Lipid metabolism is dysregulated in a mouse model of diabetes.
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ABSTRACT:
SUBMITTER: Furse S
PROVIDER: S-EPMC9156495 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Lipid metabolism is dysregulated in a mouse model of diabetes.
Metabolomics : Official journal of the Metabolomic Society 20220531 6
Much evidence for diabetes mellitus being associated with dysregulated lipid metabolism has been accrued from studies using blood plasma. However, the systemic dysregulation these results point to is not understood. This study used Lipid Traffic Analysis on data from a mouse model of diabetes to test the hypothesis that the systemic control of lipid metabolism differed in a model of diabetes. This provided eidence for changes in the systemic control of both triglyceride and phospholipid metaboli ...[more]
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Project description:BackgroundGestational diabetes is associated with increased risk of type 2 diabetes mellitus and cardiovascular disease for the mother in the decade after delivery. However, the molecular mechanisms that drive these effects are unknown. Recent studies in humans have shown that lipid metabolism is dysregulated before diagnosis of and during gestational diabetes and we have shown previously that lipid metabolism is also altered in obese female mice before, during and after pregnancy. These observations led us to the hypothesis that this persistent dysregulation reflects an altered control of lipid distribution throughout the organism.MethodsWe tested this in post-weaning (PW) dams using our established mouse model of obese GDM (high fat, high sugar, obesogenic diet) and an updated purpose-built computational tool for plotting the distribution of lipid variables throughout the maternal system (Lipid Traffic Analysis v2.3).ResultsThis network analysis showed that unlike hyperglycaemia, lipid distribution and traffic do not return to normal after pregnancy in obese mouse dams. A greater range of phosphatidylcholines was found throughout the lean compared to obese post-weaning dams. A range of triglycerides that were found in the hearts of lean post-weaning dams were only found in the livers of obese post-weaning dams and the abundance of odd-chain FA-containing lipids differed locally in the two groups. We have therefore shown that the control of lipid distribution changed for several metabolic pathways, with evidence for changes to the regulation of phospholipid biosynthesis and FA distribution, in a number of tissues.ConclusionsWe conclude that the control of lipid metabolism is altered following an obese pregnancy. These results support the hypothesis that obese dams that developed GDM maintain dysregulated lipid metabolism after pregnancy even when glycaemia returned to normal, and that these alterations could contribute to the increased risk of later type 2 diabetes and cardiovascular disease.
| S-EPMC8847647 | biostudies-literature
Project description:The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams' systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.
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Project description:ObjectiveTrisomy 21 is one of the most complex genetic perturbations compatible with postnatal survival. Dosage imbalance arising from the triplication of genes on human chromosome 21 (Hsa21) affects multiple organ systems. Much of Down syndrome (DS) research, however, has focused on addressing how aneuploidy dysregulates CNS function leading to cognitive deficit. Although obesity, diabetes, and associated sequelae such as fatty liver and dyslipidemia are well documented in the DS population, only limited studies have been conducted to determine how gene dosage imbalance affects whole-body metabolism. Here, we conduct a comprehensive and systematic analysis of key metabolic parameters across different physiological states in the Ts65Dn trisomic mouse model of DS.MethodsTs65Dn mice and euploid littermates were subjected to comprehensive metabolic phenotyping under basal (chow-fed) state and the pathophysiological state of obesity induced by a high-fat diet (HFD). RNA sequencing of liver, skeletal muscle, and two major fat depots were conducted to determine the impact of aneuploidy on tissue transcriptome. Pathway enrichments, gene-centrality, and key driver estimates were performed to provide insights into tissue autonomous and non-autonomous mechanisms contributing to the dysregulation of systemic metabolism.ResultsUnder the basal state, chow-fed Ts65Dn mice of both sexes had elevated locomotor activity and energy expenditure, reduced fasting serum cholesterol levels, and mild glucose intolerance. Sexually dimorphic deterioration in metabolic homeostasis became apparent when mice were challenged with a high-fat diet. While obese Ts65Dn mice of both sexes exhibited dyslipidemia, male mice also showed impaired systemic insulin sensitivity, reduced mitochondrial activity, and elevated fibrotic and inflammatory gene signatures in the liver and adipose tissue. Systems-level analysis highlighted conserved pathways and potential endocrine drivers of adipose-liver crosstalk that contribute to dysregulated glucose and lipid metabolism.ConclusionsA combined alteration in the expression of trisomic and disomic genes in peripheral tissues contribute to metabolic dysregulations in Ts65Dn mice. These data lay the groundwork for understanding the impact of aneuploidy on in vivo metabolism.
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Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients.Scope of reviewIn this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk.Major conclusionsAlterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.
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Project description:The efficacy of a traditional remedy was tested, based on an aqueous extract of Moringa oleifera Lam. seeds (MOES). Then, the small RNAs have been extracted from the MOES (mol-miR pool) and used for the treatments. Two tissues, in particular, were analyzed: the liver and the adipose tissue, both in vitro (HepG2 and 3T3-L1) and in vivo (C57BL/6J mice) models.
2019-01-19 | GSE125346 | GEO
Project description:Dyslipidaemia is a hallmark of chronic kidney disease (CKD). The severity of dyslipidaemia not only correlates with CKD stage but is also associated with CKD-associated cardiovascular disease and mortality. Understanding how lipids are dysregulated in CKD is, however, challenging owing to the incredible diversity of lipid structures. CKD-associated dyslipidaemia occurs as a consequence of complex interactions between genetic, environmental and kidney-specific factors, which to understand, requires an appreciation of perturbations in the underlying network of genes, proteins and lipids. Modern lipidomic technologies attempt to systematically identify and quantify lipid species from biological systems. The rapid development of a variety of analytical platforms based on mass spectrometry has enabled the identification of complex lipids at great precision and depth. Insights from lipidomics studies to date suggest that the overall architecture of free fatty acid partitioning between fatty acid oxidation and complex lipid fatty acid composition is an important driver of CKD progression. Available evidence suggests that CKD progression is associated with metabolic inflexibility, reflecting a diminished capacity to utilize free fatty acids through β-oxidation, and resulting in the diversion of accumulating fatty acids to complex lipids such as triglycerides. This effect is reversed with interventions that improve kidney health, suggesting that targeting of lipid abnormalities could be beneficial in preventing CKD progression.
| S-EPMC9146017 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) has a high mortality rate and early detection of HCC is crucial for the application of effective treatment strategies. HCC is typically caused by either viral hepatitis infection or by fatty liver disease. To diagnose and treat HCC it is necessary to elucidate the underlying molecular mechanisms. As a major cause for development of HCC is fatty liver disease, we here investigated anomalies in regulation of lipid metabolism in the liver. We applied a tailored network-based approach to identify signaling hubs associated with regulation of this part of metabolism. Using transcriptomics data of HCC patients, we identified significant dysregulated expressions of lipid-regulated genes, across many different lipid metabolic pathways. Our findings, however, show that viral hepatitis causes HCC by a distinct mechanism, less likely involving lipid anomalies. Based on our analysis we suggest signaling hub genes governing overall catabolic or anabolic pathways, as novel drug targets for treatment of HCC that involves lipid anomalies.
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Project description:These sequences support the following paper abstract: "Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.”
2025-03-10 | GSE262778 | GEO
Project description:BackgroundSensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism.MethodsIncuCyte S3 was used to explore the difference in the responsiveness of hematological tumor cells and solid tumor cells to GSK126. Transcriptome and metabolome of B16F10 cells after GSK126 treatment were analyzed and the distinct changes in the metabolic profile were revealed. Real-time quantitative PCR and western blot experiments were used to further verify the multi-omics data. ChIP-qPCR was performed to detected H3K27me3 enrichment of target genes. Finally, the anti-tumor effects of combining GSK126 and lipid metabolism drugs were observed with IncuCyte S3 platform, CCK-8 and animal model respectively.FindingsWe found that although the proliferative phenotype did not show strong difference upon treatment with GSK126, the transcriptome and metabolome changed profoundly. GSK126 treatment led to broad shifts in glucose, amino acid, and lipid metabolism. Lipid synthesis was strengthened manifested by the increasing abundance of unsaturated fatty acids. SCD1 and ELOVL2 were regulated by H3K27me3 at gene regulatory region, and upregulated by EZH2 knockdown and inhibitors. SCD1 knockdown increased cellular sensitivity to GSK126. Based on the findings above, the application of the combination with SCD1 inhibitor significantly attenuated the proliferation of cancer and increased the sensitivity to GSK126 by suppressing desaturation of fatty acids.InterpretationDysregulated lipid metabolism can blunt the sensitivity of cancer cells to GSK126. These characteristics shed light on the novel combination therapy strategies to combat tumor resistance.FundingNational Natural Science Foundation of China (No. 81672091, No.91749107 and No. 81972966).
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Project description:Carotenoids affect a rich variety of physiological functions in nature and are beneficial for human health. However, knowledge about their biological action and the consequences of their dietary accumulation in mammals is limited. Progress in this research field is limited by the expeditious metabolism of carotenoids in rodents and the confounding production of apocarotenoid signaling molecules. Herein, we established a mouse model lacking the enzymes responsible for carotenoid catabolism and apocarotenoid production, fed on either a β-carotene- or a zeaxanthin-enriched diet. Applying a genome wide microarray analysis, we assessed the effects of the parent carotenoids on the liver transcriptome. Our analysis documented changes in pathways for liver lipid metabolism and mitochondrial respiration. We biochemically defined these effects, and observed that β-carotene accumulation resulted in an elevation of liver triglycerides and liver cholesterol, while zeaxanthin accumulation increased serum cholesterol levels. We further show that carotenoids were predominantly transported within HDL particles in the serum of mice. Finally, we provide evidence that carotenoid accumulation influenced whole-body respiration and energy expenditure. Thus, we observed that accumulation of parent carotenoids interacts with lipid metabolism and that structurally related carotenoids display distinct biological functions in mammals.
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