Biomedical subjects

Julie St-Pierre

Publications and source records attributed to Julie St-Pierre.

At least 19 recordsLinked to original sources

PubMed2006

Low plasma adiponectin exacerbates the risk of premature coronary artery disease in familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is characterized by increased risk for premature coronary artery disease (CAD). This risk is exacerbated in the presence of abdominal obesity and insulin resistance. Low adiponectin is part of the clustering of metabolic abnormalities associated with abdominal obesity and insulin resistance. The present study, therefore, aims to examine the relationship between plasma adiponectin and age at CAD diagnosis in FH patients. Plasma adiponectin was measured by ELISA in 568 non-diabetic FH individuals of French-Canadian origin. CAD was defined according to strict clinical criteria. Prior to analyses, patients were grouped according to age and gender-specific tertiles of plasma adiponectin levels. Multivariate Cox proportional hazards regression was used to estimate the association between plasma adiponectin levels and age at diagnosis of CAD. Overall, FH patients in the lowest tertile of plasma adiponectin exhibited CAD at a significantly younger age (hazard ratio=1.73, confidence interval 95%: [1.19-2.53]; p=0.004). These results suggest that low plasma adiponectin is associated with an increased risk of premature CAD over and above the already exaggerated risk seen in FH patients.

Adiponectin↗

PubMed2006

Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.

PPARgamma coactivator 1alpha (PGC-1alpha) is a potent stimulator of mitochondrial biogenesis and respiration. Since the mitochondrial electron transport chain is the main producer of reactive oxygen species (ROS) in most cells, we examined the effect of PGC-1alpha on the metabolism of ROS. PGC-1alpha is coinduced with several key ROS-detoxifying enzymes upon treatment of cells with an oxidative stressor; studies with RNAi or null cells indicate that PGC-1alpha is required for the induction of many ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1alpha null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, respectively. Increasing PGC-1alpha levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1alpha is a broad and powerful regulator of ROS metabolism, providing a potential target for the therapeutic manipulation of these important endogenous toxins.

Animals↗

PubMed2006

Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.

Alterations in cellular metabolism are among the most consistent hallmarks of cancer. Herein we have investigated the relationship between increased aerobic lactate production and mitochondrial physiology in tumor cells. To diminish the ability of malignant cells to metabolize pyruvate to lactate, lactate dehydrogenase A (LDH-A) levels were knocked down by means of LDH-A short hairpin RNAs. Reduction in LDH-A activity resulted in stimulation of mitochondrial respiration and decrease of mitochondrial membrane potential. It also compromised the ability of these tumor cells to proliferate under hypoxia. The tumorigenicity of the LDH-A-deficient cells was severely diminished, and this phenotype was reversed by complementation with the human ortholog LDH-A protein. These results demonstrate that LDH-A plays a key role in tumor maintenance.

Adenosine Triphosphate↗

PubMed2006

Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation.

Mitochondria play an essential role in the ability of brown fat to generate heat, and the PGC-1 coactivators control several aspects of mitochondrial biogenesis. To investigate their specific roles in brown fat cells, we generated immortal preadipocyte lines from the brown adipose tissue of mice lacking PGC-1alpha. We could then efficiently knockdown PGC-1beta expression by shRNA expression. Loss of PGC-1alpha did not alter brown fat differentiation but severely reduced the induction of thermogenic genes. Cells deficient in either PGC-1alpha or PGC-1beta coactivators showed a small decrease in the differentiation-dependant program of mitochondrial biogenesis and respiration; however, this increase in mitochondrial number and function was totally abolished during brown fat differentiation when both PGC-1alpha and PGC-1beta were deficient. These data show that PGC-1alpha is essential for brown fat thermogenesis but not brown fat differentiation, and the PGC-1 coactivators play an absolutely essential but complementary function in differentiation-induced mitochondrial biogenesis.

Adipocytes↗

PubMed2005

Genetic aspects of diabetes and its cardiovascular complications: contribution of genetics to risk assessment and clinical management.

Diabetes mellitus is a source of great concern in contemporary cardiology. It is a heterogeneous disease and patients are often characterized by features of the insulin resistance syndrome, also referred to as the metabolic syndrome. The objectives of the present review were to discuss some genes that potentially modulate the risk of coronary artery disease in diabetes mellitus; to address how the genes' respective contributions could possibly influence the global risk assessment of coronary artery disease among diabetic patients; and to present simple clinical markers, such as plasma glycerol concentration and the 'hypertriglyceridemic waist' phenotype, that could help to identify high-risk individuals.

Albuminuria↗

PubMed2004

Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice.

PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

Adaptation, Physiological↗

PubMed2004

Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK.

The transcriptional coactivator PPAR gamma coactivator 1 alpha (PGC-1alpha) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1alpha in humans have been associated with type II diabetes. PGC-1alpha contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1alpha by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and beta-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160MBP) as a repressor of PGC-1alpha. The binding and repression of PGC-1alpha by p160MBP is disrupted by p38 MAPK phosphorylation of PGC-1alpha. Adenoviral expression of p160MBP in myoblasts strongly reduces PGC-1alpha's ability to stimulate mitochondrial respiration and the expression of the genes of the electron transport system. This repression does not require removal of PGC-1alpha from chromatin, suggesting that p160MBP is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160MBP is a powerful negative regulator of PGC-1alpha function and provide a molecular mechanism for the activation of PGC-1alpha by p38 MAPK. The discovery of p160MBP as a PGC-1alpha regulator has important implications for the understanding of energy balance and diabetes.

Animals↗

PubMed2003

Superoxide and hydrogen peroxide production by Drosophila mitochondria.

Drosophila melanogaster is a key model organism for genetic investigation of the role of free radicals in aging, but biochemical understanding is lacking. Superoxide production by Drosophila mitochondria was measured fluorometrically as hydrogen peroxide, using its dependence on substrates, inhibitors, and added superoxide dismutase to determine sites of production and their topology. Glycerol 3-phosphate dehydrogenase and center o of complex III in the presence of antimycin had the greatest maximum capacities to generate superoxide on the cytosolic side of the inner membrane. Complex I had significant capacity on the matrix side. Center i of complex III, cytochrome c, and complex IV produced no superoxide. Native superoxide generation by isolated mitochondria was also measured without added inhibitors. There was a high rate of superoxide production with sn-glycerol 3-phosphate as substrate; two-thirds mostly from glycerol 3-phosphate dehydrogenase on the cytosolic side and one-third on the matrix side from complex I following reverse electron transport. There was little superoxide production from any site with NADH-linked substrate. Superoxide production by complex I following reverse electron flow from glycerol 3-phosphate was particularly sensitive to membrane potential, decreasing 70% when potential decreased 10 mV, showing that mild uncoupling lowers superoxide production in the matrix very effectively.

Animals↗

PubMed2003

Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells.

Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several components of energy metabolism, particularly certain aspects of adaptive thermogenesis in brown fat and skeletal muscle, hepatic gluconeogenesis, and fiber type switching in skeletal muscle. PGC-1alpha has been shown to induce mitochondrial biogenesis when expressed in muscle cells, and preliminary analysis has suggested that this molecule may specifically increase the fraction of uncoupled versus coupled respiration. In this paper, we have performed detailed bioenergetic analyses of the function of PGC-1alpha and its homolog PGC-1beta in muscle cells by monitoring simultaneously oxygen consumption and membrane potential. Cells expressing PGC-1alpha or PGC-1beta display higher proton leak rates at any given membrane potential than control cells. However, cells expressing PGC-1alpha have a higher proportion of their mitochondrial respiration linked to proton leak than cells expressing PGC-1beta. Although these two proteins cause a similar increase in the expression of many mitochondrial genes, PGC-1beta preferentially induces certain genes involved in the removal of reactive oxygen species, recently recognized as activators of uncoupling proteins. Together, these data indicate that PGC-1alpha and PGC-1beta profoundly alter mitochondrial metabolism and suggest that these proteins are likely to play different physiological functions.

Adenosine Triphosphate↗

PubMed2003

Visceral obesity attenuates the effect of the hepatic lipase -514C>T polymorphism on plasma HDL-cholesterol levels in French-Canadian men.

UNLABELLED: The dyslipidemic state of visceral obesity is characterized by increased plasma triglyceride (TG) levels, low HDL-cholesterol concentrations and alterations in LDL composition and concentration. A functional, non-coding -514C>T single nucleotide polymorphism (SNP) of the hepatic lipase gene (LIPC) has been related to variation in HDL-cholesterol concentrations. OBJECTIVES: To investigate the hypotheses that the LIPC -514C>T polymorphism may be associated with a deteriorated lipoprotein-lipid profile and that environmental factor, such as abdominal obesity, alters this association. METHODS: A total of 235 French-Canadian men from the greater Quebec City area were assigned into three groups on the basis of their LIPC -514C>T SNP, including 149 CC homozygotes, 75 CT heterozygotes, and 11 TT homozygotes. RESULTS: In the present study, the highest values of BMI, waist circumference, and accumulation of visceral adipose tissue (VAT) were observed among TT homozygotes (p<0.05). After adjustment for age and BMI, TT homozygotes still showed higher plasma apolipoprotein (apo) AI and HDL-TG concentrations than the two other groups (p<0.05). When the two genotype groups (CC vs CT/TT) were further divided on the basis of VAT accumulation using a cut-off point of 130 cm(2) (high vs low) it appears that irrespective of the genotype subjects with low VAT had higher HDL(2)-cholesterol concentrations (p<0.0001). However, lean carriers of the T allele had higher plasma HDL(2)-cholesterol levels than lean CC homozygotes. The beneficial effect of the T allele on plasma HDL(2)-cholesterol levels was abolished in the presence of visceral obesity (VAT>130 cm(2)). CONCLUSION: In summary, the presence of visceral obesity attenuates the impact of the LIPC -514C>T polymorphism on plasma HDL(2)-cholesterol levels.

Adult↗

PubMed2003

Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction.

Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type 2 diabetes. The mechanism for loss of glucose responsiveness is unknown. Uncoupling protein 2 (UCP2), by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak. Since obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic beta cells, a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced beta cell dysfunction. This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness is prevented by reduction of mitochondrial superoxide production or gene knockout of UCP2. Importantly, reduction of superoxide has no beneficial effect in the absence of UCP2, and superoxide levels are increased further in the absence of UCP2, demonstrating that the adverse effects of superoxide on beta cell glucose sensing are caused by activation of UCP2. Therefore, superoxide-mediated activation of UCP2 could play an important role in the pathogenesis of beta cell dysfunction and type 2 diabetes.

Adenosine Triphosphate↗

PubMed2002

Topology of superoxide production from different sites in the mitochondrial electron transport chain.

We measured production of reactive oxygen species by intact mitochondria from rat skeletal muscle, heart, and liver under various experimental conditions. By using different substrates and inhibitors, we determined the sites of production (which complexes in the electron transport chain produced superoxide). By measuring hydrogen peroxide production in the absence and presence of exogenous superoxide dismutase, we established the topology of superoxide production (on which side of the mitochondrial inner membrane superoxide was produced). Mitochondria did not release measurable amounts of superoxide or hydrogen peroxide when respiring on complex I or complex II substrates. Mitochondria from skeletal muscle or heart generated significant amounts of superoxide from complex I when respiring on palmitoyl carnitine. They produced superoxide at considerable rates in the presence of various inhibitors of the electron transport chain. Complex I (and perhaps the fatty acid oxidation electron transfer flavoprotein and its oxidoreductase) released superoxide on the matrix side of the inner membrane, whereas center o of complex III released superoxide on the cytoplasmic side. These results do not support the idea that mitochondria produce considerable amounts of reactive oxygen species under physiological conditions. Our upper estimate of the proportion of electron flow giving rise to hydrogen peroxide with palmitoyl carnitine as substrate (0.15%) is more than an order of magnitude lower than commonly cited values. We observed no difference in the rate of hydrogen peroxide production between rat and pigeon heart mitochondria respiring on complex I substrates. However, when complex I was fully reduced using rotenone, rat mitochondria released significantly more hydrogen peroxide than pigeon mitochondria. This difference was solely due to an elevated concentration of complex I in rat compared with pigeon heart mitochondria.

Aging↗

PubMed2002

Contribution of abdominal obesity and hypertriglyceridemia to impaired fasting glucose and coronary artery disease.

Multiple logistic regression models were used in a cross-sectional study to determine the relation of fasting glycemia to angiographically assessed coronary artery disease (CAD) in 569 men (aged 18 to 69 years) who were stratified according to fasting blood glucose concentrations (<6.1 mmol/L, and 6.1 to 6.9 mmol/L or 110 to 124 mg/dl), waist circumference (<90 vs >or=90 cm), and fasting triglyceridemia (<2.0 vs >or=2.0 mmol/L or <177 vs >or=177 mg/dl). For this purpose, nondiabetic impaired fasting glucose was defined as from 6.1 to 6.9 mmol/L (110 to 124 mg/dl) compared with 250 normoglycemic controls (fasting glycemia <6.1 mmol/L or <124 mg/dl) without history of CAD. In the absence of "hypertriglyceridemic waist," impaired fasting glucose was not predictive of CAD. However, the risk of CAD was markedly higher among subjects characterized by both the hypertriglyceridemic waist phenotype and the presence of impaired fasting glucose (odds ratio 8.5, 95% confidence intervals 3.5 to 20.4; p <0.05) compared with the normoglycemic group with low waist circumferences and triglyceride levels. Thus, the results of the present study emphasizes the importance of other underlying metabolic abnormalities, such as abdominal obesity and related atherogenic dyslipidemia, in the modulation of the CAD risk associated with hyperglycemia.

Abdomen↗

PubMed2002

Superoxide activates mitochondrial uncoupling proteins.

Uncoupling protein 1 (UCP1) diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose tissue by catalysing a regulated leak of protons across the inner membrane. The functions of its homologues, UCP2 and UCP3, in other tissues are debated. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. Here we show that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2 and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. It correlates with the tissue expression of UCPs, appears in mitochondria from yeast expressing UCP1, and is absent in skeletal muscle mitochondria from UCP3 knockout mice. Our findings indicate that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria.

Adipose Tissue, Brown↗

PubMed2002

Visceral obesity and hyperinsulinemia modulate the impact of the microsomal triglyceride transfer protein -493G/T polymorphism on plasma lipoprotein levels in men.

The dyslipidemic state of visceral obesity is characterized by increased plasma triglyceride levels, low high-density lipoprotein-cholesterol concentration and alterations in low-density lipoprotein (LDL) composition and concentration. A functional, non-coding microsomal triglyceride transfer protein (MTP) -493G/T polymorphism of the microsomal triglyceride transfer protein gene has been related to variations in LDL-cholesterol levels. To study the effect of the MTP -493G/T polymorphism on lipoprotein levels in visceral obesity and hyperinsulinemia, a total of 227 men were assigned into two groups on the basis of their MTP -493G/T polymorphism, including 121 GG homozygotes and 105 carriers of the T allele (92 GT and 13 TT). The two genotypic groups did not differ for their physiological characteristics nor for lipoprotein--lipid profiles, before and after adjustment for age. However, GG homozygotes were characterized by higher fasting insulin levels than carriers of the T allele (P<0.05). When the two genotypic groups were further divided on the basis of their visceral adipose tissue (AT) accumulation, assessed by computed tomography, we observed that T allele carriers with low levels of visceral AT (<130 cm(2)) had decreased plasma total cholesterol and LDL-apolipoprotein B (LDL-apoB) levels compared to viscerally obese men (P=0.035 and P=0.0001, respectively). Among GG homozygotes, no significant difference were observed. Although not significant, T allele carriers characterized by visceral obesity tended to have smaller, denser LDL particles than T allele carriers characterized by a low accumulation of visceral AT. When subjects were divided on the basis of their fasting insulin levels, it appears that hyperinsulinemic men were characterized by a deteriorated lipoprotein--lipid profile when they were carriers of the T allele compared to normoinsulinemic men. In summary, visceral obesity and hyperinsulinemia modulate the impact of the MTP -493G/T polymorphism on plasma total cholesterol and LDL-apoB levels, as well as on LDL peak particle diameter.

Abdomen↗

PubMed2002

Effect of apolipoprotein E, peroxisome proliferator-activated receptor alpha and lipoprotein lipase gene mutations on the ability of fenofibrate to improve lipid profiles and reach clinical guideline targets among hypertriglyceridemic patients.

Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist which regulates the transcription of genes encoding proteins involved in triglyceride (TG)-rich lipoproteins and lipoprotein lipase (LPL) metabolism. The aim of the present study was to investigate the relation between TG-related parameters considered in different clinical guidelines used in industrialized countries for the management of lipid disorders (namely fasting plasma TG, high density-lipoprotein cholesterol (HDL-C), non-HDL-C concentrations and total-C/HDL-C ratio) and the presence of LPL-null (P207L), LPL-defective (D9N), PPARalpha -L162V, apolipoprotein (apo) E and PPARgamma-P12A gene mutations, in a sample of 292 hypertriglyceridemic subjects treated with fenofibrate for 3 months. Although fenofibrate induced a decrease in plasma TG level and an increase in HDL-C level in all studied genotypes, mutation-specific differences were observed. After adjustment for age, gender, body mass index and the presence of apo E2 genotype, the LPL-P207L mutation was associated with residual post-treatment hypertriglyceridemia [TG > 2.0 mmol/l, odds ratio (OR) = 3.07, P = 0.005] and total-C/HDL-C ratio > 5 (OR = 2.68; P = 0.03). This effect was significantly related to higher plasma TG concentrations at baseline among carriers of a LPL-null mutation. Compared to apo E3 and E4 variants, the apo E2 allele was associated with a better response to fenofibrate on all lipid parameter, especially among PPARalpha -L162V carriers, whereas the simultaneous presence of apo E2 and PPARalpha -L162V tended to improve fenofibrate response among LPL-P207L heterozygotes. Finally, the LPL-D9N and PPARgamma -P12A mutations did not affect fenofibrate lipid-lowering action. This study suggests that frequent genetic variations in genes encoding proteins involved in TG-rich lipoprotein metabolism could modulate the response to fenofibrate treatment, as defined in clinical guidelines.

Adult↗

PubMed2002

Primary causes of decreased mitochondrial oxygen consumption during metabolic depression in snail cells.

Cells isolated from the hepatopancreas of estivating snails (Helix aspersa) have strongly depressed mitochondrial respiration compared with controls. Mitochondrial respiration was divided into substrate oxidation (which produces the mitochondrial membrane potential) and ATP turnover and proton leak (which consume it). The activity of substrate oxidation (and probably ATP turnover) decreased, whereas the activity of proton leak remained constant in estivation. These primary changes resulted in a lower mitochondrial membrane potential in hepatopancreas cells from estivating compared with active snails, leading to secondary decreases in respiration to drive ATP turnover and proton leak. The respiration to drive ATP turnover and proton leak decreased in proportion to the overall decrease in mitochondrial respiration, so that the amount of ATP turned over per O2 consumed remained relatively constant and aerobic efficiency was maintained in this hypometabolic state. At least 75% of the total response of mitochondrial respiration to estivation was caused by primary changes in the kinetics of substrate oxidation, with only 25% or less of the response occurring through primary effects on ATP turnover.

Adenosine Triphosphate↗

PubMed2002

Going with the flow or life in the fast lane: contrasting mitochondrial responses to thermal change.

Temperature is one of the most important environmental factors affecting the physiology of animals. Seasonal fluctuations in temperature are of particular importance in aquatic ectotherms since their body temperature is in equilibrium with their environment. When an organism faces adverse environmental conditions, it can either remain active or enter into metabolic depression, adopting the strategy that maximises its fitness. Physiological responses to environmental stress occur at many different levels of organisation in an animal. Here, we focus on mitochondria, given their central importance in cellular energy metabolism. We contrast the thermal biology of skeletal muscle mitochondria from cold-active species with that of species that spend their winters in a metabolically depressed state. Specifically, we examine the modifications of mitochondrial properties during thermal/seasonal acclimation and examine mechanisms by which these modifications can arise. While compensatory responses to cold acclimation include increases in mitochondrial abundance, in the oxidative capacities of individual mitochondria and adjustments of ADP affinities, metabolic depression can reduce tissue levels of mitochondrial enzymes and mitochondrial proton leak rates.

Acclimatization↗