PAS kinase drives lipogenesis through SREBP-1 maturation.

Elevated hepatic synthesis of fatty acids and triglycerides, driven by hyperactivation of the SREBP-1c transcription factor, has been implicated as a causal feature of metabolic syndrome. SREBP-1c activation requires the proteolytic maturation of the endoplasmic-reticulum-bound precursor to the active, nuclear transcription factor, which is stimulated by feeding and insulin signaling. Here, we show that feeding and insulin stimulate the hepatic expression of PASK. We also demonstrate, using genetic and pharmacological approaches, that PASK is required for the proteolytic maturation of SREBP-1c in cultured cells and in the mouse and rat liver. Inhibition of PASK improves lipid and glucose metabolism in dietary animal models of obesity and dyslipidemia. Administration of a PASK inhibitor decreases hepatic expression of lipogenic SREBP-1c target genes, decreases serum triglycerides, and partially reverses insulin resistance. While the signaling network that controls SREBP-1c activation is complex, we propose that PASK is an important component with therapeutic potential.

Enhanced ability of the progenipoietin-1 to suppress apoptosis in human hematopoietic cells.

Repopulating hematopoietic cell compartments after myeloablative chemotherapy remains a key factor in a successful chemotherapy program. Modified and chimeric cytokines have been developed to help reduce inflammation, fever and hospitalization time for patients. A chimeric cytokine, progenipoietin-1 (ProGP-1), containing the G-CSF and FL receptor agonists binds both the G-CSF receptor and FLT-3. It also stimulates the growth of dendritic cells, which play an important role in immunotherapy. While in vivo effects of ProGP-1 are well described, the mechanisms by which it stimulates growth are not well understood. We have investigated the effects of ProGP-1 on prevention of apoptosis in the human hematopoietic cell line OCI-AML.5. ProGP-1 promoted cellular proliferation better than G-CSF or FL separately but stimulated proliferation similar to their co-addition as demonstrated by growth curves and [3H]-thymidine incorporation. ProGP-1 prevented apoptosis to a greater degree than G-CSF or FL alone as determined by annexin V/propidium iodide binding and TUNEL assays. ProGP-1 promoted maintenance of the mitochondrial membrane potential better than G-CSF or FL alone. In addition, Pro-GP promoted a lower redox potential as higher levels of free radicals were detected after cytokine treatment than in cytokine-deprived cells implying increased respiration. These data indicate that ProGP-1 promotes the proliferation and prevents the apoptosis of human hematopoietic cells better than FL or G-CSF alone, and to a similar extent as their co-addition. Thus, ProGP-1 can be used to repopulate certain hematopoietic cells as a single entity rather than the introduction of two different cytokines.

Initial Studies on the Effect of Inhaled Misoprostol in a Guinea Pig Model of Allergic Bronchoconstriction.

Inhaled E series prostaglandins (PGEs) have been shown to modulate responses to both allergic and nonallergic provocation. Little is known about the effect of inhaled misoprostol on the airway and whether its antiasthmatic activity would be similar to other PGEs. In the present study, nebulized solutions of misoprostol and PGE(2) (0.3--300 &mgr;g ml(minus sign1)) effectively blocked the acute bronchospasm due to inhaled antigen challenge in actively sensitized guinea pigs. A 300-&mgr;g ml(minus sign1) solution nebulized for 10 s (about 0.25 ml), 5 min prior to challenge, provided nearly complete inhibition with significant reductions seen at 30 and 3 &mgr;g ml(minus sign1) in certain experiments. Misoprostol treatment resulted in a significant reduction in the number of eosinophils present in bronchoalveolar lavage 24 h after antigen challenge. This combination of effects suggests that inhaled misoprostol may be effective in the treatment of the acute and chronic symptoms of asthma.