Evidence for fatty acid oxidation in human placenta, and the relationship of fatty acid oxidation enzyme activities with gestational age.
ABSTRACT Fetal disorders of mitochondrial fatty acid oxidation have recently been associated with obstetric complications including pre-eclampsia, Hemolysis, Elevated Liver enzymes, Low Platelets (HELLP) syndrome, placental floor infarct, and Acute Fatty Liver of Pregnancy (AFLP). These diseases occur in about a third of the mothers who are heterozygous for a defect in long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) enzyme and who bear a fetus homozygous for the defect. The mechanism of this association is not clearly understood. In this study, we provide evidence that the placenta may be the site of production of toxic intermediates of fatty acid metabolism, which accumulate to cause liver damage in the mother. We show that two critical enzymes of long chain fatty acid metabolism, long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), are active in the normal human placenta. There is an inverse correlation between the enzyme activity of both the enzymes and maternal gestational age during the second and third trimesters. We believe that the demonstration of fatty acid oxidation enzyme activity by the placenta is the first step towards assessing a possible role for fetal/placental fatty acid oxidation defects in the pathogenesis of a subset of pregnancy complications.
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ABSTRACT: Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome are serious maternal illnesses occurring in the third trimester of pregnancy with significant perinatal and maternal mortality. AFLP may result from mitochondrial defects in the beta-oxidation of fatty acids, in particular a deficiency of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) in the fetus. Clinical findings in AFLP vary and its diagnosis is complicated by a significant overlap in clinical and biochemical features with HELLP syndrome. We report the case of 2 siblings who died, the first one in the neonatal period of asphyxia with multivisceral presentation and the second one from sudden death at 7 months. Autopsy of the latter infant revealed hepatic steatosis associated with cardiomyopathy, which led to suspicion of a fatty acid oxidation deficiency. Mutation analysis demonstrated that both children were homozygous for the common mutation c.1528G>C and the parents were heterozygous for this same mutation. This case demonstrates the importance of screening mothers with acute fatty liver disease of pregnancy and their children at birth for a metabolic disease. This article proposes several metabolic tests for mother and child suspected of having beta-oxidation of a fatty acid disorder.Archives de Pédiatrie 03/2012; 19(3):277-81. · 0.41 Impact Factor
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ABSTRACT: Preeclampsia is one of the most important and complexed disorders for women's health. Searching for novel proteins as biomarkers to reveal pathogenesis, proteomic approaches using 2DE has become a valuable tool to understanding of preeclampsia. To analyze the proteomic profiling of preclamptic placenta compared to that of normal pregnancy for better understanding of pathogenesis in preeclampsia, placentas from each group were handled by use of proteomics approach using 2DE combined with MALDI-TOF-MS. The 20 spots of showing differences were analysed and identified. Among differentially expressed protein spots Hsp 27 and Hsp 70 were selected for validation using Western blot analysis. In preeclamptic placenta 9 differentially expressed proteins were down-regulated with Hsp 70, serum albumin crystal structure chain A, lamin B2, cytokeratin 18, actin cytoplasmic, alpha fibrinogen precursor, septin 2, dihydrolipoamide branched chain transacylase E2 and firbrinogen beta chain. The 11 up-regulated proteins were fibrinogen gamma, cardiac muscle alpha actin proprotein, cytokeratin 8, calumenin, fibrinogen fragment D, F-actin capping protein alpha-1 subunit, Hsp 27, Hsp 40, annexin A4, enoyl-CoA delta isomerase and programmed cell death protein 6. The western blot analysis for validation also showed significant up-regulation of Hsp 27 and down-regulation of Hsp 70 in the placental tissues with preeclmaptic pregnancies. This proteomic profiling of placenta using 2DE in preeclampsia successfully identifies various proteins involved in apoptosis, mitochondrial dysfunction, as well as three Hsps with altered expression, which might play a important role for the understanding of pathogenesis in preeclampsia. Graphical AbstractJournal of Korean Medical Science 05/2015; 30(6):770-778. DOI:10.3346/jkms.2015.30.6.770 · 1.25 Impact Factor
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ABSTRACT: Abstract Peroxisome proliferator-activated receptor-gamma (PPAR-γ) belongs to the nuclear hormone receptor superfamily. Apart from being involved in lipid metabolism, like its other subtypes PPAR α and β, it is implicated to be crucial for successful placentation. While its role in extravillous trophoblast (EVT) differentiation has been studied, the involvement in villous trophoblast (VT) differentiation, fatty-acid metabolism, inflammatory responses, and oxidative pathways during pregnancy deserves more attention. PPAR-γ's potential role in balancing structural development and functional responsibilities at the maternal-fetal interface suggest a more central role for the receptor. The central role of PPAR-γ in pathways related to placental pathologies suggests a potential role of PPAR-γ in placental function. The molecular regulation of PPAR-γ in this context has been widely disregarded. In this review, we discuss the less explored functions of PPAR-γ in the areas of immunological responses and management of oxidative stress in the placenta. We also shed light on the involvement of PPAR-γ in pathologic pregnancies and briefly discuss the current models in the field. The ability to modulate PPAR-γ's activity using already available drugs makes it a tempting therapeutic target. Elucidation of the molecular pathways and specific targets regulated by PPAR-γ will provide more information on the role of PPAR-γ in placentation and related disorders in pregnancy. Furthermore it will close the critical gap in our knowledge about the differential regulation of PPAR-γ in the two trophoblast lineages. This will help to evaluate the usefulness and timing of PPAR-γ modulation in at risk pregnancies to improve placental and endothelial function.Systems Biology in Reproductive Medicine 12/2014; 61(2):1-7. DOI:10.3109/19396368.2014.991881 · 1.70 Impact Factor