Lipidomic and metabolomic characterization of a genetically modified mouse model of the early stages of human type 1 diabetes pathogenesis.
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ABSTRACT:
SUBMITTER: Overgaard AJ
PROVIDER: S-EPMC4648980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose of reviewThe underlying factors triggering a cascade of autoimmune response that leads to the death of pancreatic beta cells and type 1 diabetes are to large extent unknown. Aberrations in the lipid balance have been suggested, either as factors directly contributing to autoimmunity or as a reflection of external factors, such as the diet or chemical exposure, which may increase the risk or even trigger the autoimmunity cascade.Recent findingsA small number of recent studies have investigated the blood lipidome before and after the onset of type 1 diabetes with a goal of identifying biomarkers of disease progression. Phosphatidylcholine levels in particular have been suggested to be reduced prior to the onset of type 1 diabetes. In this review, we approach this question through a quantitative analysis of the reported lipids. We quantify the extent of consensus between these heterogeneous studies, describe the overall lipidomic pattern that has been reported, and call for more independent replication of the findings that we highlight in this review.
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Project description:The research community is in a race to understand the molecular mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, to repurpose currently available antiviral drugs and to develop new therapies and vaccines against coronavirus disease 2019 (COVID-19). One major challenge in achieving these goals is the paucity of suitable preclinical animal models. Mice constitute ~70% of all the laboratory animal species used in biomedical research. Unfortunately, SARS-CoV-2 infects mice only if they have been genetically modified to express human ACE2. The inherent resistance of wild-type mice to SARS-CoV-2, combined with a wealth of genetic tools that are available only for modifying mice, offers a unique opportunity to create a versatile set of genetically engineered mouse models useful for COVID-19 research. We propose three broad categories of these models and more than two dozen designs that may be useful for SARS-CoV-2 research and for fighting COVID-19.
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Project description:Pancreatic cystic neoplasms (PCNs) are a highly prevalent disease of the pancreas. Among PCNs, Intraductal Papillary Mucinous Neoplasms (IPMNs) are common lesions that may progress from low-grade dysplasia (LGD) through high-grade dysplasia (HGD) to invasive cancer. Accurate discrimination of IPMN-associated neoplastic grade is an unmet clinical need. Targeted (semi)quantitative analysis of 100 metabolites and >1000 lipid species were performed on peri-operative pancreatic cyst fluid and pre-operative plasma from IPMN and serous cystic neoplasm (SCN) patients in a pancreas resection cohort (n = 35). Profiles were correlated against histological diagnosis and clinical parameters after correction for confounding factors. Integrated data modeling was used for group classification and selection of the best explanatory molecules. Over 1000 different compounds were identified in plasma and cyst fluid. IPMN profiles showed significant lipid pathway alterations compared to SCN. Integrated data modeling discriminated between IPMN and SCN with 100% accuracy and distinguished IPMN LGD or IPMN HGD and invasive cancer with up to 90.06% accuracy. Free fatty acids, ceramides, and triacylglycerol classes in plasma correlated with circulating levels of CA19-9, albumin and bilirubin. Integrated metabolomic and lipidomic analysis of plasma or cyst fluid can improve discrimination of IPMN from SCN and within PMNs predict the grade of dysplasia.
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Project description:Diseases of oxalate, such as nephrolithiasis and primary hyperoxaluria, affect a significant portion of the US population and have limited treatment options. Oxalobacter formigenes, an obligate oxalotrophic bacterium in the mammalian intestine, has generated great interest as a potential probiotic or therapeutic treatment for oxalate-related conditions due to its ability to degrade both exogenous (dietary) and endogenous (metabolic) oxalate, lowering the risk of hyperoxaluria/hyperoxalemia. Although all oxalotrophs degrade dietary oxalate, Oxalobacter formigenes is the only species shown to initiate intestinal oxalate secretion to draw upon endogenous, circulating oxalate for consumption. Evidence suggests that Oxalobacter regulates oxalate transport proteins in the intestinal epithelium using an unidentified secreted bioactive compound, but the mechanism of this function remains elusive. It is essential to gain an understanding of the biochemical relationship between Oxalobacter and the host intestinal epithelium for this microbe to progress as a potential remedy for oxalate diseases. This investigation includes the first profiling of the metabolome and lipidome of Oxalobacter formigenes, specifically the human strain HC1 and rat strain OxWR, the only two strains shown thus far to initiate net intestinal oxalate secretion across native gut epithelia. This study was performed using untargeted and targeted metabolomics and lipidomics methodologies utilizing ultra-high-performance liquid chromatography-mass spectrometry. We report our findings that the metabolic profiles of these strains, although largely conserved, show significant differences in their expression of many compounds. Several strain-specific features were also detected. Discussed are trends in the whole metabolic profile as well as in individual features, both identified and unidentified. Graphical abstract ᅟ.
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Project description:The prevalence of diabetes type 1 (T1D) in the world populations is continuously growing. Although treatment methods are improving, the diagnostic is still symptom-based and sometimes far after onset of the disease. In this context, the aim of the study was the search of new biomarkers of the disease in red blood cells (RBCs), until now unexplored. The metabolomic and the lipidomic profile of RBCs from T1D patients and matched healthy controls was determined by NMR spectroscopy, and different multivariate discrimination models were built to select the metabolites and lipids that change most significantly. Relevant metabolites were further confirmed by univariate statistical analysis. Robust separation in the metabolomic and lipidomic profiles of RBCs from patients and controls was confirmed by orthogonal projection on latent structure discriminant analysis (OPLS-DA), random forest analysis, and significance analysis of metabolites (SAM). The main changes were detected in the levels of amino acids, organic acids, creatine and phosphocreatine, lipid change length, and choline derivatives, demonstrating changes in glycolysis, BCAA metabolism, and phospholipid metabolism. Our study proves that robust differences exist in the metabolic and lipidomic profile of RBCs from T1D patients, in comparison with matched healthy individuals. Some changes were similar to alterations found already in RBCs of T2D patients, but others seemed to be specific for type 1 diabetes. Thus, many of the metabolic differences found could be biomarker candidates for an earlier diagnosis or monitoring of patients with T1D.
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Project description:Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals. From the disease etiology it is obvious that a tight regulation between lipid uptake, triacylglycerol synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent triacylglycerol deposition in the liver. In addition to triacylglycerol, also a tight control of other neutral lipid ester classes, i.e. cholesteryl esters and retinyl esters, is crucial for the maintenance of a healthy liver. Excessive cholesteryl ester accumulation is a hallmark of cholesteryl ester storage disease or Wolman disease, which is associated with premature death. The loss of hepatic vitamin A stores (retinyl ester stores of hepatic stellate cells) is incidental to the onset of liver fibrosis. Importantly, this more advanced stage of liver disease usually does not resolve but progresses to life threatening stages, i.e. liver cirrhosis and cancer. Therefore, understanding the enzymes and pathways that mobilize hepatic neutral lipid esters is crucial for the development of strategies and therapies to ameliorate pathophysiological conditions associated with derangements of hepatic neutral lipid ester stores, including liver steatosis, steatohepatitis, and fibrosis. This review highlights the physiological roles of enzymes governing the mobilization of neutral lipid esters at different sites in liver cells, including cytosolic lipid droplets, endoplasmic reticulum, and lysosomes. This article is part of a Special Issue entitled Molecular Basis of Disease: Animal models in liver disease.
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Project description:Xenotransplantation using porcine donors is rapidly approaching clinical applicability as an alternative therapy for treatment of many end-stage diseases including type 1 diabetes. Porcine neonatal islet cell clusters (NICC) have normalised blood sugar levels for relatively short periods in the preclinical diabetic rhesus model but have met with limited success in the stringent baboon model. Here we report that NICC from genetically modified (GM) pigs deleted for αGal and expressing the human complement regulators CD55 and CD59 can cure diabetes long-term in immunosuppressed baboons, with maximum graft survival exceeding 22 months. Five diabetic baboons were transplanted intraportally with 9,673 - 56,913 islet equivalents (IEQ) per kg recipient weight. Immunosuppression consisted of T cell depletion with an anti-CD2 mAb, tacrolimus for the first 4 months, and maintenance with belatacept and anti-CD154; no anti-inflammatory treatment or cytomegalovirus (CMV) prophylaxis/treatment was given. This protocol was well tolerated, with all recipients maintaining or gaining weight. Recipients became insulin-independent at a mean of 87 ± 43 days post-transplant and remained insulin-independent for 397 ± 174 days. Maximum graft survival was 675 days. Liver biopsies showed functional islets staining for all islet endocrine components, with no evidence of the inflammatory blood-mediated inflammatory reaction (IBMIR) and minimal leukocytic infiltration. The costimulation blockade-based immunosuppressive protocol prevented an anti-pig antibody response in all recipients. In conclusion, we demonstrate that genetic modification of the donor pig enables attenuation of early islet xenograft injury, and in conjunction with judicious immunosuppression provides excellent long-term function and graft survival in the diabetic baboon model.
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Project description:BackgroundSperm from C57BL/6 mice are difficult to cryopreserve and recover. Yet, the majority of genetically modified (GM) lines are maintained on this genetic background.Methodology/principal findingsReported here is the development of an easily implemented method that consistently yields fertilization rates of 70+/-5% with this strain. This six-fold increase is achieved by collecting sperm from the vas deferens and epididymis into a cryoprotective medium of 18% raffinose (w/v), 3% skim milk (w/v) and 477 microM monothioglycerol. The sperm suspension is loaded into 0.25 mL French straws and cooled at 37+/-1 degrees C/min before being plunged and then stored in LN(2). Subsequent to storage, the sperm are warmed at 2,232+/-162 degrees C/min and incubated in in vitro fertilization media for an hour prior to the addition of oocyte cumulus masses from superovulated females. Sperm from 735 GM mouse lines on 12 common genetic backgrounds including C57BL/6J, BALB/cJ, 129S1/SvImJ, FVB/NJ and NOD/ShiLtJ were cryopreserved and recovered. C57BL/6J and BALB/cByJ fertilization rates, using frozen sperm, were slightly reduced compared to rates involving fresh sperm; fertilization rates using fresh or frozen sperm were equivalent in all other lines. Developmental capacity of embryos produced using cryopreserved sperm was equivalent, or superior to, cryopreserved IVF-derived embryos.Conclusions/significanceCombined, these results demonstrate the broad applicability of our approach as an economical and efficient option for archiving and distributing mice.
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Project description:Some genetically modified (GM) plants have transgenes that confer tolerance to abiotic stressors. Meanwhile, other transgenes may interact with abiotic stressors, causing pleiotropic effects that will affect the plant physiology. Thus, physiological alteration might have an impact on the product safety. However, routine risk assessment (RA) analyses do not evaluate the response of GM plants exposed to different environmental conditions. Therefore, we here present a proteome profile of herbicide-tolerant maize, including the levels of phytohormones and related compounds, compared to its near-isogenic non-GM variety under drought and herbicide stresses. Twenty differentially abundant proteins were detected between GM and non-GM hybrids under different water deficiency conditions and herbicide sprays. Pathway enrichment analysis showed that most of these proteins are assigned to energetic/carbohydrate metabolic processes. Among phytohormones and related compounds, different levels of ABA, CA, JA, MeJA and SA were detected in the maize varieties and stress conditions analysed. In pathway and proteome analyses, environment was found to be the major source of variation followed by the genetic transformation factor. Nonetheless, differences were detected in the levels of JA, MeJA and CA and in the abundance of 11 proteins when comparing the GM plant and its non-GM near-isogenic variety under the same environmental conditions. Thus, these findings do support molecular studies in GM plants Risk Assessment analyses.
| S-EPMC5330488 | biostudies-literature
Project description:BackgroundThe risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation.MethodsMatched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used.ResultsAt 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1.ConclusionsInfants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk.FundingThe establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women's Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).
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