Lipid phosphate phosphatase 3 enables efficient thymic egress

Lipid phosphate phosphatase 3 in endothelial and epithelial cells promotes efficient T cell emigration from the thymus to the periphery

Liver-specific deletion of the Plpp3 gene alters plasma lipid composition and worsens atherosclerosis in apoE(-/-) mice

The PLPP3 gene encodes for a ubiquitous enzyme that dephosphorylates several lipid substrates. Genome-wide association studies identified PLPP3 as a gene that plays a role in coronary artery disease susceptibility. The aim of the study was to investigate the effect of Plpp3 deletion on atherosclerosis development in mice. Because the constitutive deletion of Plpp3 in mice is lethal, conditional Plpp3 hepatocyte-specific null mice were generated by crossing floxed Plpp3 mice with animals expressing Cre recombinase under control of the albumin promoter. The mice were crossed onto the athero-prone apoE(-/-) background to obtain Plpp3(f/f)apoE(-/-) Alb-Cre(+) and Plpp3(f/f)apoE(-/-) Alb-Cre(-) offspring, the latter of which were used as controls. The mice were fed chow or a Western diet for 32 or 12 weeks, respectively. On the Western diet, Alb-Cre+ mice developed more atherosclerosis than Alb-Cre- mice, both at the aortic sinus and aorta. Lipidomic analysis showed that hepatic Plpp3 deletion significantly modified the levels of several plasma lipids involved in atherosclerosis, including lactosylceramides, lysophosphatidic acids, and lysophosphatidylinositols. In conclusion, Plpp3 ablation in mice worsened atherosclerosis development. Lipidomic analysis suggested that the hepatic Plpp3 deletion may promote atherosclerosis by increasing plasma levels of several low-abundant pro-atherogenic lipids, thus providing a molecular basis for the observed results

Liver-specific deletion of the Plpp3 gene alters plasma lipid composition and worsens atherosclerosis in apoE -/- mice

The PLPP3 gene encodes for a ubiquitous enzyme that dephosphorylates several lipid substrates. Genome-wide association studies identified PLPP3 as a gene that plays a role in coronary artery disease susceptibility. The aim of the study was to investigate the effect of Plpp3 deletion on atherosclerosis development in mice. Because the constitutive deletion of Plpp3 in mice is lethal, conditional Plpp3 hepatocyte-specific null mice were generated by crossing floxed Plpp3 mice with animals expressing Cre recombinase under control of the albumin promoter. The mice were crossed onto the athero-prone apoE -/- background to obtain Plpp3 f/f apoE -/- Alb-Cre + and Plpp3 f/f apoE -/- Alb-Cre - offspring, the latter of which were used as controls. The mice were fed chow or a Western diet for 32 or 12 weeks, respectively. On the Western diet, Alb-Cre + mice developed more atherosclerosis than Alb-Cre - mice, both at the aortic sinus and aorta. Lipidomic analysis showed that hepatic Plpp3 deletion significantly modified the levels of several plasma lipids involved in atherosclerosis, including lactosylceramides, lysophosphatidic acids, and lysophosphatidylinositols. In conclusion, Plpp3 ablation in mice worsened atherosclerosis development. Lipidomic analysis suggested that the hepatic Plpp3 deletion may promote atherosclerosis by increasing plasma levels of several low-abundant pro-atherogenic lipids, thus providing a molecular basis for the observed results

Lipid phosphate phosphatase 3 in vascular pathophysiology

LPP3 is an integral membrane protein belonging to a family of enzymes (LPPs) that display broad substrate specificity and catalyse dephosphorylation of several lipid substrates, including lysophosphatidic acid and sphingosine-1-phosphate. In mammals, the LPP family consists of three enzymes named LPP1, LPP2 and LPP3, which are encoded by three independent genes, PLPP1, PLPP2 and PLPP3, respectively (formerly known as PPAP2A, PPAP2C, PPAP2B). These three enzymes, in vitro, do not seem to differ for catalytic activities and substrate preferences. However, in vivo targeted inactivation of the individual genes has indicated that the enzymes do not have overlapping functions and that LPP3, specifically, plays a crucial role in vascular development. In 2011, two genome-wide association studies have identified PLPP3 as a novel locus associated with coronary artery disease susceptibility. Shortly after these reports, tissue specific inactivation of PLPP3 in mice highlighted a specific role for LPP3 in vascular pathophysiology and, more recently, in atherosclerosis development. This review is aimed at providing an updated overview on the function of LPP3 in embryonic cardiovascular development and on the experimental and clinical evidences relating this enzyme to vascular cell functions and cardiovascular disease

Mir-290–295 deficiency in mice results in partially penetrant embryonic lethality and germ cell defects

Mir-290 through mir-295 (mir-290–295) is a mammalian-specific microRNA (miRNA) cluster that, in mice, is expressed specifically in early embryos and embryonic germ cells. Here, we show that mir-290–295 plays important roles in embryonic development as indicated by the partially penetrant lethality of mutant embryos. In addition, we show that in surviving mir-290–295-deficient embryos, female but not male fertility is compromised. This impairment in fertility arises from a defect in migrating primordial germ cells and occurs equally in male and female mutant animals. Male mir-290–295−/− mice, due to the extended proliferative lifespan of their germ cells, are able to recover from this initial germ cell loss and are fertile. Female mir-290–295−/− mice are unable to recover and are sterile, due to premature ovarian failure.National Institutes of Health (U.S.) (Grant 5-F32-HD051190)National Institutes of Health (U.S.) (Grant RO1-GM34277)National Institutes of Health (U.S.) (Grant 5R37CA084198)National Institutes of Health (U.S.) (Grant 5R01-HD045022)National Cancer Institute (U.S.) (Grant PO1-CA42063)National Cancer Institute (U.S.) (Core Grant P30-CA14051)Howard Hughes Medical Institut