Inhibition of the NFAT kinases, GSK3beta and Dyrk1a, increases human beta cell proliferation and islet mass

Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets most likely as a result of combined inhibition of Dyrk1a and GSK3b. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore β-cell mass, and highlights a tractable pathway for future drug discovery efforts

The Phospholipid Transfer Protein Gene Is a Liver X Receptor Target Expressed by Macrophages in Atherosclerotic Lesions

The liver X receptors (LXRs) are members of the nuclear receptor superfamily that are activated by oxysterols. In response to ligand binding, LXRs regulate a variety of genes involved in the catabolism, transport, and uptake of cholesterol and its metabolites. Here we demonstrate that LXRs also regulate plasma lipoprotein metabolism through control of the phospholipid transfer protein (PLTP) gene. LXR ligands induce the expression of PLTP in cultured HepG2 cells and mouse liver in vivo in a coordinate manner with known LXR target genes. Moreover, plasma phospholipid transfer activity is increased in mice treated with the synthetic LXR ligand GW3965. Unexpectedly, PLTP expression was also highly inducible by LXR in macrophages, a cell type not previously recognized to express this enzyme. The ability of synthetic and oxysterol ligands to regulate PLTP mRNA in macrophages and liver is lost in animals lacking both LXRα and LXRβ, confirming the critical role of these receptors. We further demonstrate that the PLTP promoter contains a high-affinity LXR response element that is bound by LXR/RXR heterodimers in vitro and is activated by LXR/RXR in transient-transfection studies. Finally, immunohistochemistry studies reveal that PLTP is highly expressed by macrophages within human atherosclerotic lesions, suggesting a potential role for this enzyme in lipid-loaded macrophages. These studies outline a novel pathway whereby LXR and its ligands may modulate lipoprotein metabolism

Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth

Cancer cells have the ability to use aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. PHGDH is amplified or overexpressed in a subset of breast cancer and melanoma, and critical for the viability of those cells. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines and PHGDH knockdown in these cells leads to a decrease in the levels of serine production and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established xenograft tumor mouse models, suggesting that PHGDH-dependent cell growth is only observed in the in vitro context. Our finding indicates that PHGDH is dispensable for tumor maintenance and growth in vivo, which suggests that other mechanisms or pathways may bypass the function of PHGDH in human breast cancer cells