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Gene expression profiling in primary human skeletal myotubes with small molecule inhibitors of lipid accumulation

ABSTRACT: The development of insulin resistance is strongly associated with accumulation of intracellular lipid in tissues outside of adipose including skeletal muscle, liver and heart. In obese humans, intramyocellular lipid (IMCL) is negatively correlated with whole body insulin sensitivity. The skeletal myocyte imports fatty acids (FA) into the cell from circulating free fatty acids or lipoprotein particles such as VLDL, to support energy production. Once transported into the cell, FAs are oxidized for ATP production, used to build membranes, or stored as triglyceride. However, in the long term, increased delivery of fatty acids can exceed mitochondrial oxidative capacity and set the stage for a vicious cycle of cellular lipotoxicity. We have recently identified a novel small molecule inhibitor of lipid accumulation in skeletal mycytes termed SBI-477. Microarray transcriptomics was performed in primary human skeletal myotubes following oleate loading and treatment with SBI-477. This was also compared to A922500, a diacylglycerol transferase 1 (DGAT1) inhibitor. SBI-477 treatment reversed many of the transcriptomic effects of oleate loading in these cells but also produced a transcriptomic profile distinct from the DGAT1 inhibitor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77212 | GEO | 2016/08/08

SECONDARY ACCESSION(S): PRJNA309711

REPOSITORIES: GEO

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Gene expression profiling in primary human skeletal myotubes with small molecule inhibitors of lipid accumulation

Project description:The development of insulin resistance is strongly associated with accumulation of intracellular lipid in tissues outside of adipose including skeletal muscle, liver and heart. In obese humans, intramyocellular lipid (IMCL) is negatively correlated with whole body insulin sensitivity. The skeletal myocyte imports fatty acids (FA) into the cell from circulating free fatty acids or lipoprotein particles such as VLDL, to support energy production. Once transported into the cell, FAs are oxidized for ATP production, used to build membranes, or stored as triglyceride. However, in the long term, increased delivery of fatty acids can exceed mitochondrial oxidative capacity and set the stage for a vicious cycle of cellular lipotoxicity. We have recently identified a novel small molecule inhibitor of lipid accumulation in skeletal mycytes termed SBI-477. Microarray transcriptomics was performed in primary human skeletal myotubes following oleate loading and treatment with SBI-477. This was also compared to A922500, a diacylglycerol transferase 1 (DGAT1) inhibitor. SBI-477 treatment reversed many of the transcriptomic effects of oleate loading in these cells but also produced a transcriptomic profile distinct from the DGAT1 inhibitor. Microarray expression profiling was performed with total RNA isolated from differentiated primary human skeletal myotubes. These cells were treated with BSA (control for oleate), 100micromolar oleic acid, oleate + 10micromolar SBI-477 and oleate + 1micromolar A922500 for 24 hours. Oleate and test compound were added at the same time to the cells. Two biologic replicates for each condition were included.

2016-08-08 | E-GEOD-77212 | biostudies-arrayexpress

Expression data from differentiated 3T3-L1 pre-adipocytes.

Project description:Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme catalyzing the conversion of saturated fatty acids palmitate and stearate to monounsaturated fatty acids palmitoleate and oleate. During adipocyte differentiation, SCD expression increases concomitantly with several transcription factors and lipogenic genes. We used microarrays to examine gene expression in differentiated pre-adipocytes treated with and without an SCD inhibitor. On day 7 of adipocyte differentiation, total RNA was extracted from adipocytes. Two conditions were selected for comparison: total RNA extracted from adipocytes treated with DMSO (control) and or a SCD inhibitor.

2014-04-04 | E-GEOD-51905 | biostudies-arrayexpress

Transcriptomic Analysis on Lipid Loaded HepaRG Model for Steatosis Reveal the Influence on the Regulation of Drug Metabolizing Enzymes and Transporters

Project description:The present study was aimed to mimic steatosis in in-vitro HepaRG model and test the effect of lipid loading on drug metabolizing enzymes and transporters (DMET) in steatosis. HepaRG cells, differentiated in-house were exposed to mixture of saturated and unsaturated fatty acids, 0.5 mM palmitate and oleate (1:2) conjugated to BSA (0.02%) for 72h. Following the incubation, the model system was characterized using ORO staining for neutral lipids, tested for toxicity with WST-1 assay and triglyceride (TAG) accumulation was measured using TAG calorimetric assay. Increased lipid accumulation and 6-fold increase in TAG was observed (P < 0.05, n=4). The whole transcriptome was analyzed using RNA sequencing. Differentially expressed transcripts were identified upon FA treatment versus (vs.) control in HepaRG cell line (393 total transcripts, 89 up- and 304 downregulated). Lipid loading, led to significant down-regulation in gene expression levels of various DMET, nuclear receptors and transcription factors such as CYP3A4, 1A2, 2B6, 2C8, 2C9 and 2C19, along with this UGT1A9, UGT1A6, ABCB1, NR1I2 and HNF4α (P < 0.05, n=3). The accumulation of saturated and polyunsaturated fatty acids may selectively inhibit certain DME pathways.

2020-12-31 | GSE122151 | GEO

Expression data from differentiated 3T3-L1 pre-adipocytes.

2014-04-04 | GSE51905 | GEO

Free fatty acids and TNF-alpha in hepg2/c3a cell culture

Project description:free fatty acids(palmitate, oleate, linoleate) 0.7mM and tnf-alpha (0 20,100 ng/ml) were subjected to HepG2 cell line to study the cytotoxicity induced by these two factors Keywords: stress response

2006-08-04 | GSE5441 | GEO

Pleiotropic effects of the gene diacylglycerol-O-transferase 1 (DGAT1) polymorphism in the mammary gland tissue of dairy cows

Project description:The objective of this study was to determine the effect of the DGAT1 K232A polymorphism on the global mRNA expression pattern of genes in the mammary gland tissue of grazing dairy cows in order to get more insight into the effects of this polymorphism on the physiology of the mammary glandgland of grazing dairy cows. Microarray analysis was used to identify genes whose expression was affected by the DGAT1 polymorphism in the mammary gland biopsies of 9 A232A cows, 13 K232A cows, and 4 K232K cows. The Microarray Analysis of Variance (MAANOVA) and Factor Analysis for Multiple Testing method (FAMT) were used to associate the expression of the genes present on Affymettrix Bovine Genome Arrays with the DGAT1 polymorphism. The data was also analysed at the level of functional modules by gene set enrichment analysis. In this experimental setting, DGAT1 polymorphism did not modify milk yield and composition significantly, although changes occurred in the yields of C14:0, C16:1cis-9, and some long chain fatty acids in milk. The DGAT1 polymorphism resulted in 30 differentially expressed genes related to cell growth, proliferation and development, signalling, remodelling and immune system. At the functional level, the pathways most affected by DGAT1 polymorphism were related to lipid biosynthesis, which likely reflected counter mechanisms of mammary tissue to respond to changes in milk FA composition, signalling, as well as immune system responses.

2012-12-01 | GSE33720 | GEO

Feeding Angptl4-/- mice trans fat promotes foam cell formation in mesenteric lymph nodes without leading to ascites

Project description:ANGPTL4 regulates plasma triglyceride levels by inhibiting lipoprotein lipase. Inactivation of ANGPTL4 decreases plasma triglycerides and reduces risk of coronary artery disease. Unfortunately, targeting ANGPTL4 for the therapeutic management of dyslipidemia and atherosclerosis is hampered by the observation that mice and monkeys in which ANGPTL4 is inactivated exhibit lipid accumulation in mesenteric lymph nodes. In mice these pathological events exclusively unfold upon feeding a high saturated fatty acid diet and are followed by an ultimately lethal pro-inflammatory response and chylous ascites. Here we show that Angptl4-/- mice fed a diet rich in trans fatty acids develop numerous lipid-filled giant cells in their mesenteric lymph nodes, yet do not have elevated serum amyloid and haptoglobin, do not exhibit ascites, and survive, unlike Angptl4-/- mice fed a saturated fatty acid-rich diet. In RAW264.7 macrophages the saturated fatty acid palmitate markedly increases markers of inflammation and the unfolded protein response, whereas the trans-unsaturated elaidate and the cis-unsaturated oleate have the opposite effect. In conclusion, trans and saturated fatty acids have very distinct biological effects. Furthermore, lipid accumulation in mesenteric lymph nodes is uncoupled from activation of an acute-phase response and chylous ascites, suggesting that ANGPTL4 should not be fully dismissed as target for dyslipidemia.

2017-04-27 | GSE98303 | GEO

RNA sequencing of SiHa cells treated with oleic acid and radiation

Project description:The impact of obesity on radiation therapy outcome is unclear. Previously, we reported that obese patients with cervical cancer have superior outcomes following chemoradiation. We hypothesized that excess mono- and di- unsaturated fatty acids (uFFAs) enhance response to radiation. Here, using preclinical models, we show that uFFAs radiosensitize cervical cancer through a novel p53-dependent mechanism. UFFAs signaled through PPARgand p53 to promote lipid uptake, storage and metabolism after radiation. Stable isotope labeling confirmed that cervical cancer cells increase both catabolic and anabolic oleate metabolism in response to radiation, with associated increases in dependence on mitochondrial fatty acid oxidation for survival. In vivo, supplementation with exogenous oleate improved tumor growth delay in xenografts after radiation, an effect which could be partially mimicked in tumors from high fat diet induced obese mice. These results suggest that supplementation with uFFAs may improve tumor responses to radiation therapy, particularly in TP53 wild type tumors.

2022-10-04 | GSE214501 | GEO

Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [Hepa1-6 cells]

Project description:Scope: Consumption of industrial trans fatty acids unfavourably alters plasma cholesterol and has been linked to NAFLD. However, the mechanisms underlying these deleterious effects of trans fatty acids are unclear. Here, we aim to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods & Results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells showed that elaidate but not oleate or palmitate induced expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate was mediated by increased SREBP2 and dependent on SCAP, yet independent of LXR and UBXD8. Elaidate decreased intracellular free cholesterol levels and repressed the anti-cholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increased the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, ALT activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro via activation of the SCAP-SREBP axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

2019-08-27 | GSE136278 | GEO

Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [liver]

2019-08-27 | GSE136271 | GEO

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