RESUMEN

Angiopoietin-like protein (ANGPTL)4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia. However, ANGPTL4 inactivation in mice fed a high fat diet causes chylous ascites, an acute-phase response, and mesenteric lymphadenopathy. Here, we studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4-/- mice. Angptl4 expression in peritoneal and bone marrow-derived macrophages was highly induced by lipids. Recombinant ANGPTL4 decreased lipid uptake in macrophages, whereas deficiency of ANGPTL4 increased lipid uptake, upregulated lipid-induced genes, and increased respiration. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. Angptl4-hypomorphic mice with partial expression of a truncated N-terminal ANGPTL4 exhibited reduced fasting plasma triglyceride, cholesterol, and NEFAs, strongly resembling Angptl4-/- mice. However, during high fat feeding, Angptl4-hypomorphic mice showed markedly delayed and attenuated elevation in plasma serum amyloid A and much milder chylous ascites than Angptl4-/- mice, despite similar abundance of lipid-laden giant cells in mesenteric lymph nodes. In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acute-phase response in mice.

Asunto(s)

Adipocitos/metabolismo , Proteína 4 Similar a la Angiopoyetina/deficiencia , Proteína 4 Similar a la Angiopoyetina/genética , Técnicas de Inactivación de Genes , Macrófagos/metabolismo , Animales , Respiración de la Célula , Ascitis Quilosa/genética , Ascitis Quilosa/patología , Exones/genética , Regulación de la Expresión Génica , Lipoproteína Lipasa/metabolismo , Linfadenopatía/genética , Linfadenopatía/patología , Ratones , Ratones Endogámicos C57BL , Triglicéridos/sangre

Asunto(s)

Neuropatías Amiloides Familiares/diagnóstico por imagen , Ascitis Quilosa/diagnóstico por imagen , Insuficiencia Cardíaca/diagnóstico por imagen , Multimorbilidad , Anciano , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/terapia , Ascitis Quilosa/genética , Ascitis Quilosa/terapia , Terapia Combinada , Ecocardiografía/métodos , Enfermedades Endémicas , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Tomografía de Emisión de Positrones/métodos , Pronóstico , Enfermedades Raras , Medición de Riesgo , España , Tomografía Computarizada por Rayos X/métodos

RESUMEN

BACKGROUND: Thanatophoric dysplasia (TD) results from sporadic de novo mutations in the FGFR3 gene. Upon confirming intrauterine diagnosis of this perinatal disease, pregnancy termination is recommended. There is limited information on the natural history of longer-term survivors with type 1 TD. CASE REPORT: A full-term neonate was confirmed via postnatal genetic testing to have type 1 TD. At 28 days, chylous ascites developed. Medium-chain triglyceride use improved the ascites. Cerebral ventriculomegaly worsened throughout life. Death due to respiratory failure occurred at age 5 months. CONCLUSION: The chylous ascites in this child with type 1 TD and survival past the neonatal stage suggests that type 1 TD may be accompanied by abnormalities of the lymphatic channels. Moreover, ventriculomegaly can be progressive.

Asunto(s)

Ascitis Quilosa/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/deficiencia , Displasia Tanatofórica/complicaciones , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Displasia Tanatofórica/genética

Asunto(s)

Adenocarcinoma del Pulmón/complicaciones , Adenocarcinoma del Pulmón/genética , Ascitis Quilosa/etiología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/enzimología , Adenocarcinoma del Pulmón/patología , Anciano , Ascitis Quilosa/enzimología , Ascitis Quilosa/genética , Ascitis Quilosa/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , Mutación

RESUMEN

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte content. Despite these defects, animals lacking endothelial Map4k4 were protected from skeletal muscle microvascular rarefaction in obesity, and primary ECs lacking Map4k4 displayed reduced senescence and increased metabolic capacity. Thus endothelial Map4k4 has complex and opposing functions in the blood and lymphatic endothelium postdevelopment. Whereas blood endothelial Map4k4 promotes vascular dysfunction and impairs glucose homeostasis in adult animals, lymphatic endothelial Map4k4 is required to maintain lymphatic vascular integrity and regulate immune cell trafficking in obesity.

Asunto(s)

Aterosclerosis/genética , Ascitis Quilosa/genética , Células Endoteliales/metabolismo , Metabolismo Energético/genética , Resistencia a la Insulina/genética , Linfangiogénesis/genética , Obesidad/genética , Proteínas Serina-Treonina Quinasas/genética , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Animales , Aterosclerosis/metabolismo , Glucemia/metabolismo , Senescencia Celular/genética , Citometría de Flujo , Prueba de Tolerancia a la Glucosa , Linfocitos , Ratones , Ratones Noqueados , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica/genética , Obesidad/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Quinasa de Factor Nuclear kappa B

RESUMEN

Congenital plaque-type glomuvenous malformation (GVM) is caused by loss of function mutations in glomulin gene. We report a newborn with this rare vascular disorder associated with chylous ascites. The common mesenchymal origin of GVM and lymphatic vessels as well as the glomulin expression in vascular smooth muscle cells in utero could help explain this unusual prenatal complication of glomuvenous malformations.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética , Ascitis Quilosa/complicaciones , Ascitis Quilosa/genética , Ascitis Quilosa/congénito , Femenino , Tumor Glómico/complicaciones , Tumor Glómico/congénito , Tumor Glómico/genética , Humanos , Recién Nacido , Vasos Linfáticos/patología , Vasos Linfáticos/fisiología , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiología , Paraganglioma Extraadrenal/complicaciones , Paraganglioma Extraadrenal/congénito , Paraganglioma Extraadrenal/genética

RESUMEN

VEGF and Angiopoietin-1 requisitely collaborate during blood vessel development. While Angiopoietin-1 obligately activates its Tie2 receptor, Angiopoietin-2 can activate Tie2 on some cells, while it blocks Tie2 activation on others. Our analysis of mice lacking Angiopoietin-2 reveals that Angiopoietin-2 is dispensable for embryonic vascular development but is requisite for subsequent angiogenic remodeling. Unexpectedly, mice lacking Angiopoietin-2 also exhibit major lymphatic vessel defects. Genetic rescue with Angiopoietin-1 corrects the lymphatic, but not the angiogenesis, defects, suggesting that Angiopoietin-2 acts as a Tie2 agonist in the former setting, but as an antagonist in the latter setting. Our studies define a vascular growth factor whose primary role is in postnatal angiogenic remodeling and also demonstrate that members of the VEGF and Angiopoietin families collaborate during development of the lymphatic vasculature.

Asunto(s)

Inductores de la Angiogénesis/fisiología , Tipificación del Cuerpo , Sistema Linfático/crecimiento & desarrollo , Glicoproteínas de Membrana/fisiología , Neovascularización Fisiológica/fisiología , Angiopoyetina 1 , Angiopoyetina 2 , Animales , Ascitis Quilosa/genética , Ascitis Quilosa/patología , ADN Complementario/genética , Edema/genética , Edema/patología , Ojo/irrigación sanguínea , Regulación del Desarrollo de la Expresión Génica , Marcación de Gen , Homocigoto , Sistema Linfático/patología , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas , Vasos Retinianos/patología

RESUMEN

Fetal abnormalities including chylous ascites, polyhydramnios, claw hands, and hammer toes were identified in an infant who had a missense mutation R106P and a 52bp deletion in the gene for a peroxisomal beta-oxidation enzyme, D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase, D-bifunctional protein. The patient had psychomotor retardation and craniofacial dysmorphism and died at 7 months of age. The patient had atypical fetal manifestations of this enzyme deficiency.

Asunto(s)

17-Hidroxiesteroide Deshidrogenasas , 3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , Ascitis Quilosa/congénito , Ascitis Quilosa/complicaciones , Contractura/congénito , Contractura/complicaciones , Enoil-CoA Hidratasa , Deformidades Congénitas del Pie/complicaciones , Deformidades Congénitas de la Mano/complicaciones , Hidroliasas/deficiencia , Complejos Multienzimáticos/deficiencia , Polihidramnios/complicaciones , 3-Hidroxiacil-CoA Deshidrogenasas/genética , Ascitis Quilosa/genética , Contractura/genética , Resultado Fatal , Femenino , Deformidades Congénitas del Pie/genética , Eliminación de Gen , Deformidades Congénitas de la Mano/genética , Humanos , Hidroliasas/genética , Lactante , Recién Nacido , Masculino , Complejos Multienzimáticos/genética , Mutación Missense/genética , Proteína-2 Multifuncional Peroxisomal , Embarazo

RESUMEN

Phosphoinositide 3-kinases produce 3'-phosphorylated phosphoinositides that act as second messengers to recruit other signalling proteins to the membrane. Pi3ks are activated by many extracellular stimuli and have been implicated in a variety of cellular responses. The Pi3k gene family is complex and the physiological roles of different classes and isoforms are not clear. The gene Pik3r1 encodes three proteins (p85 alpha, p55 alpha and p50 alpha) that serve as regulatory subunits of class IA Pi3ks (ref. 2). Mice lacking only the p85 alpha isoform are viable but display hypoglycaemia and increased insulin sensitivity correlating with upregulation of the p55 alpha and p50 alpha variants. Here we report that loss of all protein products of Pik3r1 results in perinatal lethality. We observed, among other abnormalities, extensive hepatocyte necrosis and chylous ascites. We also noted enlarged skeletal muscle fibres, brown fat necrosis and calcification of cardiac tissue. In liver and muscle, loss of the major regulatory isoform caused a great decrease in expression and activity of class IA Pi3k catalytic subunits; nevertheless, homozygous mice still displayed hypoglycaemia, lower insulin levels and increased glucose tolerance. Our findings reveal that p55 alpha and/or p50 alpha are required for survival, but not for development of hypoglycaemia, in mice lacking p85 alpha.

Asunto(s)

Anomalías Múltiples/genética , Ascitis Quilosa/genética , Genes Letales , Hipoglucemia/genética , Hígado/patología , Fosfatidilinositol 3-Quinasas/deficiencia , Isoformas de Proteínas/deficiencia , Tejido Adiposo Pardo/patología , Animales , Animales no Consanguíneos , Calcinosis/genética , Cardiomiopatías/genética , Catálisis , Cruzamientos Genéticos , Dimerización , Inducción Enzimática , Femenino , Genes , Genotipo , Vida Libre de Gérmenes , Glucosa/metabolismo , Glucosa/farmacología , Hipertrofia , Insulina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Fibras Musculares Esqueléticas/patología , Necrosis , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/fisiología , Fosforilación , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Procesamiento Proteico-Postraduccional/genética , Subunidades de Proteína , Sistemas de Mensajero Secundario/genética

RESUMEN

A male infant, whose parents were first cousins, was born with tense chylous ascites, mild generalized oedema and facial dysmorphism. The baby initially seemed well but subsequently probably aspirated, developed septicaemia and finally died at 26 days from a bleeding diathesis, possibly secondary to liver dysfunction. No cause for the chylous ascites was found at post mortem. This case is presumed to represent an example of recessively determined chylous ascites. The mouse mutant Chy may be an homologous condition.

Asunto(s)

Ascitis Quilosa/genética , Genes Recesivos , Animales , Modelos Animales de Enfermedad , Humanos , Recién Nacido , Masculino , Ratones

RESUMEN

Chylous ascites is a disorder visible as a white fluid in the peritoneal cavity of suckling mice. It is due to inadequate lymphatic drainage from the small intestine. An initial genetic study showed it to be a pleiotropic effect of ragged, Ra. There were four main studies. These involved seven major mutants segregating with ragged. Four of the mutants had no effect on chylous ascites, but two mutants linked with ragged, and one unlinked, showed a complex situation involving enhancement, inhibition, epistacy and other interactions. The overall phenotypic effects which these mutants are known to have do not explain how they produce their interaction with ragged in terms of chylous ascites. The studies also indicate the existence of a single major modifier controlling penetrance and expression, and there is evidence for cumulatively acting minor modifiers. In neonates the male sex is more liable to chylous ascites, and in adults this condition affects fertility and fecundity.

Asunto(s)

Ascitis Quilosa/genética , Ratones Mutantes/genética , Animales , Femenino , Ligamiento Genético , Marcadores Genéticos , Masculino , Ratones , Mutación , Fenotipo

RESUMEN

We report a brother and sister with congenital chylous ascites. Parents were first cousins, and autosomal recessive inheritance may be the cause of the condition in these sibs.

Asunto(s)

Ascitis Quilosa/genética , Consanguinidad , Ascitis Quilosa/congénito , Femenino , Genes Recesivos , Humanos , Lactante , Masculino , Linaje