Inhibition of brain and liver 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase in experimental hyperphenylalaninemia

Castillo, M.; Zafra, M. F.; Garcia-Peregrin, E.

doi:10.1007/bf00973296

Cited by 44 publications

(28 citation statements)

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“…These findings are in contrast to previous studies revealing lower serum cholesterol concentrations in patients with PKU [16], [17], [27], especially while under good metabolic control [18], and also compared to patients with a protein-restricted diet due to other inborn errors of amino acid metabolism [27]. Other studies showed a possible inhibition of cholesterol synthesis in vitro [31] and in animal models of PKU [32]. Colomé et al [27] detected an inverse correlation of phenylalanine and cholesterol concentrations in serum and hypothesized high plasma phenylalanine concentrations to inhibit cholesterol synthesis.…”

Section: Discussioncontrasting

confidence: 99%

Metabolomics of Dietary Fatty Acid Restriction in Patients with Phenylketonuria

Mütze¹,

Beblo²,

Kortz

et al. 2012

PLoS ONE

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BackgroundPatients with phenylketonuria (PKU) have to follow a lifelong phenylalanine restricted diet. This type of diet markedly reduces the intake of saturated and unsaturated fatty acids especially long chain polyunsaturated fatty acids (LC-PUFA). Long-chain saturated fatty acids are substrates of mitochondrial fatty acid oxidation for acetyl-CoA production. LC-PUFA are discussed to affect inflammatory and haemostaseological processes in health and disease. The influence of the long term PKU diet on fatty acid metabolism with a special focus on platelet eicosanoid metabolism has been investigated in the study presented here.Methodology/Principal Findings12 children with PKU under good metabolic control and 8 healthy controls were included. Activated fatty acids (acylcarnitines C6–C18) in dried blood and the cholesterol metabolism in serum were analyzed by liquid chromatographic tandem mass spectrometry (LC-MS/MS). Fatty acid composition of plasma glycerophospholipids was determined by gas chromatography. LC-PUFA metabolites were analyzed in supernatants by LC-MS/MS before and after platelet activation and aggregation using a standardized protocol. Patients with PKU had significantly lower free carnitine and lower activated fatty acids in dried blood compared to controls. Phytosterols as marker of cholesterol (re-) absorption were not influenced by the dietary fatty acid restriction. Fatty acid composition in glycerophospholipids was comparable to that of healthy controls. However, patients with PKU showed significantly increased concentrations of y-linolenic acid (C18:3n-6) a precursor of arachidonic acid. In the PKU patients significantly higher platelet counts were observed. After activation with collagen platelet aggregation and thromboxane B2 and thromboxane B3 release did not differ from that of healthy controls.Conclusion/SignificanceLong-term dietary fatty acid restriction influenced the intermediates of mitochondrial beta-oxidation. No functional influence on unsaturated fatty acid metabolism and platelet aggregation in patients with PKU was detected.

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Section: Discussioncontrasting

confidence: 99%

Metabolomics of Dietary Fatty Acid Restriction in Patients with Phenylketonuria

Mütze¹,

Beblo²,

Kortz

et al. 2012

PLoS ONE

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“…Furthermore, there are several regulatory mechanisms which contribute to cholesterol homeostasis. Although in this study we have only analyzed the blood lipid profile of patients with PKU, it is worth mentioning that an in vivo study, in which experimental hyperphenylalaninemia was induced in an animal model, demonstrated that there was an inhibition of two of the main regulatory enzymes of brain and liver cholesterogenesis: 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase [29]; and therefore a reduced cholesterol synthesis in the brain may indicate an association between impaired myelination and mental retardation in patients with PKU.…”

Section: Discussionmentioning

confidence: 99%

Lipid profile status and other related factors in patients with Hyperphenylalaninaemia

Couce

Vitoria

Aldámiz‐Echevarría

et al. 2016

Orphanet J Rare Dis

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BackgroundThe mainstay of treating patients with phenylketonuria (PKU) is based on a Phe-restricted diet, restrictive in natural protein combined with Phe-free L-amino acid supplements and low protein foods. This PKU diet seems to reduce atherogenesis and confer protection against cardiovascular diseases but the results from the few published studies have been inconclusive. The aim of our study was to evaluate the relationship between the lipid profile and several treatment-related risk factors in patients with hyperphenylalaninaemia (HPA) in order to optimize their monitoring.MethodsWe conducted a cross-sectional multicentre study. A total of 141 patients with HPA were classified according to age, phenotype, type of treatment and dietary adherence. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, blood pressure (BP) and biochemical parameters [(triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), apolipoprotein A (ApoA), apolipoprotein B (ApoB), vitamin B12, total homocysteine (tHcy), Methionine (Met), high sensitivity C-Reactive Protein (hsCRP)] were collected for each patient.ResultsPlasma TC levels were lower in patients with PKU than in the mild-HPA group (150 ± 31 vs. 164 ± 22 mg/dL), and there was a weak inverse correlation between plasma TC and Phe levels. HDL-C, LDL-C, ApoA and ApoB levels were lower in the PKU group than in mild-HPA. Patients with PKU had higher systolic BP than the mild-HPA group and there was found a quadratic correlation between median Phe levels and systolic BP (p = 6.42e-5) and a linear correlation between median Phe levels and diastolic BP (p = 5.65e-4). In overweight or obese PKU patients (24.11 %), biochemical parameters such as TC, triglycerides, LDL-C, tHcy, hsCRP and BP were higher. By contrast, HDL-C was lower in these patients.ConclusionOur data show a direct correlation between lipid profile parameters and good adherence to the diet in PKU patients. However, lipid profile in overweight or obese patients displayed an atherogenic profile, in addition to higher hsCRP concentrations and BP. Our study contributes to a better understanding of the relationship between phenotype and treatment in patients with HPA, which could be useful in improving follow-up strategies and clinical outcome.Trial registrationResearch Ethics Committee of Santiago-Lugo 2015/393. Registered 22 September 2015, retrospectively registered.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0508-x) contains supplementary material, which is available to authorized users.

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“…The cell culture medium of control cells was found to contain a residual level of Phe (278 mmol/L). However, this was below the level of Phe reported to inhibit either HMG-CoA reductase or MRC complex I-III activity and therefore it is unlikely that this basal level of Phe would be inhibitory to either MRC complex I activity or CoQ 10 synthesis (Castillo et al 1988;Rech et al 2002).…”

Section: Discussionmentioning

confidence: 95%

“…More specifically, squalene synthase has a lower affinity than trans-prenyl transferase for farnesyl pyrophosphate, so a reduction in the concentration of farnesyl pyrophosphate due to high Phe would be expected to have a less profound effect upon CoQ 10 synthesis than cholesterol synthesis (Faust et al 1980). Hence, although hyperphenylalaninaemia has been reported to inhibit cholesterol synthesis this would not necessarily result in a decrease in cellular CoQ 10 levels (Castillo et al 1988).…”

Section: Discussionmentioning

confidence: 99%

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Assessment of mitochondrial respiratory chain function in hyperphenylalaninaemia

Kyprianou

Murphy

Lee

et al. 2009

J of Inher Metab Disea

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Phenylketonuria (PKU) is an autosomal recessive disorder resulting in neurological and intellectual disability when untreated. However, even in treated patients there may be residual neurological impairment such as tremor. It has been suggested that the hyperphenylalaninaemia in patients with PKU reduces complex I (NADH:ubiquinone reductase) activity of the mitochondrial respiratory chain (MRC) and/or biosynthesis of coenzyme Q(10) (CoQ(10)), which acts as an electron carrier in the MRC, leading to impaired energy metabolism in the brain of patients with PKU and hence the neurological pathology. The aim of this study was to elucidate the mechanism of phenylalanine (Phe) toxicity on the MRC. We compared mean plasma and blood-spot Phe and mononuclear CoQ(10) levels in 17 patients with PKU and a tremor compared to 22 patients without tremor. Human 1321N1 astrocytoma cells were exposed to hyperphenylalaninaemia by the addition of 300 or 900 micromol/L of Phe to the cell culture medium. Following 96 h of culture we measured complex I and citrate synthase activities and CoQ(10) level. Results showed no significant difference in Phe or CoQ(10) levels in patients with tremor compared to those without tremor. Further, hyperphenylalaninaemia did not cause a significant reduction in complex I activity or CoQ(10) biosynthesis, even when taking into account the mitochondrial enrichment of the cell samples by expressing complex I and CoQ(10) as a ratio to citrate synthase. In conclusion, the results of this study suggest that hyperphenylalaninaemia does not contribute to the pathophysiology of PKU by causing a decrease in MRC complex I activity and/or CoQ(10) biosynthesis.

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Inhibition of brain and liver 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase in experimental hyperphenylalaninemia

Cited by 44 publications

References 28 publications

Metabolomics of Dietary Fatty Acid Restriction in Patients with Phenylketonuria

Metabolomics of Dietary Fatty Acid Restriction in Patients with Phenylketonuria

Lipid profile status and other related factors in patients with Hyperphenylalaninaemia

Assessment of mitochondrial respiratory chain function in hyperphenylalaninaemia

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