ABSTRACT
Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl‐CoA subunits that are produced from a number of different pathways within the cell, most ...commonly carbohydrate catabolism. In addition to glucose which most commonly supplies carbon units for DNL, fructose is also a profoundly lipogenic substrate that can drive DNL, important when considering the increasing use of fructose in corn syrup as a sweetener. In the context of disease, DNL is thought to contribute to the pathogenesis of non‐alcoholic fatty liver disease, a common condition often associated with the metabolic syndrome and consequent insulin resistance. Whether DNL plays a significant role in the pathogenesis of insulin resistance is yet to be fully elucidated, but it may be that the prevalent products of this synthetic process induce some aspect of hepatic insulin resistance.
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•We review the current advantages of IM-MS spectrometry in lipidomics.•Collision Cross-Section (CCS) values enhance confidence in lipid identification.•IM separation coupled with ...fragmentation of precursor ions results in cleaner product ion spectra, allowing improved data interpretation.•IM-MS improves separation of isomeric lipids.
Lipids are a large and highly diverse family of biomolecules, which play essential structural, storage and signalling roles in cells and tissues. Although traditional mass spectrometry (MS) approaches used in lipidomics are highly sensitive and selective, lipid analysis remains challenging due to the chemical diversity of lipid structures, multiple isobaric species and incomplete separation using many forms of chromatography. Ion mobility (IM) separates ions in the gas phase based on their physicochemical properties. Addition of IM to the traditional lipidomic workflow both enhances separation of complex lipid mixtures, beneficial for lipid identification, and improves isomer resolution. Herein, we discuss the recent developments in IM-MS for lipidomics.
Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the ...precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.
In 1999 the journal Xenobiotica published a perspective article detailing the new concept of metabonomics and its application to toxicology. The approach was to apply analytical chemistry techniques, ...and in particular
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H NMR spectroscopy, to profile biofluids and tissues to assess the metabolic effects of xenobiotics. Metabonomics has been shown to be sensitive not only to organ specific toxicity but also provides information on the cells, tissues and mechanisms involved, as well as their interactions with the host's sex, age, diet and environment. This review assesses the impact of metabonomics on drug toxicology over the past twenty years and its future prospects. These applications include:
Pharmacometabonomics - the prediction of drug effects through the analysis of predose, biofluid metabolite profiles, which reflect both genetic and environmental influences on physiology.
The microbiomes role in toxicology - understanding how xenobiotics can be modified by the microbiome dramatically changing their impact on the host.
Development of expert systems for toxicity prediction.
Data fusion of different omics to better understand the underlying mechanisms of drug toxicity.
Metabonomics and exposome - understanding how multiple environmental toxicants might interact with the host organism to produce their overall phenotype. While there has been huge growth in the use of metabonomics within toxicology these applications are set to increase as the tools become more sensitive and robust, as well as the increased use of both experimental and in silico databases to aid prediction of toxicology.
The complex aetiology of type 2 diabetes makes effective screening, diagnosis and prognosis a substantial challenge for the physician. The rapidly developing area of metabolomics, which uses ...analytical techniques such as mass spectrometry and nuclear magnetic resonance, has emerged as a promising approach to identify biomarkers of diabetes and the insulin-resistant state that precedes overt pathology. Initial successes with metabolomic studies have indicated potential biomarkers for insulin resistance and for identifying people at risk of developing diabetes, with particular focus on aminoacids and lipid metabolism. These biomarkers will help to improve research and management of diabetes. In particular, several biomarkers identified could be used for early identification of diabetes risk. Furthermore, changes in selected biomarkers can indicate effectiveness of therapeutic interventions for type 2 diabetes and the metabolic syndrome. Indeed, there is much promise that branched-chain aminoacids might provide a screening biomarker for type 2 diabetes risk, allowing early dietary and exercise interventions to treat or even prevent the disease.
Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood ...outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.
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•Nutritional ketone bodies can promote the advantageous aspects to starvation ketosis•Nutritional ketosis alters the hierarchy of substrate competition for respiration in exercise•Ketosis increases metabolic flexibility during exercise, reducing glycolysis and increasing muscle fat oxidation•Improved performance during cycling time trial suggests ketosis during exercise may be beneficial for some athletes
Cox et al. show the metabolic benefit of ketone metabolism through the administration of a ketone ester-based drink to athletes during exercise. The physiological alterations achieved by acute nutritional ketosis may improve human physical performance in some athletes as indicated by initial endurance test results.
The early stages of nonalcoholic fatty liver disease (NAFLD) are characterized by the accumulation of fat in the liver (steatosis). This can lead to cell injury and inflammation resulting in ...nonalcoholic steatohepatitis (NASH). To determine whether lipid profiling of liver tissue can identify metabolic signatures associated with disease presence and severity, we explored liquid extraction surface analysis mass spectrometry (LESA–MS) as a novel sampling tool. Using LESA–MS, lipids were extracted directly from the surface of ultrathin slices of liver tissue prior to detection by high-resolution mass spectrometry (MS). An isotopically labeled internal standard mix was incorporated into the extraction solvent to attain semiquantitative data. Data mining and multivariate statistics were employed to evaluate the generated lipid profiles and abundances. With this approach, we were able to differentiate healthy and NAFLD liver in mouse and human tissue samples, finding several triacylglyceride (TAG) and free fatty acid (FFA) species to be significantly increased. Furthermore, LESA–MS was able to successfully differentiate between simple steatosis and more severe NASH, based on a set of short-chain TAGs and FFAs. We compared the data obtained by LESA–MS to that from liquid chromatography (LC)–MS and matrix-assisted laser desorption ionization MS. Advantages of LESA–MS include rapid analysis, minimal sample preparation, and high lipid coverage. Furthermore, since tissue slices are routinely used for diagnostics in clinical settings, LESA–MS is ideally placed to complement traditional histology. Overall LESA–MS is found to be a robust, fast, and discriminating approach for determining NAFLD presence and severity in clinical samples.
Background and Aims
Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control ...of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state‐of‐the‐art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC.
Approach and Results
Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis.
Conclusions
Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC.
Abstract
Background and Aims
The inflammatory bowel diseases IBD, Crohn’s disease and ulcerative colitis, are chronic, idiopathic gastrointestinal diseases. Although their precise aetiology is ...unknown, it is thought to involve a complex interaction between genetic predisposition and an abnormal host immune response to environmental exposures, probably microbial. Microbial dysbiosis has frequently been documented in IBD. Metabolomics the study of small molecular intermediates and end products of metabolism in biological samples provides a unique opportunity to characterize disease-associated metabolic changes and may be of particular use in quantifying gut microbial metabolism. Numerous metabolomic studies have been undertaken in IBD populations, identifying consistent alterations in a range of molecules across several biological matrices. This systematic review aims to summarize these findings.
Methods
A comprehensive, systematic search was carried out using Medline and Embase. All studies were reviewed by two authors independently using predefined exclusion criteria. Sixty-four relevant papers were assessed for quality and included in the review.
Results
Consistent metabolic perturbations were identified, including increases in levels of branched chain amino acids and lipid classes across stool, serum, plasma and tissue biopsy samples, and reduced levels of microbially modified metabolites in both urine such as hippurate and stool such as secondary bile acids samples.
Conclusions
This review provides a summary of metabolomic research in IBD to date, highlighting underlying themes of perturbed gut microbial metabolism and mammalian–microbial co-metabolism associated with disease status.
The endoplasmic reticulum unfolded protein response (UPRER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and ...influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPRER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Δ9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity.
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•Xbp-1s expression decreases total fat but increases oleic acid (OA) levels•OA supplementation increases lifespan in wild-type, but not xbp-1-s-expressing, worms•Increased lysosomal lipase and Δ9 desaturase activity may underlie these changes•OA supplementation is sufficient to protect animals against proteotoxicity
Imanikia et al. find that expressing the transcription factor xbp-1s in C. elegans remodels lipid metabolism, decreasing triglyceride and increasing oleic acid (OA) levels. Increased OA levels may involve the activity of lysosomal lipases and a Δ9 desaturase, and are sufficient to increase lifespan and protect animals from proteotoxicity.
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