Similarities and differences in lipidomics profiles among healthy monozygotic twin pairs.

Differences in genetic background and/or environmental exposure among individuals are expected to give rise to differences in measurable characteristics, or phenotypes. Consequently, genetic resemblance and similarities in environment should manifest as similarities in phenotypes. The metabolome reflects many of the system properties, and is therefore an important part of the phenotype. Nevertheless, it has not yet been examined to what extent individuals sharing part of their genome and/or environment indeed have similar metabolomes. Here we present the results of hierarchical clustering of blood plasma lipid profile data obtained by liquid chromatographymass spectrometry from 23 healthy, 18-year-old twin pairs, of which 21 pairs were monozygotic, and 8 of their siblings. For 13 monozygotic twin pairs, within-pair similarities in relative concentrations of the detected lipids were indeed larger than the similarities with any other study participant. We demonstrate such high coclustering to be unexpected on basis of chance. The similarities between dizygotic twins and between nontwin siblings, as well as between nonfamilial participants, were less pronounced. In a number of twin pairs, within-pair dissimilarity of lipid profiles positively correlated with increased blood plasma concentrations of C-reactive protein in one twin. In conclusion, this study demonstrates that in healthy individuals, the individual genetic background contributes to the blood plasma lipid profile. Furthermore, lipid profiling may prove useful in monitoring health status, for example, in the context of personalized medicine. © 2008 Mary Ann Liebert, Inc. Chemicals / CAS: C-Reactive Protein, 9007-41-4; Lipid

The Human Milk Oligosaccharide 2 '-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2 '-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2 '-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2 '-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2 '-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2 '-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2 '-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2 '-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2 '-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2 '-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2 '-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2 '-fucosyllactose to correct dysmetabolism and insulin resistance

The Human Milk Oligosaccharide 2 '-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2 '-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2 '-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2 '-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2 '-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2 '-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2 '-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2 '-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2 '-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2 '-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2 '-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2 '-fucosyllactose to correct dysmetabolism and insulin resistance.Proteomic

Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

Contains fulltext : 184147.pdf (publisher's version ) (Open Access)16 p

The onset of type 2 diabetes: Proposal for a multi-scale model

Background: Type 2 diabetes mellitus (T2D) is a common age-related disease, and is a major health concern, particularly in developed countries where the population is aging, including Europe. The multi-scale immune system simulator for the onset of type 2 diabetes (MISSION-T2D) is a European Union-funded project that aims to develop and validate an integrated, multilevel, and patient-specific model, incorporating genetic, metabolic, and nutritional data for the simulation and prediction of metabolic and inflammatory processes in the onset and progression of T2D. The project will ultimately provide a tool for diagnosis and clinical decision making that can estimate the risk of developing T2D and predict its progression in response to possible therapies. Recent data showed that T2D and its complications, specifically in the heart, kidney, retina, and feet, should be considered a systemic disease that is sustained by a pervasive, metabolically-driven state of inflammation. Accordingly, there is an urgent need (1) to understand the complex mechanisms underpinning the onset of this disease, and (2) to identify early patient-specific diagnostic parameters and related inflammatory indicators. Objective: We aim to accomplish this mission by setting up a multi-scale model to study the systemic interactions of the biological mechanisms involved in response to a variety of nutritional and metabolic stimuli and stressors. Methods: Specifically, we will be studying the biological mechanisms of immunological/inflammatory processes, energy intake/expenditure ratio, and cell cycle rate. The overall architecture of the model will exploit an already established immune system simulator as well as several discrete and continuous mathematical methods for modeling of the processes critically involved in the onset and progression of T2D. We aim to validate the predictions of our models using actual biological and clinical data. Results: This study was initiated in March 2013 and is expected to be completed by February 2016. Conclusions: MISSION-T2D aims to pave the way for translating validated multilevel immune-metabolic models into the clinical setting of T2D. This approach will eventually generate predictive biomarkers for this disease from the integration of clinical data with metabolic, nutritional, immune/inflammatory, genetic, and gut microbiota profiles. Eventually, it should prove possible to translate these into cost-effective and mobile-based diagnostic tools