Grant A Mitchell

CHU Sainte-Justine, Montréal, Quebec, Canada

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Publications (180)1064.3 Total impact

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    ABSTRACT: Deficiency of pyridox(am)ine 5'-phosphate oxidase (PNPO, OMIM 610090) is a treatable autosomal recessive inborn error of metabolism. Neonatal epileptic encephalopathy and a low cerebrospinal fluid (CSF) pyridoxal 5'-phosphate level are the reported hallmarks of PNPO deficiency, but its clinical and biochemical spectra are not fully known. A girl born at 33 3/7 weeks of gestation developed seizures in the first hours of life. Her seizures initially responded to GABAergic agonists, but she subsequently developed a severe epileptic encephalopathy. Brain MRI and infectious and metabolic evaluations at birth, including urinary alpha-aminoadipic semialdehyde (AASA), were normal. Lumbar puncture at age 3 months showed: pyridoxal 5'-phosphate, 52 nmol/L (normal, 23-64); homovanillic acid, 392 nmol/L (normal, 450-1,132); 5-hydroxyindoleacetic acid, 341 nmol/L (normal, 179-711); and 3-ortho-methyldopa, 30 nmol/L (normal, below 300). The patient was not being treated with pyridoxine nor with pyridoxal 5'-phosphate at the time of the lumbar puncture. She died at age 14 months. A sequencing panel targeting 53 epilepsy-related genes revealed a homozygous missense mutation in PNPO (c.674G>A, p.R225H). Homozygosity was confirmed by parental testing. Expression studies of mutant p.R225H PNPO revealed greatly reduced activity. In conclusion, a normal CSF level of pyridoxal 5'-phosphate does not rule out PNPO deficiency.
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    ABSTRACT: Introduction: Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities. Methods: Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively. Results: We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research. Conclusions: The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial.
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    ABSTRACT: Addition of the trinucleotide CCA to the 3'end of transfer RNAs (tRNAs) is essential for translation and is catalyzed by the enzyme TRNT1 (tRNA nucleotidyl transferase), which functions in both the cytoplasm and mitochondria. Exome sequencing revealed TRNT1 mutations in two unrelated subjects with different clinical features. The first presented with acute lactic acidosis at 3 weeks of age, and developed severe developmental delay, hypotonia, microcephaly, seizures, progressive cortical atrophy, neurosensorial deafness, sideroblastic anemia and renal Fanconi syndrome, dying at 21 months. The second, presented at 3.5 years with gait ataxia, dysarthria, gross motor regression, hypotonia, ptosis and ophthalmoplegia, and had abnormal signals in brainstem and dentate nucleus. In subject 1, muscle biopsy showed combined oxidative phosphorylation (OXPHOS) defects, but there was no OXPHOS deficiency in fibroblasts from either subject, despite a tenfold-reduction in TRNT1 protein levels in fibroblasts of the first subject. Furthermore, in normal controls, TRNT1 protein levels are ten-fold lower in muscle than in fibroblasts. High resolution Northern blots of subject fibroblast RNA suggested incomplete CCA addition to the non-canonical mitochondrial tRNASer(AGY), but no obvious qualitative differences in other mitochondrial or cytoplasmic tRNAs. Complete knockdown of TRNT1 in patient fibroblasts rendered mitochondrial tRNASer(AGY) undetectable, and markedly reduced mitochondrial translation, except polypeptides lacking Ser(AGY) codons. These data suggest that the clinical phenotypes associated with TRNT1 mutations are largely due to impaired mitochondrial translation, resulting from defective CCA addition to mitochondrial tRNASer(AGY), and that the severity of this biochemical phenotype determines the severity and tissue distribution of clinical features.
    Human Molecular Genetics 02/2015; DOI:10.1093/hmg/ddv044 · 6.68 Impact Factor
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    ABSTRACT: KIF1A is a neuron specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the motor domain. Transfection studies suggested that at least five of these mutations affect the transport of the motor domain along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, and peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the motor domain of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene. This article is protected by copyright. All rights reserved.
    Human Mutation 01/2015; 36(1). DOI:10.1002/humu.22709 · 5.05 Impact Factor
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    ABSTRACT: Genes and the environment both influence the metabolic processes that determine fitness. To illustrate the importance of metabolism for human brain evolution and health, we use the example of lipid energy metabolism, i.e. the use of fat (lipid) to produce energy and the advantages that this metabolic pathway provides for the brain during environmental energy shortage. We briefly describe some features of metabolism in ancestral organisms, which provided a molecular toolkit for later development. In modern humans, lipid energy metabolism is a regulated multi-organ pathway that links triglycerides in fat tissue to the mitochondria of many tissues including the brain. Three important control points are each suppressed by insulin. (1) Lipid reserves in adipose tissue are released by lipolysis during fasting and stress, producing fatty acids (FAs) which circulate in the blood and are taken up by cells. (2) FA oxidation. Mitochondrial entry is controlled by carnitine palmitoyl transferase 1 (CPT1). Inside the mitochondria, FAs undergo beta oxidation and energy production in the Krebs cycle and respiratory chain. (3) In liver mitochondria, the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) pathway produces ketone bodies for the brain and other organs. Unlike most tissues, the brain does not capture and metabolize circulating FAs for energy production. However, the brain can use ketone bodies for energy. We discuss two examples of genetic metabolic traits that may be advantageous under most conditions but deleterious in others. (1) A CPT1A variant prevalent in Inuit people may allow increased FA oxidation under nonfasting conditions but also predispose to hypoglycemic episodes. (2) The thrifty genotype theory, which holds that energy expenditure is efficient so as to maximize energy stores, predicts that these adaptations may enhance survival in periods of famine but predispose to obesity in modern dietary environments. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Journal of Human Evolution 12/2014; 77. DOI:10.1016/j.jhevol.2014.06.013 · 3.87 Impact Factor
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    ABSTRACT: Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal ( facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource ( that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
    Molecular Genetics and Metabolism 12/2014; DOI:10.1016/j.ymgme.2014.11.016 · 2.83 Impact Factor
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    ABSTRACT: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by marked dilatation of the bladder and microcolon and decreased intestinal peristalsis. Recent studies indicate that heterozygous variants in ACTG2, which codes for a smooth muscle actin, cause MMIHS. However, such variants do not explain MMIHS cases that show an autosomal recessive mode of inheritance. We performed exome sequencing in a newborn with MMIHS and prune belly phenotype whose parents are consanguineous and identified a homozygous variant (c.3598A>T: p.Lys1200Ter) in MYH11, which codes for the smooth muscle myosin heavy chain. Previous studies showed that loss of Myh11 function in mice causes a bladder and intestinal phenotype that is highly reminiscent of MMIHS. All together, these observations strongly suggest that loss-of-function variants in MYH11 cause MMIHS. The documentation of variants in ACTG2 and MYH11 thus points to the involvement of the contractile apparatus of the smooth muscle in MMIHS. Interestingly, dominant-negative variants in MYH11 have previously been shown to cause thoracic aortic aneurism and dilatation. Different mechanisms of MYH11 disruption may thus lead to distinct patterns of smooth muscle dysfunction.European Journal of Human Genetics advance online publication, 19 November 2014; doi:10.1038/ejhg.2014.256.
    European journal of human genetics: EJHG 11/2014; DOI:10.1038/ejhg.2014.256 · 3.56 Impact Factor
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    ABSTRACT: Triglyceride (TG) synthesis, storage, and degradation together constitute cytoplasmic TG metabolism (CTGM). CTGM is mostly studied in adipocytes, where starting from glycerol-3-phosphate and fatty acyl (FA)-coenzyme A (CoA), TGs are synthesized then stored in cytoplasmic lipid droplets. TG hydrolysis proceeds sequentially, producing FAs and glycerol. Several reactions of CTGM can be catalyzed by more than one enzyme, creating great potential for complex tissue-specific physiology. In adipose tissue, CTGM provides FA as a systemic energy source during fasting and is related to obesity. Inborn errors and mouse models have demonstrated the importance of CTGM for non-adipose tissues, including skeletal muscle, myocardium and liver, because steatosis and dysfunction can occur. We discuss known inborn errors of CTGM, including deficiencies of: AGPAT2 (a form of generalized lipodystrophy), LPIN1 (childhood rhabdomyolysis), LPIN2 (an inflammatory condition, Majeed syndrome, described elsewhere in this issue), DGAT1 (protein loosing enteropathy), perilipin 1 (partial lipodystrophy), CGI-58 (gene ABHD5, neutral lipid storage disease (NLSD) with ichthyosis and "Jordan's anomaly" of vacuolated polymorphonuclear leukocytes), adipose triglyceride lipase (ATGL, gene PNPLA2, NLSD with myopathy, cardiomyopathy and Jordan's anomaly), hormone-sensitive lipase (HSL, gene LIPE, hypertriglyceridemia, and insulin resistance). Two inborn errors of glycerol metabolism are known: glycerol kinase (GK, causing pseudohypertriglyceridemia) and glycerol-3-phosphate dehydrogenase (GPD1, childhood hepatic steatosis). Mouse models often resemble human phenotypes but may diverge markedly. Inborn errors have been described for less than one-third of CTGM enzymes, and new phenotypes may yet be identified.
    Journal of Inherited Metabolic Disease 10/2014; DOI:10.1007/s10545-014-9767-7 · 4.14 Impact Factor
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    ABSTRACT: In male mice, deficiency of hormone sensitive lipase (HSL, Lipe gene, E.C. causes deficient spermatogenesis, azoospermia and infertility. Postmeiotic germ cells express a specific HSL isoform that includes a 313 amino acid N-terminus encoded by a testis-specific exon (exon T1). The remainder of testicular HSL is identical to adipocyte HSL. The amino acid sequence of the testis-specific exon is poorly conserved, showing only a 46 amino acid identity with orthologous human and rat sequences, compared with 87% over the remainder of the HSL coding sequence, providing no evidence in favor of a vital functional role for the testis-specific N-terminus of HSL. However, exon T1 is important for Lipe transcription: in mouse testicular mRNA, we identified 3 major Lipe transcription start sites, finding numerous testicular transcription factor binding motifs upstream of the transcription start site. We directly explored two possible mechanisms for the infertility of HSL-deficient mice, using mice that expressed mutant HSL transgenes only in postmeiotic germ cells, on a HSL-deficient background. One transgene expressed human HSL lacking enzyme activity but containing the testis-specific N-terminus (HSL-/-muttg mice). The other transgene expressed catalytically-inactive HSL with the testis-specific N-terminal peptide (HSL-/-atg mice). HSL-/-muttg mice were infertile, with abnormal histology of the seminiferous epithelium and absence of spermatozoa in the epididymal lumen. In contrast, HSL-/-atg mice had normal fertility and normal testicular morphology. In conclusion, while the catalytic function of HSL is necessary for spermatogenesis in mice, the presence of the N-terminal testis-specific fragment is not essential.
    Endocrinology 05/2014; 155(8):en20141031. DOI:10.1210/en.2014-1031 · 4.72 Impact Factor
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    ABSTRACT: Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total ketone body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of ketone body metabolism. Defects in ketogenesis include mitochondrial HMG-CoA synthase (mHS) deficiency and HMG-CoA lyase (HL) deficiency. mHS deficiency should be considered in non-ketotic hypoglycemia if a fatty acid beta-oxidation defect is suspected, but cannot be confirmed. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even in adolescents and adults. Succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency and beta-ketothiolase (T2) deficiency are two defects in ketolysis. Permanent ketosis is pathognomonic for SCOT deficiency. However, patients with "mild" SCOT mutations may have nonketotic periods. T2-deficient patients with "mild" mutations may have normal blood acylcarnitine profiles even in ketoacidotic crises. T2 deficient patients cannot be detected in a reliable manner by newborn screening using acylcarnitines. We review recent data on clinical presentation, metabolite profiles and the course of these diseases in adults, including in pregnancy.
    Journal of Inherited Metabolic Disease 04/2014; DOI:10.1007/s10545-014-9704-9 · 4.14 Impact Factor
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    ABSTRACT: Prompt post-hypoxia-ischemia (HI) revascularization has been suggested to improve outcome in adults and newborn subjects. Other than hypoxia-inducible factor, sensors of metabolic demand remain largely unknown. During HI, anaerobic respiration is arrested resulting in accumulation of carbohydrate metabolic intermediates. As such succinate readily increases, exerting its biological effects via a specific receptor, G-protein-coupled receptor (GPR) 91. We postulate that succinate/GPR91 enhances post-HI vascularization and reduces infarct size in a model of newborn HI brain injury. The Rice-Vannucci model of neonatal HI was used. Succinate was measured by mass spectrometry, and microvascular density was evaluated by quantification of lectin-stained cryosection. Gene expression was evaluated by real-time polymerase chain reaction. Succinate levels rapidly increased in the penumbral region of brain infarcts. GPR91 was foremost localized not only in neurons but also in astrocytes. Microvascular density increased at 96 hours after injury in wild-type animals; it was diminished in GPR91-null mice leading to an increased infarct size. Stimulation with succinate led to an increase in growth factors implicated in angiogenesis only in wild-type mice. To explain the mode of action of succinate/GPR91, we investigated the role of PGE2-prostaglandin E receptor 4, previously proposed in neural angiogenesis. Succinate-induced vascular endothelial growth factor expression was abrogated by a cyclooxygenase inhibitor and a selective prostaglandin E receptor 4 antagonist. This antagonist also abolished succinate-induced neovascularization. We uncover a dominant metabolic sensor responsible for post-HI neurovascular adaptation, notably succinate/GPR91, acting via PGE2-prostaglandin E receptor 4 to govern expression of major angiogenic factors. We propose that pharmacological intervention targeting GPR91 could improve post-HI brain recovery.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2013; 34(2). DOI:10.1161/ATVBAHA.113.302131 · 6.34 Impact Factor
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    ABSTRACT: We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39months in patients with mild and moderate DD/ID, respectively, and 11years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes.
    Molecular Genetics and Metabolism 11/2013; DOI:10.1016/j.ymgme.2013.10.018 · 2.83 Impact Factor
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    Dataset: mmc1
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    ABSTRACT: We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/glutamate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs.
    Neuron 10/2013; 80(2):429-41. DOI:10.1016/j.neuron.2013.08.013 · 15.77 Impact Factor
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    ABSTRACT: To describe the long-term ophthalmologic outcomes of patients with methylmalonic aciduria and homocystinuria, cobalamin C type (cblC). Retrospective case series. All patients with cblC referred to the Department of Ophthalmology of the Centre Hospitalier Universitaire Sainte-Justine from 1984 through 2012 were studied. Twelve such patients were identified. Clinical ophthalmic examinations, neuroimaging, electroretinography, and the results of MMACHC mutation analysis were reviewed retrospectively. We examined visual acuity, ocular alignment, presence of maculopathy and peripheral retinopathy, optic atrophy, and nystagmus. Photopic and scotopic electroretinograms were reviewed. We examined and compared mutations in the MMACHC gene. Neuroimaging abnormalities were compiled when available. Twelve cblC patients were followed up from 2 to 23 years (average, 10 years). Eleven of 12 patients were diagnosed before the age of 1 year (range, birth-2 years). An initial ophthalmic examination was performed within the first year of age in 9 of 12 patients. Visual acuity at the time of presentation was variable, ranging from light perception to 20/20. Visual acuity was worse than 20/100 in 75% (9/12) of patients at last follow-up. Eight patients (67%) had obvious maculopathy on fundus examination. Other findings included peripheral retinopathy (8/12 [67%]), nystagmus (8/12 [67%]), strabismus (5/12 [42%]), and optic atrophy (6/12 [50%]). Funduscopic deterioration was documented in 1 patient, whereas electrophysiologic changes occurred in 4 patients. Neuroimaging results were available in 7 of the patients, revealing corpus callosum atrophy (7/7 [100%]) and periventricular white matter loss (6/7 [85%]). Most children in our series had early-onset disease with neurologic manifestations and abnormal ophthalmologic examination results. Despite early treatment, many early-onset cblC patients have poor visual function. The author(s) have no proprietary or commercial interest in any materials discussed in this article.
    Ophthalmology 10/2013; 121(1). DOI:10.1016/j.ophtha.2013.08.034 · 5.56 Impact Factor
  • Canadian Journal of Diabetes 10/2013; 37S4:S58. DOI:10.1016/j.jcjd.2013.08.172 · 0.46 Impact Factor
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    ABSTRACT: The scavenger receptor CD36 plays a central role in lipid metabolism by promoting macrophage cholesterol efflux with the potential to reduce atherosclerotic lesions. However, the effect of CD36 on de novo cholesterol synthesis is not known. Here, we describe the cellular mechanism by which CD36 activation induces cholesterol depletion in HepG2 cells. Using the CD36 ligand hexarelin, we found a rapid phosphorylation of HMG-CoA reductase Ser-872 in treated cells, resulting in inactivation of the rate-limiting enzyme in sterol synthesis. Degradation of HMG-CoA reductase by the ubiquitin-proteasome pathway was also enhanced by hexarelin, through an increased recruitment of the anchor proteins insulin-induced gene (Insig)-1 and Insig-2. Genes encoding key enzymes involved in cholesterol synthesis and under the control of transcription factor sterol regulatory element-binding protein (SREBP)-2 remained unresponsive to sterol depletion, due to retention of the SREBP-2 escort protein Scap by Insig-1/2. Insig1 and Insig2 gene expression was also increased through activation of nuclear receptor peroxisome-proliferator activating receptor γ (PPARγ) by CD36, which lifted the inhibitory effect of PPARγ1 Ser-84 phosphorylation. Recruitment of coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) to activated AMPKα was also promoted, resulting in PGC-1α transcriptional activation through Sirt1-mediated deacetylation, increased recruitment of PPARγ, and up-regulation of Insig-1/2, revealing a regulatory role of CD36 on PGC-1α signaling. Our data identify CD36 as a novel regulator of HMG-CoA reductase function and Insig-1/2 expression, 2 critical steps regulating cholesterol synthesis in hepatocytes.-Rodrigue-Way, A., Caron, V., Bilodeau, S., Keil, S., Hassan, M., Lévy, E., Mitchell. G. A., Tremblay, A. Scavenger receptor CD36 mediates inhibition of cholesterol synthesis via activation of the PPARγ/PGC-1α pathway and Insig1/2 expression in hepatocytes.
    Canadian Journal of Diabetes 10/2013; 37S4(4):S65. DOI:10.1016/j.jcjd.2013.08.196 · 0.46 Impact Factor
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    ABSTRACT: Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-coenzyme A (CoA) esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Carboxylation of [2-(14)C] pyruvate diminished following incubation of HLLKO hepatocytes with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function, demonstrating an acyl-CoA-related mechanism for this complication.
    PLoS ONE 07/2013; 8(7):e60581. DOI:10.1371/journal.pone.0060581 · 3.53 Impact Factor
  • Movement Disorders 07/2013; 28(8). DOI:10.1002/mds.25538 · 5.63 Impact Factor

Publication Stats

6k Citations
1,064.30 Total Impact Points


  • 1994–2015
    • CHU Sainte-Justine
      • Department of Medical Genetics
      Montréal, Quebec, Canada
  • 1992–2013
    • Université de Montréal
      • Department of Pediatrics
      Montréal, Quebec, Canada
  • 1990–2013
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 2011
    • University of Liège
      Luik, Walloon Region, Belgium
  • 2008
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
  • 2005–2008
    • McGill University
      • Department of Pediatrics
      Montréal, Quebec, Canada
  • 2007
    • University of Toronto
      Toronto, Ontario, Canada
  • 2004
    • SickKids
      Toronto, Ontario, Canada
  • 2000
    • Oregon Health and Science University
      • Department of Molecular & Medical Genetics
      Portland, OR, United States
  • 1999
    • University of California, San Diego
      San Diego, California, United States
  • 1994–1997
    • Kingston General Hospital
      Kingston, Ontario, Canada
  • 1996
    • Gifu University Hospital
      Gihu, Gifu, Japan
  • 1994–1996
    • Medical College of Wisconsin
      • Department of Biochemistry
      Milwaukee, WI, United States
  • 1988–1992
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Johns Hopkins University
      • Department of Pediatrics
      Baltimore, Maryland, United States
  • 1989
    • University of Helsinki
      Helsinki, Uusimaa, Finland