Maladies héréditaires du métabolisme et apports de la métabolomique

Les maladies héréditaires du métabolisme ou erreurs innées du métabolisme sont des maladies rares, mais très diverses, puisqu’on estime leur nombre à 500. Ce chiffre explique les difficultés rencontrées dans les diagnostics et les traitements. Ces maladies sont dues à des mutations de gènes codant pour des protéines impliquées dans les voies métaboliques. Les maladies héréditaires du métabolisme les plus fréquentes sont dues à l’accumulation de certains intermédiaires ou métabolites, ou correspondent à des déficits énergétiques, par exemple les déficits de la chaîne respiratoire, de l’oxydation des acides gras ou du métabolisme glucidique, ou encore à des perturbations du métabolisme de molécules complexes. Les biochimistes apportent une aide souvent essentielle au diagnostic et au suivi du traitement nutritionnel ou médicamenteux. Les diagnostics biochimiques reposent principalement sur des dosages de métabolites et des mesures d’activités enzymatiques, plus rarement sur la recherche de mutations. Une meilleure prise en charge des patients concernés impose une amélioration du dépistage néonatal et l’accroissement de l’efficacité de laboratoires de biochimie spécialisée. C’est pour cela que se développe la métabolomique, qui regroupe l’ensemble des approches technologiques permettant de doser un très grand nombre de métabolites. Parmi ces approches, la spectrométrie de masse en tandem constitue une méthode de choix.Both hope and illusion, the recent progress in biology has raised our expectations that one day it will be possible to introduce a biological sample into an apparatus which will then deliver in a few minutes thousands of qualitative and quantitative data concerning the genome, transcriptome, proteome and metabolome, thereby contributing to diagnosis and follow-up of diseases which are now difficult to identify. Such machines do not exist yet and, in any case, should be associated with the appropriate and adequate clinical work on the disease and with the patient. This « total » approach is of course being pushed by the recent decoding of the genomes of several species (genomics), the development of high throughput analysis of mRNAs (transcriptomics), and the efforts to identify the protein products on a large scale (proteomics). Wide sectors of medicine are waiting for the results of these new medium and high throughput technological approaches, for example, in order to identify early markers of diseases. The object of this article is to present a biochemist’s point of view on hereditary metabolic diseases (also referred to as inborn errors of metabolism), a field of medicine and research covering very diverse clinical and biochemical aspects. Significant advances will be made possible by improving the present methods of analysis of the metabolome which establishes a link between genotypes and phenotypes, an area now called metabolomics. The contribution of proteomics will be important as well but will still require some time

Uncoupling Protein 1 of Brown Adipocytes, the Only Uncoupler: A Historical Perspective

Uncoupling protein 1 (UCP1), is a unique mitochondrial membranous protein devoted to adaptive thermogenesis, a specialized function performed by brown adipocytes. Whereas the family of mitochondrial metabolite carriers comprises ∼40 members, UCP1 is the only memberable to translocate protons through the inner membrane of brown adipocyte mitochondria. By this process, UCP1 uncouples respiration from ATP synthesis and therefore provokes energy dissipation in the form of heat while, also stimulating high levels of fatty acid oxidation. UCP1 homologs were identified but they are biochemically and physiologically different from UCP1. Thirty five years after its identification, UCP1 still appears as a fascinating component. The recent renewal of the interest in human brown adipose tissue makes UCP1 as a potential target for strategies of treatment of metabolic disorders

Fundamental mechanisms of thermogenesis

Thermogenesis is an obligatory consequence of cellular metabolism and is identified as a unique property of homeotherms which have to maintain constant their body temperature in a cold environment. Physiologically, thermogenesis is made of basal metabolism, post-prandial thermogenesis, exercise-induced thermogenesis and adaptive thermogenesis induced by changes in the environmental temperature. Biochemically, thermogenesis comes from exergonic reactions from a loose coupling between endergonic and exergonic reactions. In cells, respiration and oxidations occur in mitochondria which ensure the coupling of oxidative energy to ATP synthesis. Identification of mitochondrial uncoupling proteins UCP allowed further understanding of the mechanism of coupling or uncoupling of respiration to ADP phosphorylation. Such data maybe of help in the understanding, or possible treatment, of certain types of obesity

White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma

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Deletion of UCP2 in iNOS Deficient Mice Reduces the Severity of the Disease during Experimental Autoimmune Encephalomyelitis

Uncoupling protein 2 is a member of the mitochondrial anion carrier family that is widely expressed in neurons and the immune cells of humans. Deletion of Ucp2 gene in mice pre-activates the immune system leading to higher resistance toward infection and to an increased susceptibility to develop chronic inflammatory diseases as previously exemplified with the Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for multiple sclerosis. Given that oxidative stress is enhanced in Ucp2−/− mice and that nitric oxide (NO) also plays a critical function in redox balance and in chronic inflammation, we generated mice deficient for both Ucp2 and iNos genes and submitted them to EAE. Mice lacking iNos gene exhibited the highest clinical score (3.4+/−0.5 p<0.05). Surprisingly, mice deficient for both genes developed milder disease with reduced immune cell infiltration, cytokines and ROS production as compared to iNos−/− mice

Innate immunity, assessed by plasma NO measurements, is not suppressed during the incubation fast in eiders

Immunity is hypothesized to share limited resources with other physiological functions and may mediate life history trade-offs, for example between reproduction and survival. However, vertebrate immune defense is a complex system that consists of three components. To date, no study has assessed all of these components for the same animal model and within a given situation. Previous studies have determined that the acquired immunity of common eiders (Somateria mollissima) is suppressed during incubation. The present paper aims to assess the innate immune response in fasting eiders in relation to their initial body condition. Innate immunity was assessed by measuring plasma nitric oxide (NO) levels, prior to and after injection of lipopolysaccharides (LPS), a method which is easily applicable to many wild animals. Body condition index and corticosterone levels were subsequently determined as indicators of body condition and stress level prior to LPS injection. The innate immune response in eiders did not vary significantly throughout the incubation period. The innate immune response of eiders did not vary significantly in relation to their initial body condition but decreased significantly when corticosterone levels increased. However, NO levels after LPS injection were significantly and positively related to initial body condition, while there was a significant negative relationship with plasma corticosterone levels. Our study suggests that female eiders preserve an effective innate immune response during incubation and this response might be partially determined by the initial body condition

Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities

The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe