production in the heart. Here, we hypothesize that capillary endothelial fatty acid binding protein 4 (FABP4) and FABP5 play an important role in providing sufficient FAs to the myocardium. Both FABP4/5 were abundantly expressed in capillary endothelium in the heart and skeletal muscle. The uptake of a FA analogue, 125I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid, was significantly reduced in these tissues in double-knockout (DKO) mice for FABP4/5 compared with wild-type mice. In contrast, the uptake of a glucose analogue, 18F-fluorodeoxyglucose, was remarkably increased in DKO mice. The expression of transcripts for the oxidative catabolism of FAs was reduced during fasting, whereas transcripts for the glycolytic pathway were not altered in DKO hearts. Notably, metabolome analysis revealed that phosphocreatine and ADP levels were significantly lower in DKO hearts, whereas ATP content was kept at a normal level. The protein expression levels of the glucose transporter Glut4 and the phosphorylated form of phosphofructokinase-2 were increased in DKO hearts, whereas the phosphorylation of insulin receptor-β and Akt was comparable between wild-type and DKO hearts during fasting, suggesting that a dramatic increase in glucose usage during fasting is insulin independent and is at least partly attributed to the post-transcriptional and allosteric regulation of key proteins that regulate glucose uptake and glycolysis. Capillary endothelial FABP4/5 are required for FA transport into FA-consuming tissues that include the heart. These findings identify FABP4/5 as promising targets for controlling the metabolism of energy substrates in FA-consuming organs that have muscle-type continuous capillary.

脂肪酸（FAs）是心脏产生能量的主要底物。在此，我们假设毛细血管内皮脂肪酸结合蛋白4（FABP4）和FABP5在为心肌提供充足的脂肪酸方面发挥重要作用。 FABP4/5在心脏和骨骼肌的毛细血管内皮中大量表达。与野生型小鼠相比，FABP4/5双敲除（DKO）小鼠的这些组织对脂肪酸类似物125I - 15 -（对碘苯基）- 3 -（R，S）-甲基十五烷酸的摄取显著减少。相反，DKO小鼠对葡萄糖类似物18F - 氟脱氧葡萄糖的摄取显著增加。在禁食期间，脂肪酸氧化分解代谢的转录本表达降低，而糖酵解途径的转录本在DKO心脏中未改变。值得注意的是，代谢组分析显示，DKO心脏中的磷酸肌酸和ADP水平显著降低，而ATP含量保持在正常水平。DKO心脏中葡萄糖转运蛋白Glut4和磷酸果糖激酶 - 2的磷酸化形式的蛋白表达水平增加，而在禁食期间野生型和DKO心脏之间胰岛素受体 - β和Akt的磷酸化相当，这表明禁食期间葡萄糖使用的显著增加是不依赖胰岛素的，并且至少部分归因于调节葡萄糖摄取和糖酵解的关键蛋白的转录后和变构调节。 毛细血管内皮FABP4/5是脂肪酸转运到包括心脏在内的脂肪酸消耗组织所必需的。这些发现确定FABP4/5是控制具有肌型连续性毛细血管的脂肪酸消耗器官中能量底物代谢的有希望的靶点。