Cardiac phenotype in adolescents and young adults with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.

PURPOSE: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) is a rare fatty acid oxidation disorder characterized by recurrent episodes of metabolic decompensation and rhabdomyolysis, as well as retinopathy, peripheral neuropathy, and cardiac involvement, such as infantile dilated cardiomyopathy. Because LCHADD patients are surviving longer, we sought to characterize LCHADD-associated major cardiac involvement in adolescence and young adulthood. METHODS: A retrospective cohort of 16 adolescent and young adult participants with LCHADD was reviewed for cardiac phenotype. RESULTS: Major cardiac involvement occurred in 9 of 16 participants, including sudden death, out-of-hospital cardiac arrest, acute cardiac decompensations with heart failure and/or in-hospital cardiac arrest, end-stage dilated cardiomyopathy, and moderate restrictive cardiomyopathy. Sudden cardiac arrest was more common in males and those with a history of infant cardiomyopathy. CONCLUSION: The cardiac manifestations of LCHADD in adolescence and early adulthood are complex and distinct from the phenotype seen in infancy. Life-threatening arrhythmia occurs at substantial rates in LCHADD, often in the absence of metabolic decompensation or rhabdomyolysis. The potential risk factors identified here-male sex and history of infant cardiomyopathy-may hint at strategies for risk stratification and possibly the prevention of these events.

Different Lipid Signature in Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders.

Long-chain fatty acid oxidation disorders (lc-FAOD) are a group of diseases affecting the degradation of long-chain fatty acids. In order to investigate the disease specific alterations of the cellular lipidome, we performed undirected lipidomics in fibroblasts from patients with carnitine palmitoyltransferase II, very long-chain acyl-CoA dehydrogenase, and long-chain 3-hydroxyacyl-CoA dehydrogenase. We demonstrate a deep remodeling of mitochondrial cardiolipins. The aberrant phosphatidylcholine/phosphatidylethanolamine ratio and the increased content of plasmalogens and of lysophospholipids support the theory of an inflammatory phenotype in lc-FAOD. Moreover, we describe increased ratios of sphingomyelin/ceramide and sphingomyelin/hexosylceramide in LCHAD deficiency which may contribute to the neuropathic phenotype of LCHADD/mitochondrial trifunctional protein deficiency.

Blood cytokine patterns suggest a modest inflammation phenotype in subjects with long-chain fatty acid oxidation disorders.

Excessive cellular accumulation or exposure to lipids such as long-chain acylcarnitines (LCACs), ceramides, and others is implicated in cell stress and inflammation. Such a situation might manifest when there is a significant mismatch between long-chain fatty acid (LCFA) availability versus storage and oxidative utilization; for example, in cardiac ischemia, increased LCACs may contribute to tissue cell stress and infarct damage. Perturbed LCFAß-oxidation is also seen in fatty acid oxidation disorders (FAODs). FAODs typically manifest with fasting- or stress-induced symptoms, and patients can manage many symptoms through control of diet and physical activity. However, episodic clinical events involving cardiac and skeletal muscle myopathies are common and can present without an obvious molecular trigger. We have speculated that systemic or tissue-specific lipotoxicity and activation of inflammation pathways contribute to long-chain FAOD pathophysiology. With this in mind, we characterized inflammatory phenotype (14 blood plasma cytokines) in resting, overnight-fasted (~10 h), or exercise-challenged subjects with clinically well-controlled long-chain FAODs (n = 12; 10 long-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD]; 2 carnitine palmitoyltransferase 2 [CPT2]) compared to healthy controls (n = 12). Across experimental conditions, concentrations of three cytokines were modestly but significantly increased in FAOD (IFNγ, IL-8, and MDC), and plasma levels of IL-10 (considered an inflammation-dampening cytokine) were significantly decreased. These novel results indicate that while asymptomatic FAOD patients do not display gross body-wide inflammation even after moderate exercise, ß-oxidation deficiencies might be associated with chronic and subtle activation of "sterile inflammation." Further studies are warranted to determine if inflammation is more apparent in poorly controlled long-chain FAOD or when long-chain FAOD-associated symptoms are present.

Two Fungicides Alter Reproduction of the Small Brown Planthopper Laodelphax striatellus by Influencing Gene and Protein Expression.

Aside from their intended actions, fungicides can drive pest insect outbreaks due to virtually continuous use and pest evolution. Small brown planthopper (SBPH), Laodelphax striatellus, outbreaks occurred recently in many provinces in China, with devastating rice losses. Because exposure to the fungicide jinggangmycin (JGM) increased reproduction of the brown plant hopper, Nilaparvata lugens, via its influence on fatty acid synthase, we posed the hypothesis that JGM and carbendazim (CBM) influence SBPH reproduction via their influence on enzymes involved in other aspects of lipid metabolism. Exposure to the fungicide CBM stimulated SBPH reproduction (egg-laying up by 78%) and to another fungicide, JGM, led to decreased egg-laying (down by 47.3%). These inverse effects are mediated by down-regulated expression of l-3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) in JGM-treated females and up-regulated expression of hydroxysteroid dehydrogenase-like protein 2-like (HSD) in CBM-treated females. RNAi knockdown of, separately, LCHAD and HSD led to reduced egg-laying (down by 52% for dsLCHAD and by 73% for dsHSD). dsLCHAD, dsHSD, and JGM treatments also led to severely reduced ovarian development in experimental SBPH, with shorted and thinned valvula and lack of egg cells in ovaries. Valvula of CBM-treated females enlarged, with banana-shaped eggs in ovaries. These data strongly support our hypothesis.

Oligo(cis-1,4-isoprene) aldehyde-oxidizing dehydrogenases of the rubber-degrading bacterium Gordonia polyisoprenivorans VH2.

The actinomycete Gordonia polyisoprenivorans strain VH2 is well-known for its ability to efficiently degrade and catabolize natural rubber [poly(cis-1,4-isoprene)]. Recently, a pathway for the catabolism of rubber by strain VH2 was postulated based on genomic data and the analysis of mutants (Hiessl et al. in Appl Environ Microbiol 78:2874-2887, 2012). To further elucidate the degradation pathway of poly(cis-1,4-isoprene), 2-dimensional-polyacrylamide gel electrophoresis was performed. The analysis of the identified protein spots by matrix-assisted laser desorption/ionization-time of flight tandem mass spectrometry confirmed the postulated intracellular pathway suggesting a degradation of rubber via ß-oxidation. In addition, other valuable information on rubber catabolism of G. polyisoprenivorans strain VH2 (e.g. oxidative stress response) was provided. Identified proteins, which were more abundant in cells grown with rubber than in cells grown with propionate, implied a putative long-chain acyl-CoA-dehydrogenase, a 3-ketoacyl-CoA-thiolase, and an aldehyde dehydrogenase. The amino acid sequence of the latter showed a high similarity towards geranial dehydrogenases. The expression of the corresponding gene was upregulated > 10-fold under poly(cis-1,4-isoprene)-degrading conditions. The putative geranial dehydrogenase and a homolog were purified and used for enzyme assays. Deletion mutants for five aldehyde dehydrogenases were generated, and growth with poly(cis-1,4-isoprene) was investigated. While none of the mutants had an altered phenotype regarding growth with poly(cis-1,4-isoprene) as sole carbon and energy source, purified aldehyde dehydrogenases were able to catalyze the oxidation of oligoisoprene aldehydes indicating an involvement in rubber degradation.

Caring for the woman with acute fatty liver of pregnancy.

Acute fatty liver of pregnancy, although rare, is usually a third trimester of pregnancy occurrence that may be life threatening for both the pregnant woman and the fetus. Often, the onset resembles gastroenteritis or cholecystitis and correct diagnosis is delayed. Because it can also present with preeclampsia and eclampsia, it may be mistakenly diagnosed as hemolysis, elevated liver enzymes, low platelet syndrome. This article presents diagnostic differences between liver conditions that can complicate pregnancy and management strategies for treating and maintaining the well-being of pregnant women, fetuses, and infants who are affected by acute fatty liver of pregnancy. Early recognition and rapid intervention from antepartum diagnosis through delivery and the postpartum period are required by the nursing team and medical providers to reduce maternal and neonatal morbidity and mortality.

Long-chain fatty acid oxidation changes in a ß2 glycoprotein I-induced preeclampsia-like mouse model.

INTRODUCTION: Abnormal fatty acid oxidation (FAO) and lipid metabolism have been found related to preeclampsia (PE). Antiphospholipid syndrome (APS) as a clinical risk factor for PE has also been reported with abnormal lipid metabolism. However, the role of FAO in PE accompanied with APS is unknown. We aimed to investigate long-chain FAO changes in a PE-like rodent model induced by beta 2-glycoprotein I (ß2GPI). METHODS: The PE-like model was established by injection of ß2GPI (ß2GPI group) or normal saline (control group) into C57BL/6J mice which were sacrificed on day 14 or 18 of gestation. Serum levels of anti-cardiolipin antibodies (aCL), anti-ß2GPI antibodies (aß2GPI) and serum lipids were assayed. Lipid deposition in the placenta and maternal liver was detected by lipid staining. Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) mRNA and protein expression in the placenta and maternal liver was analyzed. RESULTS: The ß2GPI group showed PE-like symptoms including hypertension, proteinuria and adverse pregnancy outcomes. Serum aCL, aß2GPI, free fatty acid (FFA) and triglyceride (TG) levels in the ß2GPI group were significantly elevated compared with the corresponding control group (P < 0.05), while cholesterol showed no significant changes. Placenta and maternal liver fatty infiltration was found in the ß2GPI group. LCHAD mRNA and protein expression in the placenta and maternal liver in the ß2GPI group were significantly elevated compared with the corresponding control group (P < 0.05). CONCLUSION: ß2GPI can induce PE-like symptoms, elevated serum FFA and TG, and abnormal LCHAD expression in pregnant mice. Changes in long-chain FAO could be a factor linking PE and APS.

[Interaction mechanism and influence between fatty acid oxidation in trophoblast cells and p38MAPK signal transduction pathway of severe preeclampsia].

OBJECTIVE: To investigate the effects of expression of mitochondria long-chain fatty acid oxidative enzyme (long-chain 3 hyroxyacyl CoA dehydrogenase, LCHAD) and p38 mitogen activated protein kinase (p38MAPK) signal transduction pathway in severe preeclampsia. METHODS: Serum-free trophoblast cells cultured in vitro were stimulated by early onset severe preeclampsia serum (E-PE group), late onset severe preeclampsia serum (L-PE group), HELLP syndrome serum (HELLP group), and normal pregnancy serum (NP group) respectively; each group was added DMEM/F12 medium, reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (NADPH-I) and p38MAPK inhibitor (p38-I) to stimulate cells. Expression of mRNA and protein of LCHAD in trophoblast cells were detected by real-time PCR and western blot. RESULTS: (1)The expression of mRNA of LCHAD: the level of mRNA of LCHAD in NP+DMEM, E-PE+DMEM, E-PE+NADPH-I, E-PE+p38-I, L-PE+DMEM, L-PE+NADPH-I, L-PE+p38-I and HELLP+DMEM, HELLP+NADPH-I, HELLP+p38-I groups were 1.00 ± 0.03, 0.14 ± 0.08, 0.95 ± 0.20, 1.43 ± 1.02, 0.37 ± 0.18, 1.51 ± 0.36, 1.60 ± 0.31, 0.10 ± 0.04, 0.49 ± 0.10, 0.44 ± 0.21, respectively. The relative expressions of mRNA of LCHAD were significantly reduced in E-PE+DMEM, L-PE+DMEM and HELLP+DMEM groups compared with the NP+DMEM group (P < 0.05). Compared with the NP groups, the relative expressions of mRNA of LCHAD were significantly increased in L-PE+NADPH-I and L-PE+p38-I group (P < 0.05), while reduced in HELLP groups(P < 0.05). (2) The expression of protein of LCHAD: the relative expressions of protein of LCHAD in NP+DMEM, E-PE+DMEM, E-PE+NADPH-I, E-PE+p38-I, L-PE+DMEM, L-PE+NADPH-I, L-PE+p38-I and HELLP+ DMEM, HELLP+NADPH-I, HELLP+p38-I groups were 19.4 ± 2.2, 10.7 ± 1.1, 17.9 ± 3.3, 19.1 ± 2.9, 16.4 ± 2.3, 20.3 ± 2.3, 20.9 ± 4.3, 12.4 ± 2.3, 17.6 ± 2.6, 17.7 ± 2.0 respectively. Compared with the NP groups, the protein expressions of LCHAD were significantly remarkably reduced in E-PE+DMEM, L-PE+DMEM and HELLP groups (P < 0.05). Compared with the DMEM groups, the protein expressions of LCHAD were significantly increased in NADPH-I and p38-I groups of E-PE, L-PE and HELLP groups (P < 0.05). CONCLUSIONS: These studies demonstrate that long chain fatty acid oxidation was involved in the pathogenesis and development of preeclampsia. The expressions of gene and protein of LCHAD were remarkably affected by early onset severe preeclampsia and HELLP syndrome. NADPH-I and p38-I may allay the disorder of fatty acid oxidation. p38MAPK signal transduction pathway may contributed in this process.