Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Nat Commun. 2018 Apr 3;9(1):1310. doi: 10.1038/s41467-018-03775-y.
Lipoprotein lipase (LPL) mediates hydrolysis of triglycerides (TGs) to supply free fatty acids (FFAs) to tissues. Here, we show that LPL activity is also required for hematopoietic stem progenitor cell (HSPC) maintenance. Knockout of Lpl or its obligatory cofactor Apoc2 results in significantly reduced HSPC expansion during definitive hematopoiesis in zebrafish. A human APOC2 mimetic peptide or the human very low-density lipoprotein, which carries APOC2, rescues the phenotype in apoc2 but not in lpl mutant zebrafish. Creating parabiotic apoc2 and lpl mutant zebrafish rescues the hematopoietic defect in both. Docosahexaenoic acid (DHA) is identified as an important factor in HSPC expansion. FFA-DHA, but not TG-DHA, rescues the HSPC defects in apoc2 and lpl mutant zebrafish. Reduced blood cell counts are also observed in Apoc2 mutant mice at the time of weaning. These results indicate that LPL-mediated release of the essential fatty acid DHA regulates HSPC expansion and definitive hematopoiesis.
脂蛋白脂肪酶（LPL）介导甘油三酯（TGs）的水解，为组织提供游离脂肪酸（FFAs）。在这里，我们表明 LPL 活性对于造血干细胞祖细胞（HSPC）的维持也是必需的。在斑马鱼中，Lpl 或其必需的辅助因子 Apoc2 的敲除导致定型造血过程中 HSPC 的扩增显著减少。人 APOC2 模拟肽或携带 APOC2 的人极低密度脂蛋白可挽救 apoc2 中的表型，但不能挽救 lpl 突变体斑马鱼中的表型。创建共生 apoc2 和 lpl 突变体斑马鱼可挽救两者的造血缺陷。二十二碳六烯酸（DHA）被确定为 HSPC 扩增的重要因素。FFA-DHA，但不是 TG-DHA，可挽救 apoc2 和 lpl 突变体斑马鱼中的 HSPC 缺陷。在断奶时，Apoc2 突变小鼠的血细胞计数也减少。这些结果表明，LPL 介导的必需脂肪酸 DHA 的释放调节 HSPC 的扩增和定型造血。
