Co-Administration of Trans-Resveratrol and L-Carnitine with a High-Fat and High-Carbohydrate Diet Modulates Liver Transcriptome in Obesity-Resistant DBA/2J Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE344237 | GEO | 2026/09/03
REPOSITORIES: GEO
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Project description:Despite this large body of evidence from clinical studies that an improvement of carnitine status has beneficial effects on metabolic health, serious safety concerns with carnitine supplementation have been raised based on the recent observation that longterm carnitine supplementation (from weaning to 5 mo of age) in a transgenic mouse model of atherosclerosis (Apoe-/- mice) promotes atherosclerosis through gut microbiota-dependent formation of trimethylamine (TMA) and subsequent hepatic conversion into proatherogenic TMA-N-oxide (TMAO) (Koeth et al., 2013). In addition, Lu et al. (2017) found that carnitine supplementation to normal mice for 3 mo induces oxidative stress, liver inflammation, liver lipid accumulation and even liver damage as well as hypercholesterinemia. However, it has to be mentioned that the carnitine dose administered to the mice in the abovementioned studies was extremely high. In order to address whether safety concerns are founded under conditions of longterm supplementation of a carnitine dose used in clinical trials, the present study aimed to investigate the effect of almost lifelong daily administration of a carnitine-supplemented diet (1 g/kg diet) to mice from weaning to 18 mo of age. Considering a body weight of 50 g for an adult mice and a daily feed intake of 5 g, the daily intake of this diet results in a daily carnitine dose of 100 mg/kg body weight which better reflects the dose used in clinical trials. In order to evaluate possible detrimental effects of carnitine supplementation, we investigated parameters of lipid metabolism and stress signaling pathways in the liver and performed a genome-wide transcriptome analysis of skeletal muscle in the mice at advanced age.
2018-09-19 | GSE120120 | GEO
Project description:We used Affymetrix microarrays to investigate gene expression changes in PBMNCs isolated from female and male pigs to determine significant modulatory effects that may have been induced by the intake of GE and (or) RES during 4 months in animals fed an atherogenic diet (AD) . The aim of this work was to determine whether the intake of low doses of a Grape Extract (GE; 1 g/70 Kg animal body weight) and (or) Resveratrol (RES; 18 mg/70 Kg animal body weight) exerted any modulatory effects, at the level of gene expression, in PBMNCs isolated from female and male pigs exposed to an atherogenic diet (AD) for 4 months. We isolated PBMNCs, and the corresponding total RNA, from 2 female and 2 male pigs for each group. Pure RNA was extracted from the PBMNCs for microarrays analyses (Affymetrix) and gene differential expression determined between the AD fed animals and control (CT) animals (to determine the effects of a high-fat consumption) and between the AD fed animals supplemented with GE and (or) RES and the animals fed the AD diet alone (to determine the effects of GE and (or) RES on the fat consumption). In addition, the effects of the consumption of GE and RES against a standard control diet (CT) were also determined. Differential gene expression: 1) AD vs CT (response to exposure to a high-fat diet); 2) AD-GE vs AD (modulatory effects of the intake of a grape extract on high-fat fed animals); 3) AD-GE-RES vs AD (modulatory effects of the intake of a resveratrol-enriched grape extract on high-fat fed animals); 4) AD-RES vs AD (modulatory effects of the intake of resveratrol on high-fat fed animals); 5) CT-GE-RES vs CT (modulatory effects of the intake of a resveratrol-enriched grape extract on animals fes a standard pig chow).
2011-07-22 | E-GEOD-30874 | biostudies-arrayexpress
Project description:Carnitine is a water soluble quaternary amine which is essential for normal function of all tissues. Besides improving performance characteristics of livestock animals carnitine has attracted scientific interest due to several health-related effects, like protection against neurodegeneration, mitochondrial decay, and oxidative stress, improvement of glucose tolerance and insulin sensitivity as well as reduction of hepatic steatosis. To gain insight into mechanisms through which carnitine exerts its beneficial metabolic effects, we fed piglets either a control or a carnitine supplemented diet, and analyzed the transcriptome in the liver, which plays a central role in whole body metabolism. Total RNA was isolated from pig liver samples for hybridization on Affymetrix GeneChip porcine genome arrays. Two RNA pools, each for the control group and the carnitine group, were used. Each RNA pool comprised RNA from 4 pigs.
2010-07-15 | E-GEOD-22931 | biostudies-arrayexpress
Project description:Carnitine is a water soluble quaternary amine which is essential for normal function of all tissues. Besides improving performance characteristics of livestock animals carnitine has attracted scientific interest due to several health-related effects, like protection against neurodegeneration, mitochondrial decay, and oxidative stress, improvement of glucose tolerance and insulin sensitivity as well as reduction of hepatic steatosis. To gain insight into mechanisms through which carnitine exerts its beneficial metabolic effects, we fed piglets either a control or a carnitine supplemented diet, and analyzed the transcriptome in the liver, which plays a central role in whole body metabolism.
2010-07-15 | GSE22931 | GEO
Project description:Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg-1 day-1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR. Keywords: aging intervention study
2008-06-10 | GSE11291 | GEO
Project description:Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg-1 day-1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR. Experiment Overall Design: Heart, neocortex tissue, and gastrocnemius muscle was collected from young and old mice at 5 and 30 months of age, respectively; mice were subjected to either a calorie restricted diet or a control diet supplemented with resveratrol
2008-06-18 | E-GEOD-11291 | biostudies-arrayexpress
Project description:We used Affymetrix microarrays to investigate gene expression changes in PBMNCs isolated from female and male pigs to determine significant modulatory effects that may have been induced by the intake of resveratrol during 9 months in high-fat fed animals . The aim of this work was to determine whether the intake of dietary levels of resveratrol (RES) exerted any modulatory effects, at the level of gene expression, in PBMNCs isolated from female and male pigs exposed to a H-F diet for 9 months. We first isolated PBMNCs, and the corresponding total RNA, from 5 female pigs and 5 male pigs at time 0 (beginning of the experiment) to determine basal gene expression levels and to compare sex differential gene expression. Animals designated to the control group were then fed a normal chow (5% beef tallow) for 9 months. Animals in the H-F diet were fed a chow with 20% of beef tallow and animals in the H-F diet supplemented with resveratrol were fed the 20% fat diet plus resveratrol (8 mg/Kg body weight per day). From each group, PBMNCs were isolated from 2 female and 2 male animals. Pure RNA was extracted from the PBMNCs for microarrays analyses (Affymetrix) and gene differential expression determined between the H-F fed animals and CT animals (to determine the effects of fat consumption) and between the H-F fed animals supplemented with RES and the H-F group (to determine the effects of RES on the fat consumption).
2010-08-08 | E-GEOD-23503 | biostudies-arrayexpress
Project description:Drug-induced steatosis and steatohepatitis manifest clinically as nonalcoholic fatty liver disease (NAFLD). Drugs associated with steatosis include valproic acid (VPA). VPA has been one of the most widely used antiepileptic drugs over the past 40 years. However, clinical follow-up studies have reported that more than 40% of patients who received VPA also developed fatty liver disease. Steatosis is a typical clinical effect of VPA treatment and is characterized by an abnormal accumulation of lipids in liver cells. The aim of this study is to investigate whether activation of the farnesoid X receptor (FXR) by obeticholic acid (OCA), which is an effective agent in the treatment of NAFLD, can also prevent VPA-induced steatosis. OCA is a synthetic bile acid derivative that potently activates FXR and the FXR-regulated pathways that maintain bile acid, lipid and glucose homeostasis. Female C57BL/6 mice were fed a standard chow diet or chow containing OCA (dose 250 mg/kg body weight) for four weeks. Each group was then divided into two sub-groups: one co-treated with VPA (dose 100 mg/kg body weight) and another treated with the same volume of H2O by oral gavage daily for an additional four weeks. Mice liver were isolated and RNA isolated for RNA-Seq.
2020-05-01 | GSE138810 | GEO
Project description:Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. We identified that depletion of KG sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. KG is required for the activity of KG-dependent dioxygenases (KGDDs), and prior work has shown that changes in KGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 KGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, KG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation. The increase in histone acetylation via the KG-carnitine axis promoted HR-mediated DNA repair through site-specific histone acetylation. Finally, we observed a positive correlation between TMLHE and histone acetylation in patient samples and found that high TMLHE or acetylcarnitine correlates with worse progression free survival in patients treated with DNA damaging agents. This study demonstrates for the first time KG affects histone acetylation and provides a mechanism of HR-proficiency via carnitine synthesis. Moreover, these data provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.
2026-03-30 | PXD060690 | Pride
Project description:Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high-dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.
2025-01-07 | GSE285121 | GEO