Department of Internal Medicine, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany.
Department of Internal Medicine, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany.
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Sep;1862(9):917-928. doi: 10.1016/j.bbalip.2017.05.013. Epub 2017 Jun 6.
Suppression of fatty acid absorption is one goal to fight obesity. However, the responsible molecular mechanism is poorly understood. Aim of the present study was the search for the key regulator of the overall fatty acid absorption mechanism and its pharmaceutical modulation. As experimental tool we employed the polarized human intestinal tumor derived cell line CaCo2. Here we showed that influx of fatty acids is mediated by an apical heterotetrameric plasma membrane protein complex of which the calcium-independent membrane phospholipase A (iPLAß) is one constituent. The newly synthesized bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) blocked iPLAß, which structurally disrupted the fatty acid-uptake complex. Furthermore, the inhibition of iPLAß lead to reduction of cytosolic lysophosphatidylcholine (LPC) production which suppressed p-JNK1, as a central regulator of metabolism. In a concerted action low p-JNK1 levels prohibited synthesis of the members of the fatty acid uptake complex as well as of apolipoprotein B and the connected members of the basolateral vesicular chylomicron excretion machinery, thereby inhibiting cellular lipid excretion. The basolateral chylomicron release was shown to determine the overall fatty acid-absorption capacity as rate limiting step, whereas apical uptake replenishes the cellular stores, enabling continuous transcellular movement of fatty acids. In conclusion, the UDCA-LPE mediated inhibition of p-JNK1 represents a powerful tool to control intestinal absorption of fatty acids and, thus may be employed as a drug to treat obesity.
抑制脂肪酸吸收是对抗肥胖的一个目标。然而，其负责的分子机制还了解甚少。本研究的目的是寻找整体脂肪酸吸收机制的关键调节剂及其药物调节。作为实验工具，我们采用了极化的人肠道肿瘤衍生细胞系 CaCo2。在这里，我们表明脂肪酸的内流是由一个顶端异四聚体质膜蛋白复合物介导的，其中钙非依赖性膜磷酯酶 A（iPLAß）是其组成部分之一。新合成的胆汁酸-磷脂缀合物熊去氧胆酸-溶血磷脂酰乙醇胺（UDCA-LPE）可阻断 iPLAß，从而使脂肪酸摄取复合物的结构发生破坏。此外，iPLAß 的抑制导致细胞溶质溶血磷脂酰胆碱（LPC）的产生减少，从而抑制了作为代谢中央调节剂的 p-JNK1。在协同作用下，低水平的 p-JNK1 可抑制脂肪酸摄取复合物以及载脂蛋白 B 和基底外侧囊泡乳糜微粒分泌机制的相关成员的合成，从而抑制细胞内脂质的排泄。基底外侧乳糜微粒的释放被证明是限制整体脂肪酸吸收能力的限速步骤，而顶端摄取则补充细胞内储存，使脂肪酸能够持续进行细胞间运动。总之，UDCA-LPE 介导的 p-JNK1 抑制作用代表了控制肠道脂肪酸吸收的有力工具，因此可作为治疗肥胖症的药物。
