Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 2 hours 10 min ago

Metabolomics and Biomarkers for Drug Discovery.

Thu, 01/02/2018 - 13:36
Related Articles Metabolomics and Biomarkers for Drug Discovery. Metabolites. 2018 Jan 31;8(1): Authors: Yeung PK Abstract Metabolomics and biomarkers are increasingly used in drug discovery and development, and are applied to personalized medicine. Progress in these research areas has increased our understanding of disease pathology and improved therapeutic strategies for many diseases with unmet challenges. Further advances will ultimately result in the development of better drugs and breakthrough therapies, which will benefit millions of patients suffering from chronic and life-threatening diseases worldwide. PMID: 29385049 [PubMed]

Mass Spectrometric Methodologies for Investigating the Metabolic Signatures of Parkinson's disease: Current Progress and Future Perspectives.

Thu, 01/02/2018 - 13:36
Related Articles Mass Spectrometric Methodologies for Investigating the Metabolic Signatures of Parkinson's disease: Current Progress and Future Perspectives. Anal Chem. 2018 Jan 31;: Authors: Gill EL, Koelmel JP, Yost RA, Okun MS, Vedam-Mai V, Garrett TJ Abstract Parkinson's disease (PD) is a neurodegenerative disorder resulting from the loss of dopaminergic neurons of the substantia nigra as well as degeneration of motor and non-motor basal ganglia circuitries. Typically known for classical motor deficits (tremor, rigidity, bradykinesia), early stages of the disease are associated with a large non-motor component (depression, anxiety, apathy, etc.). Currently there are no definitive biomarkers of PD, and the measurement of dopamine metabolites does not allow for detection of prodromal PD, nor does it aid in long-term monitoring of disease progression. Given that PD is increasingly recognized as complex and heterogeneous, involving several neurotransmitters and proteins, it is of importance that we advance interdisciplinary studies to further our knowledge of the molecular and cellular pathways that are affected in PD. This approach will yield useful biomarkers for early diagnosis and will ultimately result in the development of disease-modifying therapies. Here, we discuss pre-analytical factors associated with metabolomics studies, summarize current mass spectrometric methodologies used to evaluate the metabolic signature of PD, and provide future perspectives of the rapidly developing field of MS in the context of PD. PMID: 29384654 [PubMed - as supplied by publisher]

From genomics to metabolomics, moving toward an integrated strategy for the discovery of fungal secondary metabolites.

Thu, 01/02/2018 - 13:36
Related Articles From genomics to metabolomics, moving toward an integrated strategy for the discovery of fungal secondary metabolites. Nat Prod Rep. 2018 Jan 31;: Authors: Hautbergue T, Jamin EL, Debrauwer L, Puel O, Oswald IP Abstract Fungal secondary metabolites are defined by bioactive properties that ensure adaptation of the fungus to its environment. Although some of these natural products are promising sources of new lead compounds especially for the pharmaceutical industry, others pose risks to human and animal health. The identification of secondary metabolites is critical to assessing both the utility and risks of these compounds. Since fungi present biological specificities different from other microorganisms, this review covers the different strategies specifically used in fungal studies to perform this critical identification. Strategies focused on the direct detection of the secondary metabolites are firstly reported. Particularly, advances in high-throughput untargeted metabolomics have led to the generation of large datasets whose exploitation and interpretation generally require bioinformatics tools. Then, the genome-based methods used to study the entire fungal metabolic potential are reported. Transcriptomic and proteomic tools used in the discovery of fungal secondary metabolites are presented as links between genomic methods and metabolomic experiments. Finally, the influence of the culture environment on the synthesis of secondary metabolites by fungi is highlighted as a major factor to consider in research on fungal secondary metabolites. Through this review, we seek to emphasize that the discovery of natural products should integrate all of these valuable tools. Attention is also drawn to emerging technologies that will certainly revolutionize fungal research and to the use of computational tools that are necessary but whose results should be interpreted carefully. PMID: 29384544 [PubMed - as supplied by publisher]

Septic Shock Non-Survivors have Persistently Elevated Acylcarnitines Following Carnitine Supplementation.

Thu, 01/02/2018 - 13:36
Related Articles Septic Shock Non-Survivors have Persistently Elevated Acylcarnitines Following Carnitine Supplementation. Shock. 2017 Sep 20;: Authors: Puskarich MA, Evans CR, Karnovsky A, Das AK, Jones AE, Stringer KA Abstract INTRODUCTION: Sepsis-induced metabolic disturbances include hyperlactatemia, disruption of glycolysis, protein catabolism, and altered fatty acid metabolism. It may also lower serum L-carnitine which supports the use of L-carnitine supplementation as a treatment to ameliorate several of these metabolic consequences. METHODS: To further understand the association between L-carnitine-induced changes in serum acylcarnitines, fatty acid metabolism and survival, serum samples from (T0), 12 hours following completion (T24) of L-carnitine (n = 16) or placebo (n = 15) administration, and 48 hours (T48) after enrollment from patients with septic shock enrolled in a randomized control trial were assayed for acylcarnitines, free fatty acids and insulin. Data were analyzed comparing 1-year survivors and non-survivors within treatment groups. RESULTS: Mortality was 8/16 (50%) and 12/15 (80%) at one-year, for L-carnitine and placebo-treated patients, respectively. Free carnitine, C2, C3, and C8 acylcarnitines were higher among non-survivors at enrollment. L-carnitine treatment increased levels of all measured acylcarnitines; an effect that was sustained for at least 36 hours following completion of the infusion and was more prominent among non-survivors. Several fatty acids followed a similar, though less consistent pattern. Glucose, lactate, and insulin levels did not differ based on survival or treatment arm. CONCLUSIONS: In human patients with septic shock, L-carnitine supplementation increases a broad range of acylcarnitine concentrations that persist after cessation of infusion, demonstrating both immediate and sustained effects on the serum metabolome. Non-survivors demonstrate a distinct metabolic response to L-carnitine compared to survivors, which may indicate pre-existing or more profound metabolic derangement that constrains any beneficial response to treatment. PMID: 29384504 [PubMed - as supplied by publisher]

Next-generation metabolomics in lung cancer diagnosis, treatment and precision medicine: mini review.

Thu, 01/02/2018 - 13:36
Related Articles Next-generation metabolomics in lung cancer diagnosis, treatment and precision medicine: mini review. Oncotarget. 2017 Dec 29;8(70):115774-115786 Authors: Yu L, Li K, Zhang X Abstract Lung cancer is the leading cause of cancer-related death. Next-generation metabolomics is becoming a powerful emerging technology for studying the systems biology and chemistry of health and disease. This mini review summarized the main platforms of next-generation metabolomics and its main applications in lung cancer including early diagnosis, pathogenesis, classifications and precision medicine. The period covers between 2009 and August, 2017. The major issues and future directions of metabolomics in lung cancer research and clinical applications were also discussed. PMID: 29383200 [PubMed]

Metabolite identification in fecal microbiota transplantation mouse livers and combined proteomics with chronic unpredictive mild stress mouse livers.

Thu, 01/02/2018 - 13:36
Related Articles Metabolite identification in fecal microbiota transplantation mouse livers and combined proteomics with chronic unpredictive mild stress mouse livers. Transl Psychiatry. 2018 Jan 31;8(1):34 Authors: Li B, Guo K, Zeng L, Zeng B, Huo R, Luo Y, Wang H, Dong M, Zheng P, Zhou C, Chen J, Liu Y, Liu Z, Fang L, Wei H, Xie P Abstract Major depressive disorder (MDD) is a common mood disorder. Gut microbiota may be involved in the pathogenesis of depression via the microbe-gut-brain axis. Liver is vulnerable to exposure of bacterial products translocated from the gut via the portal vein and may be involved in the axis. In this study, germ-free mice underwent fecal microbiota transplantation from MDD patients and healthy controls. Behavioral tests verified the depression model. Metabolomics using gas chromatography-mass spectrometry, nuclear magnetic resonance, and liquid chromatography-mass spectrometry determined the influence of microbes on liver metabolism. With multivariate statistical analysis, 191 metabolites were distinguishable in MDD mice from control (CON) mice. Compared with CON mice, MDD mice showed lower levels for 106 metabolites and higher levels for 85 metabolites. These metabolites are associated with lipid and energy metabolism and oxidative stress. Combined analyses of significantly changed proteins in livers from another depression model induced by chronic unpredictive mild stress returned a high score for the Lipid Metabolism, Free Radical Scavenging, and Molecule Transports network, and canonical pathways were involved in energy metabolism and tryptophan degradation. The two mouse models of depression suggest that changes in liver metabolism might be involved in the pathogenesis of MDD. Conjoint analyses of fecal, serum, liver, and hippocampal metabolites from fecal microbiota transplantation mice suggested that aminoacyl-tRNA biosynthesis significantly changed and fecal metabolites showed a close relationship with the liver. These findings may help determine the biological mechanisms of depression and provide evidence about "depression microbes" impacting on liver metabolism. PMID: 29382834 [PubMed - in process]

Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria.

Thu, 01/02/2018 - 13:36
Related Articles Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria. Proc Natl Acad Sci U S A. 2018 Jan 30;: Authors: Su YB, Peng B, Li H, Cheng ZX, Zhang TT, Zhu JX, Li D, Li MY, Ye JZ, Du CC, Zhang S, Zhao XL, Yang MJ, Peng XX Abstract The emergence and ongoing spread of multidrug-resistant bacteria puts humans and other species at risk for potentially lethal infections. Thus, novel antibiotics or alternative approaches are needed to target drug-resistant bacteria, and metabolic modulation has been documented to improve antibiotic efficacy, but the relevant metabolic mechanisms require more studies. Here, we show that glutamate potentiates aminoglycoside antibiotics, resulting in improved elimination of antibiotic-resistant pathogens. When exploring the metabolic flux of glutamate, it was found that the enzymes that link the phosphoenolpyruvate (PEP)-pyruvate-AcCoA pathway to the TCA cycle were key players in this increased efficacy. Together, the PEP-pyruvate-AcCoA pathway and TCA cycle can be considered the pyruvate cycle (P cycle). Our results show that inhibition or gene depletion of the enzymes in the P cycle shut down the TCA cycle even in the presence of excess carbon sources, and that the P cycle operates routinely as a general mechanism for energy production and regulation in Escherichia coli and Edwardsiella tarda These findings address metabolic mechanisms of metabolite-induced potentiation and fundamental questions about bacterial biochemistry and energy metabolism. PMID: 29382755 [PubMed - as supplied by publisher]

Omics techniques and biobanks to find new biomarkers for the early detection of acute lymphoblastic leukemia in middle-income countries: a perspective from Mexico.

Thu, 01/02/2018 - 13:36
Related Articles Omics techniques and biobanks to find new biomarkers for the early detection of acute lymphoblastic leukemia in middle-income countries: a perspective from Mexico. Bol Med Hosp Infant Mex. 2017 May - Jun;74(3):227-232 Authors: Aguirre-Guillén WA, Angeles-Floriano T, López-Martínez B, Reyes-Morales H, Zlotnik A, Valle-Rios R Abstract Acute lymphoblastic leukemia (ALL) affects the quality of life of many children in the world and particularly in Mexico, where a high incidence has been reported. With a proper financial investment and with well-organized institutions caring for those patients, together with solid platforms to perform high-throughput analyses, we propose the creation of a Mexican repository system of serum and cells from bone marrow and blood samples derived from tissues of pediatric patients with ALL diagnosis. This resource, in combination with omics technologies, particularly proteomics and metabolomics, would allow longitudinal studies, offering an opportunity to design and apply personalized ALL treatments. Importantly, it would accelerate the development of translational science and will lead us to further discoveries, including the identification of new biomarkers for the early detection of leukemia. PMID: 29382491 [PubMed - in process]

Omics-based biomarkers: current status and potential use in the clinic.

Thu, 01/02/2018 - 13:36
Related Articles Omics-based biomarkers: current status and potential use in the clinic. Bol Med Hosp Infant Mex. 2017 May - Jun;74(3):219-226 Authors: Quezada H, Guzmán-Ortiz AL, Díaz-Sánchez H, Valle-Rios R, Aguirre-Hernández J Abstract In recent years, the use of high-throughput omics technologies has led to the rapid discovery of many candidate biomarkers. However, few of them have made the transition to the clinic. In this review, the promise of omics technologies to contribute to the process of biomarker development is described. An overview of the current state in this area is presented with examples of genomics, proteomics, transcriptomics, metabolomics and microbiomics biomarkers in the field of oncology, along with some proposed strategies to accelerate their validation and translation to improve the care of patients with neoplasms. The inherent complexity underlying neoplasms combined with the requirement of developing well-designed biomarker discovery processes based on omics technologies present a challenge for the effective development of biomarkers that may be useful in guiding therapies, addressing disease risks, and predicting clinical outcomes. PMID: 29382490 [PubMed - in process]

Synchronous characterization of carbohydrates and ginsenosides yields deeper insights into the processing chemistry of ginseng.

Thu, 01/02/2018 - 13:36
Related Articles Synchronous characterization of carbohydrates and ginsenosides yields deeper insights into the processing chemistry of ginseng. J Pharm Biomed Anal. 2017 Oct 25;145:59-70 Authors: Zhou SS, Xu J, Kong M, Yip KM, Xu JD, Shen H, Zhao ZZ, Li SL, Chen HB Abstract Carbohydrates and ginsenosides in ginseng are biologically interrelated. Their synchronous analysis is therefore essential in chemical research on ginseng to characterize its "holistic" quality. Here we investigated the processing chemistry of red ginseng (RG), a ginseng product processed by water-steaming, for which both carbohydrates and ginsenosides were qualitatively and quantitatively determined through multiple analytical techniques. Results revealed that the steam-processing not only qualitatively and quantitatively altered the ginsenosides but also affected the polymeric carbohydrates via changing their physiochemical parameters, i.e. water-solubility, molecular size, types and ratios of constituent monosaccharides. Potential mechanisms involved in the transformation of ginseng chemicals are proposed and discussed, including hydrolysis (deglycosylation, demalonylation, deacetylation), dehydration, polymerization, volatilization, reduction and the Maillard reaction. The study strengthens the research on the processing chemistry of RG, and therefore should be helpful for elucidating the scientific basis of RG preparation and application. PMID: 28651108 [PubMed - indexed for MEDLINE]

Metabolomic response to coffee consumption: Application to a three-stage clinical trial.

Wed, 31/01/2018 - 13:12
Metabolomic response to coffee consumption: Application to a three-stage clinical trial. J Intern Med. 2018 Jan 30;: Authors: Cornelis MC, Erlund I, Michelotti GA, Herder C, Westerhuis JA, Tuomilehto J Abstract BACKGROUND: Coffee is widely consumed and contains many bioactive compounds, any of which may impact pathways related to disease development. OBJECTIVE: To identify individual metabolite changes in response to coffee. METHODS: We profiled the metabolome of fasting serum samples collected from a previously reported single blinded, 3-stage clinical trial. 47 habitual coffee consumers refrained from drinking coffee for 1 month, consumed 4 cups of coffee/d in the second month and 8 cups/d in the third month. Samples collected after each coffee stage were subject to nontargeted metabolomic profiling using UPLC-ESI-MS/MS. 733 metabolites were included for univariate and multivariate analysis. RESULTS: A total of 115 metabolites were significantly associated with coffee intake (P<0.05 and Q<0.05). 82 were of known identity and mapped to one of 33 pre-defined biological pathways. We observed a significant enrichment of metabolite members of 5 pathways (P<0.05): (1) xanthine metabolism- includes caffeine metabolites, (2) benzoate metabolism- reflects polyphenol metabolite products of gut-microbiota metabolism, (3) steroid- novel but may reflect phytosterol content of coffee, (4) fatty acid metabolism (acyl choline)- novel link to coffee and (5) endocannabinoid- novel link to coffee. CONCLUSIONS: The novel metabolites and candidate pathways we have identified may provide new insight to the mechanisms by which coffee may be exerting its health effects. This article is protected by copyright. All rights reserved. PMID: 29381822 [PubMed - as supplied by publisher]

Tests for comparison of multiple endpoints with application to omics data.

Wed, 31/01/2018 - 13:12
Tests for comparison of multiple endpoints with application to omics data. Stat Appl Genet Mol Biol. 2018 Jan 30;: Authors: Marozzi M Abstract In biomedical research, multiple endpoints are commonly analyzed in "omics" fields like genomics, proteomics and metabolomics. Traditional methods designed for low-dimensional data either perform poorly or are not applicable when analyzing high-dimensional data whose dimension is generally similar to, or even much larger than, the number of subjects. The complex biochemical interplay between hundreds (or thousands) of endpoints is reflected by complex dependence relations. The aim of the paper is to propose tests that are very suitable for analyzing omics data because they do not require the normality assumption, are powerful also for small sample sizes, in the presence of complex dependence relations among endpoints, and when the number of endpoints is much larger than the number of subjects. Unbiasedness and consistency of the tests are proved and their size and power are assessed numerically. It is shown that the proposed approach based on the nonparametric combination of dependent interpoint distance tests is very effective. Applications to genomics and metabolomics are discussed. PMID: 29381476 [PubMed - as supplied by publisher]

Variations in diet cause alterations in microbiota and metabolites that follow changes in disease severity in a multiple sclerosis model.

Wed, 31/01/2018 - 13:12
Variations in diet cause alterations in microbiota and metabolites that follow changes in disease severity in a multiple sclerosis model. Benef Microbes. 2018 Jan 30;:1-20 Authors: Libbey JE, Sanchez JM, Doty DJ, Sim JT, Cusick MF, Cox JE, Fischer KF, Round JL, Fujinami RS Abstract Multiple sclerosis (MS) is a metabolically demanding disease involving immune-mediated destruction of myelin in the central nervous system. We previously demonstrated a significant alteration in disease course in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS due to diet. Based on the established crosstalk between metabolism and gut microbiota, we took an unbiased sampling of microbiota, in the stool, and metabolites, in the serum and stool, from mice (Mus musculus) on the two different diets, the Teklad global soy protein-free extruded rodent diet (irradiated diet) and the Teklad sterilisable rodent diet (autoclaved diet). Within the microbiota, the genus Lactobacillus was found to be inversely correlated with EAE severity. Therapeutic treatment with Lactobacillus paracasei resulted in a significant reduction in the incidence of disease, clinical scores and the amount of weight loss in EAE mice. Within the metabolites, we identified shifts in glycolysis and the tricarboxylic acid cycle that may explain the differences in disease severity between the different diets in EAE. This work begins to elucidate the relationship between diet, microbiota and metabolism in the EAE preclinical model of MS and identifies targets for further study with the goal to more specifically probe the complex metabolic interaction at play in EAE that may have translational relevance to MS patients. PMID: 29380645 [PubMed - as supplied by publisher]

Cancer immunotherapy in 2017: The breakthrough of the microbiota.

Wed, 31/01/2018 - 13:12
Cancer immunotherapy in 2017: The breakthrough of the microbiota. Nat Rev Immunol. 2018 Jan 30;18(2):87-88 Authors: Kroemer G, Zitvogel L PMID: 29379189 [PubMed - in process]

Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4.

Wed, 31/01/2018 - 13:12
Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4. J Immunol. 2018 Jan 29;: Authors: Nosaka T, Baba T, Tanabe Y, Sasaki S, Nishimura T, Imamura Y, Yurino H, Hashimoto S, Arita M, Nakamoto Y, Mukaida N Abstract Macrophages in lungs can be classified into two subpopulations, alveolar macrophages (AMs) and interstitial macrophages (IMs), which reside in the alveolar and interstitial spaces, respectively. Accumulating evidence indicates the involvement of IMs in lung metastasis, but the roles of AMs in lung metastasis still remain elusive. An i.v. injection of a mouse hepatocellular carcinoma (HCC) cell line, BNL, caused lung metastasis foci with infiltration of AMs and IMs. Comprehensive determination of arachidonic acid metabolite levels revealed increases in leukotrienes and PGs in lungs in this metastasis model. A 5-lipoxygenase (LOX) inhibitor but not a cyclooxygenase inhibitor reduced the numbers of metastatic foci, particularly those of a larger size. A major 5-LOX metabolite, LTB4, augmented in vitro cell proliferation of human HCC cell lines as well as BNL cells. Moreover, in this lung metastasis course, AMs exhibited higher expression levels of the 5-LOX and LTB4 than IMs. Consistently, 5-LOX-expressing AMs increased in the lungs of human HCC patients with lung metastasis, compared with those without lung metastasis. Furthermore, intratracheal clodronate liposome injection selectively depleted AMs but not IMs, together with reduced LTB4 content and metastatic foci numbers in this lung metastasis process. Finally, IMs in mouse metastatic foci produced CCL2, thereby recruiting blood-borne, CCR2-expressing AMs into lungs. Thus, AMs can be recruited under the guidance of IM-derived CCL2 into metastatic lungs and can eventually contribute to the progression of lung metastasis by providing a potent arachidonic acid-derived tumor growth promoting mediator, LTB4. PMID: 29378914 [PubMed - as supplied by publisher]

Disruption of OsSULTR3;3 reduces phytate and phosphorus concentrations and alters the metabolite profile in rice grains.

Wed, 31/01/2018 - 13:12
Related Articles Disruption of OsSULTR3;3 reduces phytate and phosphorus concentrations and alters the metabolite profile in rice grains. New Phytol. 2016 Aug;211(3):926-39 Authors: Zhao H, Frank T, Tan Y, Zhou C, Jabnoune M, Arpat AB, Cui H, Huang J, He Z, Poirier Y, Engel KH, Shu Q Abstract Two low phytic acid (lpa) mutants have been developed previously with the aim to improve the nutritional value of rice (Oryza sativa) grains. In the present study, the impacts of lpa mutations on grain composition and underlying molecular mechanisms were investigated. Comparative compositional analyses and metabolite profiling demonstrated that concentrations of both phytic acid (PA) and total phosphorus (P) were significantly reduced in lpa brown rice, accompanied by changes in other metabolites and increased concentrations of nutritionally relevant compounds. The lpa mutations modified the expression of a number of genes involved in PA metabolism, as well as in sulfate and phosphate homeostasis and metabolism. Map-based cloning and complementation identified the underlying lpa gene to be OsSULTR3;3. The promoter of OsSULTR3;3 is highly active in the vascular bundles of leaves, stems and seeds, and its protein is localized in the endoplasmic reticulum. No activity of OsSULTR3;3 was revealed for the transport of phosphate, sulfate, inositol or inositol 1,4,5 triphosphate by heterologous expression in either yeast or Xenopus oocytes. The findings reveal that OsSULTR3;3 plays an important role in grain metabolism, pointing to a new route to generate value-added grains in rice and other cereal crops. PMID: 27110682 [PubMed - indexed for MEDLINE]

metabolomics; +19 new citations

Tue, 30/01/2018 - 16:00
19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/01/30PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +19 new citations

Tue, 30/01/2018 - 13:00
19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/01/30PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis.

Mon, 29/01/2018 - 12:47
Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis. Biochim Biophys Acta. 2018 Jan 24;: Authors: Duta-Mare M, Sachdev V, Leopold C, Kolb D, Vujic N, Korbelius M, Hofer DC, Xia W, Huber K, Auer M, Gottschalk B, Magnes C, Graier WF, Prokesch A, Radovic B, Bogner-Strauss JG, Kratky D Abstract Lysosomal acid lipase (LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and triacylglycerols in lysosomes of multiple cells and tissues. Here, we explored the role of LAL in brown adipose tissue (BAT). LAL-deficient (Lal-/-) mice exhibit markedly reduced UCP1 expression in BAT, modified BAT morphology with accumulation of lysosomes, and mitochondrial dysfunction, consequently leading to regular hypothermic events in mice kept at room temperature. Cold exposure resulted in reduced lipid uptake into BAT, thereby aggravating dyslipidemia and causing life threatening hypothermia in Lal-/- mice. Linking LAL as a potential regulator of lipoprotein lipase activity, we found Angptl4 mRNA expression upregulated in BAT. Our data demonstrate that LAL is critical for shuttling fatty acids derived from circulating lipoproteins to BAT during cold exposure. We conclude that inhibited lysosomal lipid hydrolysis in BAT leads to impaired thermogenesis in Lal-/- mice. PMID: 29374543 [PubMed - as supplied by publisher]

Beyond genomics: understanding exposotypes through metabolomics.

Sun, 28/01/2018 - 12:15
Related Articles Beyond genomics: understanding exposotypes through metabolomics. Hum Genomics. 2018 Jan 26;12(1):4 Authors: Rattray NJW, Deziel NC, Wallach JD, Khan SA, Vasiliou V, Ioannidis JPA, Johnson CH Abstract BACKGROUND: Over the past 20 years, advances in genomic technology have enabled unparalleled access to the information contained within the human genome. However, the multiple genetic variants associated with various diseases typically account for only a small fraction of the disease risk. This may be due to the multifactorial nature of disease mechanisms, the strong impact of the environment, and the complexity of gene-environment interactions. Metabolomics is the quantification of small molecules produced by metabolic processes within a biological sample. Metabolomics datasets contain a wealth of information that reflect the disease state and are consequent to both genetic variation and environment. Thus, metabolomics is being widely adopted for epidemiologic research to identify disease risk traits. In this review, we discuss the evolution and challenges of metabolomics in epidemiologic research, particularly for assessing environmental exposures and providing insights into gene-environment interactions, and mechanism of biological impact. MAIN TEXT: Metabolomics can be used to measure the complex global modulating effect that an exposure event has on an individual phenotype. Combining information derived from all levels of protein synthesis and subsequent enzymatic action on metabolite production can reveal the individual exposotype. We discuss some of the methodological and statistical challenges in dealing with this type of high-dimensional data, such as the impact of study design, analytical biases, and biological variance. We show examples of disease risk inference from metabolic traits using metabolome-wide association studies. We also evaluate how these studies may drive precision medicine approaches, and pharmacogenomics, which have up to now been inefficient. Finally, we discuss how to promote transparency and open science to improve reproducibility and credibility in metabolomics. CONCLUSIONS: Comparison of exposotypes at the human population level may help understanding how environmental exposures affect biology at the systems level to determine cause, effect, and susceptibilities. Juxtaposition and integration of genomics and metabolomics information may offer additional insights. Clinical utility of this information for single individuals and populations has yet to be routinely demonstrated, but hopefully, recent advances to improve the robustness of large-scale metabolomics will facilitate clinical translation. PMID: 29373992 [PubMed - in process]

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