Department of Medicine, Center for Human Nutrition, 660 S. Euclid Ave., Campus Box 8031, St. Louis, MO 63110, USA.
FASEB J. 2013 Mar;27(3):1191-202. doi: 10.1096/fj.12-217703. Epub 2012 Dec 11.
Genetic variants in the fatty acid (FA) translocase FAT/CD36 associate with abnormal postprandial lipids and influence risk for the metabolic syndrome. CD36 is abundant on apical enterocyte membranes in the proximal small intestine, where it facilitates FA uptake and FA-initiated signaling. We explored whether CD36 signaling influences FA-mediated secretion of cholecystokinin (CCK) and secretin, peptides released by enteroendocrine cells (EECs) in the duodenum/jejunum, which regulate events important for fat digestion and homeostasis. CD36 was immunodetected on apical membranes of secretin- and CCK-positive EECs and colocalized with cytosolic granules. Intragastric lipid administration to CD36 mice released less secretin (-60%) and CCK (-50%) compared with wild-type mice. Likewise, diminished secretin and CCK responses to FA were observed with CD36 intestinal segments in vitro, arguing against influence of alterations in fat absorption. Signaling mechanisms underlying peptide release were examined in STC-1 cells stably expressing human CD36 or a signaling-impaired mutant (CD36K/A). FA stimulation of cells expressing CD36 (vs. vector or CD36K/A) released more secretin (3.5- to 4-fold) and CCK (2- to 3-fold), generated more cAMP (2- to 2.5-fold), and enhanced protein kinase A activation. Protein kinase A inhibition (H-89) blunted secretin (80%) but not CCK release, which was reduced (50%) by blocking of calmodulin kinase II (KN-62). Coculture of STC-1 cells with Caco-2 cells stably expressing CD36 did not alter secretin or CCK release, consistent with a minimal effect of adjacent enterocytes. In summary, CD36 is a major mediator of FA-induced release of CCK and secretin. These peptides contribute to the role of CD36 in fat absorption and to its pleiotropic metabolic effects.
脂肪酸（FA）转运蛋白 FAT/CD36 的遗传变异与餐后脂质异常有关，并影响代谢综合征的风险。CD36 在近端小肠的顶膜上丰富存在，在那里它促进 FA 的摄取和 FA 起始的信号转导。我们探讨了 CD36 信号是否影响 FA 介导的胆囊收缩素（CCK）和肠促胰酶肽（secretin）的分泌，这些肽由十二指肠/空肠中的肠内分泌细胞（EEC）释放，调节脂肪消化和稳态的重要事件。CD36 在分泌 CCK 和 secretin 的 EEC 的顶膜上被免疫检测到，并与细胞质颗粒共定位。与野生型小鼠相比，CD36 小鼠胃内脂质给药后释放的 secretin（-60%）和 CCK（-50%）较少。同样，在体外观察到 CD36 肠段对 FA 的 secretin 和 CCK 反应减弱，这排除了脂肪吸收改变的影响。在稳定表达人 CD36 或信号缺陷突变体（CD36K/A）的 STC-1 细胞中，研究了肽释放的信号机制。与表达 CD36（与载体或 CD36K/A 相比）的细胞相比，FA 刺激释放更多的 secretin（3.5-至 4 倍）和 CCK（2-至 3 倍），产生更多的 cAMP（2-至 2.5 倍），并增强蛋白激酶 A 的激活。蛋白激酶 A 抑制剂（H-89）阻断了 secretin（80%）但不阻断 CCK 的释放，而 calmodulin 激酶 II（KN-62）阻断则减少了 CCK 的释放（50%）。将 STC-1 细胞与稳定表达 CD36 的 Caco-2 细胞共培养并未改变 secretin 或 CCK 的释放，这与相邻肠细胞的影响很小一致。总之，CD36 是 FA 诱导的 CCK 和 secretin 释放的主要介质。这些肽有助于 CD36 在脂肪吸收中的作用及其多效代谢效应。
