Integrated transcriptomic and translatomic exploration of the effect of betaine on lipid metabolic dysregulation induced by a high-fat diet
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE181077 | GEO | 2021/07/31
REPOSITORIES: GEO
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Project description:Purpose: Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with supplementation of CMA have not been fully elucidated. Conclusions: Our study demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.
2021-10-22 | GSE186165 | GEO
Project description:Obesity and associated increased prevalence of non-alcoholic fatty liver (NAFLD) disease is suggested to be positively modulated by a high protein (HP) diet in humans and rodents. The aim was to detect mechanisms by which a HP diet prevents hepatic lipid accumulation by means of transcriptomics. To study the acute and long term effect of a high protein ingestion on hepatic lipid accumulation under both low and high fat (HF) conditions, mice were fed combinations of high (35%) or low (10%) fat and high (50%) or normal (15%) protein diets for 1 or 12 weeks. Body composition, liver fat, VLDL production rate and gene expression were investigated. Differences in metabolic processes and functions in the liver were identified using gene set enrichment analysis on microarray data. Mice fed the HP diets developed less adiposity and decreased hepatic lipid accumulation due a combination of induced processes mainly involved in protein catabolism such as transamination, TCA cycle and oxidative phosphorylation. Feeding a HP diet can successfully prevent the development of NAFLD by using ingested energy for oxidation instead of storage. Wild type mice were fed combinations of high (35%) or low (10%) fat and high (50%) or normal (15%) protein diets for 1 or 12 weeks. After the diet intervention period, the animals were killed and liver tissue was removed. Total RNA was isolated, pooled and subjected to gene expression profiling.
2012-11-21 | E-GEOD-37897 | biostudies-arrayexpress
Project description:Nuclear receptors (NRs) play a crucial role in non-alcoholic fatty liver disease (NAFLD) and have been widely studied(Tran et al. 2018). However, the underlying mechanisms of NR regulation remain largely unclear. Here, we show that miR-20b plays a key role in modulating PPARα, a master regulator of nutrient metabolism and energy homeostasis in the pathogenesis of fatty liver(Wahli et al. 1995; Dongiovanni and Valenti 2013). Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in NAFLD patients, we revealed that miR-20b directly targets PPARα. The expression of miR-20b was remarkably upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of miR-20b dramatically increased hepatic lipid accumulation and plasma triglyceride levels. Furthermore, miR-20b significantly reduced fatty acid oxidation and mitochondrial biogenesis by directly targeting PPARα. Fenofibrate, a specific agonist of PPARα, lost its ability to ameliorate hepatic steatosis in miR-20b-introduced mice. Finally, inhibition of miR-20b dramatically increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Taken together, these results demonstrate that the novel miR-20b directly targets PPARα, plays a significant role in hepatic lipid metabolism, and presents an opportunity for the development of novel therapeutics for NAFLD.
2021-03-09 | GSE168484 | GEO
Project description:Obesity and associated increased prevalence of non-alcoholic fatty liver (NAFLD) disease is suggested to be positively modulated by a high protein (HP) diet in humans and rodents. The aim was to detect mechanisms by which a HP diet prevents hepatic lipid accumulation by means of transcriptomics. To study the acute and long term effect of a high protein ingestion on hepatic lipid accumulation under both low and high fat (HF) conditions, mice were fed combinations of high (35%) or low (10%) fat and high (50%) or normal (15%) protein diets for 1 or 12 weeks. Body composition, liver fat, VLDL production rate and gene expression were investigated. Differences in metabolic processes and functions in the liver were identified using gene set enrichment analysis on microarray data. Mice fed the HP diets developed less adiposity and decreased hepatic lipid accumulation due a combination of induced processes mainly involved in protein catabolism such as transamination, TCA cycle and oxidative phosphorylation. Feeding a HP diet can successfully prevent the development of NAFLD by using ingested energy for oxidation instead of storage.
2012-11-21 | GSE37897 | GEO
Project description:Background and aim: The Insulin-like growth factor (IGF) axis is increasingly suggested to be involved in fatty liver disease and progression. We identified IGFBP2 as transcriptional regulatory effect network in liver steatosis and conducted a translational approach of its role in liver pathology from mouse to human, and whether it is influenced by conventional clinical intervention that mitigate hepatic steatosis. Methods: Primary hepatocytes from either C57Bl6 controls, alb-SREBP-1c mice with moderate transgene induced hepatic lipid accumulation or aP2-SREBP-1c mice with massive ectopic hepatic lipid accumulation, were analyzed to identify regulatory networks based on differentially regulated hepatic gene expression. In a translational approach, serum of morbidly obese patients with and without diabetes and biopsy-proven NAFLD were used for ELISA-based validation of mouse data. Moreover, sera of patients undergoing intervention were analyzed and correlated to liver fat content. Results: Comparative knowledge-based transcriptome analysis identified IGFBP2 as top score regulatory effect network between moderate and aggravated fatty liver in mouse models. The reduced expression of IGFBP2 in aP2-SREPB-1c progressed fatty liver associated with Igfbp2 promoter hypermethylation. Reduced secretion of IGFBP2 from aP2-SREBP-1c hepatocytes was reflected in the circulation of the animals. In this phenotype, reductions of IGFBP2 were accompanied by reduced fatty acid oxidation and increased methyltransferase and SIRT activity. Physiologically, IGFBP2 has no direct impact on lipid metabolism but might modulate IGF1 action on de novo lipogenesis. In humans, IGFBP2 levels declined from non-obese men to morbidly obese men with NAFLD and NASH. In intervention study reductions in liver fat correlated with restoration of IGFBP2 serum levels to values found in healthy individuals in morbidly obese patients following bariatric surgery. Conclusion: In hepatic metabolism changes of IGFBP2 abundance is connected to lipid metabolism whereas changes in IGFBP2 secretion were directly reflected in the circulation. IGFBP2 serum concentration correlates with the degree of fatty liver, which seems to be related to plasticity of the adipose tissue. These data provide IGFBP2 as a potential non-invasive biomarker for fatty liver disease directly reflecting the degree of impaired liver function with the potential to indicate progressed fatty liver disease.
2020-06-29 | GSE139901 | GEO
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (steady-state model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the steady-state model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):e1003186.
Abstract:
Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000505
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000505 | BioModels
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (time-course model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the time-course model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):e1003186.
Abstract:
Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000506
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000506 | BioModels
Project description:The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism, especially with the accumulation of saturated fatty acids (FA). On the contrary, a diet enriched with n-3 polyunsaturated FA (n-3-PUFA) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either high-fat methionine choline-deficient diet (MCD) or standard chow (two groups fed MCD, two control groups, both with or without n-3-PUFA). Genome-wide transcriptome analysis of liver tissue was performed and revealed differences in liver mRNA transcriptomes after MCD as well as n-3-PUFA administration.
2023-12-14 | E-MTAB-13399 | biostudies-arrayexpress
Project description:The Dynamin-related GTPase, Drp1 (encoded by Dnm1l) plays a central role in mitochondrial fission and is requisite for numerous cellular processes however its role in oxidative metabolism remains unclear. Herein, we show that among human tissues, skeletal muscle exhibits the strongest correlations with the DNM1L gene. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and accumulation of intramyocellular lipids along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced Complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2, normalized Complex II activity and lipid oxidation in Drp1-KD myocytes. Drp1 appears critical in maintaining mitochondrial Complex II assembly and fatty acid oxidation, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle lipid metabolism which is of clinical significance in combatting metabolic diseases.
2024-01-26 | GSE248081 | GEO
Project description:Changes in intracellular CoA levels are known to contribute to the development of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D). The underlying genetic basis for the development and progression of these complex disorders, however, is still poorly understood. Due to their diverse susceptibility towards metabolic diseases, mouse inbred strains have been proven to serve as powerful tools in the identification of novel genetic factors that are fundamental in the pathophysiology of diabetes and NAFLD. Transcriptome analysis revealed the nucleoside diphosphate linked moiety X type motif Nudt19 as novel candidate gene responsible for NAFLD and T2D development. Knockdown (KD) of Nudt19 increased both mitochondrial and glycolytic ATP production rates in Hepa 1-6 cells. The enforced utilization of glutamine or fatty acids as energy substrate reduced uncoupled respiration in NT cells. This reduction was prevented upon knockdown of Nudt19. Furthermore, incubation with palmitate or oleate increased mitochondrial ATP production and uncoupled respiration in Nudt19 KD cells, but not in NT cells. The enhanced fatty acid oxidation in Nudt19 KD cells was accompanied by an increased abundance of Pdk4. This study describes for the first time Nudt19 as regulator of hepatic lipid metabolism and potential mediator of NAFLD and T2D development.
2022-04-11 | GSE186106 | GEO