Peroxisome proliferator-activated receptor γ ligands stimulate myeloid differentiation and lipogenensis in human leukemia NB4 cells

Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a central role in adipocyte and macrophage differentiation. Pioglitazone (Actos, AD4833), an antidiabetic drug, and 15-deoxy-Delta(12,14)-prostaglandin J2 (PGJ2) have recently been identified as synthetic and natural ligands for PPAR gamma, respectively. In this study, we examined the effects of PPAR gamma ligands on differentiation and lipogenesis in promyelocytic leukemia NB4 cells, in which PPAR gamma protein was expressed and ligand-stimulated PPAR gamma-specific transcription of adipocyte fatty-acid binding protein was confirmed. Treatment with PPAR gamma ligand (AD4833 or PGJ2) alone markedly suppressed proliferation but did not induce differentiation. The combined treatment of the cells with PPAR gamma ligand and all-trans retinoic acid (ATRA) synergistically induced myelocytic differentiation, as determined by nitroblue tetrazolium reducing ability and cell morphology. During these processes of differentiation, we observed marked accumulation of lipid droplets in the cytoplasm. The cellular triacylglycerol levels increased 2.7-fold after treatment with the inducers. Simultaneously, BODIPY-fatty acid was incorporated into the cytosol and concentrated in lipid droplets. The biosynthesis of triacylglycerol-containing BODIPY-fatty acids was increased twofold in differentiated cells. These findings clearly demonstrate that treatment with PPAR gamma ligands not only induced differentiation but also stimulated lipogenesis in NB4 cells, indicating a close association between differentiation and lipogenesis in PPAR gamma-stimulated human myeloid cells.