Expression QTL Modules as Functional Components Underlying Higher-Order Phenotypes

Systems genetics studies often involve the mapping of numerous regulatory relations between genetic loci and expression traits. These regulatory relations form a bipartite network consisting of genetic loci and expression phenotypes. Modular network organizations may arise from the pleiotropic and polygenic regulation of gene expression. Here we analyzed the expression QTL (eQTL) networks derived from expression genetic data of yeast and mouse liver and found 65 and 98 modules respectively. Computer simulation result showed that such modules rarely occurred in randomized networks with the same number of nodes and edges and same degree distribution. We also found significant within-module functional coherence. The analysis of genetic overlaps and the evidences from biomedical literature have linked some eQTL modules to physiological phenotypes. Functional coherence within the eQTL modules and genetic overlaps between the modules and physiological phenotypes suggests that eQTL modules may act as functional units underlying the higher-order phenotypes

Role of the monocarboxylate transporter MCT1 in the uptake of lactate during active recovery

Purpose We assessed the role of monocarboxylate transporter 1 (MCT1) on lactate clearance during an active recovery after high-intensity exercise, by comparing genetic groups based on the T1470A (rs1049434) MCT1 polymorphism, whose influence on lactate transport has been proven. Methods Sixteen young male elite field hockey players participated in this study. All of them completed two 400 m maximal run tests performed on different days, followed by 40 min of active or passive recovery. Lactate samples were measured immediately after the tests, and at min 10, 20, 30 and 40 of the recoveries. Blood lactate decreases were calculated for each 10-min period. Participants were distributed into three groups according to the T1470A polymorphism (TT, TA and AA). Results TT group had a lower blood lactate decrease than AA group during the 10?20 min period of the active recovery (p = 0.018). This period had the highest blood lactate for the whole sample, significantly differing from the other periods (p ? 0.003). During the passive recovery, lactate declines were constant except for the 0?10-min period (p ? 0.003), suggesting that liver uptake is similar in all the genetic groups, and that the difference seen during the active recovery is mainly due to muscle lactate uptake. Conclusions These differences according to the polymorphic variant T1470A suggest that MCT1 affects the plasma lactate decrease during a crucial period of active recovery, where the maximal lactate amount is cleared (i.e. 10?20 min period)

Pyruvate: immunonutritional effects on neutrophil intracellular amino or alpha-keto acid profiles and reactive oxygen species production

For the first time the immunonutritional role of pyruvate on neutrophils (PMN), free α-keto and amino acid profiles, important reactive oxygen species (ROS) produced [superoxide anion (O2−), hydrogen peroxide (H2O2)] as well as released myeloperoxidase (MPO) acitivity has been investigated. Exogenous pyruvate significantly increased PMN pyruvate, α-ketoglutarate, asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, glycine and serine in a dose as well as duration of exposure dependent manner. Moreover, increases in O2− formation, H2O2-generation and MPO acitivity in parallel with intracellular pyruvate changes have also been detected. Regarding the interesting findings presented here we believe, that pyruvate fulfils considerably the criteria for a potent immunonutritional molecule in the regulation of the PMN dynamic α-keto and amino acid pools. Moreover it also plays an important role in parallel modulation of the granulocyte-dependent innate immune regulation. Although further research is necessary to clarify pyruvate’s sole therapeutical role in critically ill patients’ immunonutrition, the first scientific successes seem to be very promising

Monocarboxylate transporters, Past, present, and future

We review here the 14 members of the Monocarboxylate transporter family (MCTs), their relationship based on sequence homology. The range of substrates transported by different members of this family extends from the standard monocarboxylate metabolites, lactic and pyruvic acids, to aromatic amino acids and thyroid hormones. The family is denoted Solute Carrier Family 16, or SLC16, among 43 SLC families constituting more than 300 members, which are annotated regularly at the website http://www.bioparadigms.org/slc/intro.htm. MCTs classically transport metabolites across plasma membranes with direction controlled by proton and metabolite concentrations independently of energy input, but they may also function in subcellular membranes. Their regulation may be complex, and they are implicated in leukocyte-mediated immunity, hypoxia induced cellular responses, and partitioning of the energy supply in several tissues. We focus here on histologic evidence (involving human tissue where available) and the first four ‘classical’ members; but we do annotate all 14, and note several candidate or proven genetic diseases that have arisen from MCT mutations. The review progresses through the following sections: (1) MCT1-4: genetics, kinetics, and modulation; (2) Chaperonins and targeting cofactors; (3) Tissue distribution of MCTs; (4) Intercellular lactate/pyruvate shuttles; (5) Transcriptional and translational regulation of MCTs; (6) Properties of other MCTs; and (7) Subcellular localization of MCTs and some future considerations. Along the way we posit questions or suggestions for future research

Expression of the monocarboxylate transporter MCT1 in the adult human brain cortex.

Distribution of the monocarboxylate transporter MCT1 has been investigated in the cortex of normal adult human brain. Similarly to the glucose transporter GLUT1 55 kDa isoform, MCT1 was found to be strongly expressed on blood vessels in all cortical layers. In addition, laminar analysis revealed intense MCT1 expression in the neuropil of layer IV in primary auditory (AI) and visual (VI) areas, while this expression was more homogeneous in the non-primary auditory area STA. The cellular distribution shows that MCT1 is strongly expressed by glial cells often associated with blood vessels that were identified as astrocytes. The observed distribution of MCT1 supports the concept that, under certain circumstances, monocarboxylates could be provided as energy substrates to the adult human brain. Moreover, the distinct laminar pattern of MCT1 expression between primary and non-primary cortical areas may reflect different types of neuronal activity requiring adequate supply of specific energy substrates

Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: an immunohistochemical study

The monocarboxylate transporter MCT2 belongs to a large family of membrane proteins involved in the transport of lactate, pyruvate and ketone bodies. Although its expression in rodent brain has been well documented, the presence of MCT2 in the human brain has been questioned on the basis of low mRNA abundance. In this study, the distribution of the monocarboxylate transporter MCT2 has been investigated in the cortex of normal adult human brain using an immunohistochemical approach. Widespread neuropil staining in all cortical layers was observed by light microscopy. Such a distribution was very similar in three different cortical areas investigated. At the cellular level, the expression of MCT2 could be observed in a large number of neurons, in fibers both in grey and white matter, as well as in some astrocytes, mostly localized in layer I and in the white matter. Double staining experiments combined with confocal microscopy confirmed the neuronal expression but also suggested a preferential postsynaptic localization of synaptic MCT2 expression. A few astrocytes in the grey matter appeared to exhibit MCT2 labelling but at low levels. Electron microscopy revealed strong MCT2 expression at asymmetric synapses in the postsynaptic density and also within the spine head but not in the presynaptic terminal. These data not only demonstrate neuronal MCT2 expression in human, but since a portion of it exhibits a distinct synaptic localization, it further supports a putative role for MCT2 in adjustment of energy supply to levels of activity