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Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

ABSTRACT: ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE196853 | GEO | 2023/03/06

REPOSITORIES: GEO

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Hydroxycitrate promotes muscle regeneration and delays early mortality in mice

Project description:ATP-citrate lyase (ACLY) inhibitors have the potential of modulating central processes in protein, carbohydrate, and lipid metabolism, which can have relevant physiological consequences in aging and age-related diseases. Here, we show that hepatic phospho-active ACLY correlates with overweight and Model for End-stage Liver Disease score in humans. Wild-type mice treated chronically with the ACLY inhibitor potassium hydroxycitrate exhibited delayed early mortality. In AML12 hepatocyte cultures, the ACLY inhibitors potassium hydroxycitrate, SB-204990 and bempedoic acid fostered lipid accumulation, which was also observed in the liver of healthy-fed mice treated with potassium hydroxycitrate. Analysis of soleus tissue indicated that potassium hydroxycitrate produced a profound modulation of regenerative processes. In vivo, potassium hydroxycitrate modulated physical performance towards increases in maximal force and reduced endurance in healthy-fed mice, and produced improvements in locomotor function in mice exposed to cardiotoxin-induced muscle atrophy. Our findings implicate ACLY and ACLY inhibitors in relevant aspects of aging and muscle regeneration.

2024-05-16 | GSE232837 | GEO

Expression data by ACLY knockdown

Project description:De novo lipogenesis is activated in most cancers. Several lipogenic enzymes are implicated in oncogenesis and represent potential cancer therapeutic targets. RNA interference-mediated depletion of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression in a subset of human cancer cells. Here we demonstrate the molecular basis and potential biomarkers for ACLY-targeting therapy. First, suppression of cancer cell growth by ACLY depletion involves down-regulation of fatty acid elongase ELOVL6 at the transcriptional level. Lipid profiling revealed that ACLY depletion alters fatty acid composition in triglyceride; increased palmitate and decreased longer fatty acids, in accordance with ELOVL6 down-regulation. Second, ACLY depletion increases reactive oxygen species (ROS), whereas addition of antioxidant reduces ROS and attenuates the growth suppression. Third, ACLY depletion or ROS stimulation induce phosphorylation of AMP-activated protein kinase (AMPK), a sensor of energy and lipid metabolism. Analysis of various cancer cell lines revealed that the levels of AMPK phosphorylation (p-AMPK) correlate with the basal ROS levels, and that cancer cells with low basal p-AMPK (i.e., low basal ROS) levels are highly susceptible to ACLY depletion-mediated growth suppression. Finally, in clinical colon cancer tissues, p-AMPK levels are significantly decreased in aggressive tumors and correlate with the levels of 8-hydroxydeoxyguanosine, a hallmark of ROS stimulation. Together, these data suggest that ACLY inhibition suppresses cancer growth via palmitate-mediated lipotoxicity, and p-AMPK could be a predictive biomarker for its therapeutic outcome. Two cell lines are treated with ACLY siRNA. The samples include controls of each cell line.

2014-04-13 | E-GEOD-37243 | biostudies-arrayexpress

ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via Î±-ketoglutarate

Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while Î±-ketoglutarate levels decrease under hypoxia in control cells, Î±-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with Î±-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased Î±-ketoglutarate. These results reveal that ACC1/ACLY- Î±-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.

2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress

Expression data by ACLY knockdown

2014-04-13 | GSE37243 | GEO

Comparison of fire ant adult queens with different supergene genotypes (SB/SB and SB/Sb) and different age classes (1-day-old virgins, 11-day-old virgins and reproductive queens) from 2008 and 2009

2012-11-07 | GSE42062 | GEO

Effects of the absence of ACLY or Pdca1 on the transcriptome of T cells activation

Project description:T cell activation is known to require a metabolic shift towards glycolysis, triggered by TCR-engagement . To evaluate the role of ACLY or PDH in transcriptional reprogramming. T cell-specific Pdha1 knockout mouse by crossing Pdha1fl/fl mouse with CD4CreERT2 and CD4+ T cells from conditional knockout mice with T cell-specific ablation of Acly (CD4-Cre Aclyfl/fl).

2023-03-01 | GSE225875 | GEO

Comparison of fire ant adult queens with different supergene genotypes (SB/SB and SB/Sb) and different age classes (1-day-old virgins, 11-day-old virgins and reproductive queens) from 2008 and 2009

Project description:In the fire ant Solenopsis invicta, a colony queen number is determined by the founding queen's genotypes at the 13 Mb supergene with the non-recombining variants SB and Sb. Single-queen colonies are always headed by SB/SB queens while multiple-queens colonies are always headed by SB/Sb queens. The two variants of the supergene, SB and Sb are completely linked to the two alleles (B and b) of the gene Gp-9. SB/SB and SB/Sb queens differ in many physiological traits including their maturation rate and odor. To explain why SB/SB and SB/Sb queens have different odors, and why SB/SB virgins mature faster and accumulate more fat, we measured expression of ~6000 genes in virgin queens 1 and 11 days after eclosion and in reproductive queens. Keywords: fire ants, Solenopsis invicta, Supergene, queen, Gp-9, social form, maturation, fat storage, queen odor, cuticular hydrocarbon, worker discrimination, monogyne, polygyne, transposon, chemical signaling Six-condition experiment: 1-day-old SB/SB virgins, 1-day-old SB/Sb virgins, 11-day-old SB/SB virgins, 11-day-old SB/Sb virgins, SB/SB reproductive queens, SB/Sb reproductive queens. Biological replicates: 8 for 1-day-old SB/SB virgins and 1-day-old SB/Sb virgins that were collected in 2008; 8 for 1-day-old SB/SB virgins, 1-day-old SB/Sb virgins that were collected in 2009; 7 for 11-day-old SB/SB virgins and 11-day-old SB/Sb virgins that were collected in 2008; 8 for 11-day-old SB/SB virgins and 11-day-old SB/Sb virgins that were collected in 2009; 8 for SB/SB and SB/Sb reproductive queens (only collected in 2009). Samples were labeled with Cy3 and were compared to the same common reference RNA labeled with Cy5. Samples from 2008 were hybridized on the microarrays batch I and samples from 2009 were hybridized on the microarrays batch J.

2012-11-07 | E-GEOD-42062 | biostudies-arrayexpress

ChIP-Seq to identify the enrichement of histone acetylation on the promoter of FASN and ACLY in tumors with BCAA dietary interventions.

Project description:In order to provide more evidence to prove that BCAAs catabolism mediates the expressions of FASN and ACLY by altering histone acetylation in melanoma, ChIP-seq of xenografted A2058 tumors implanted in mice receiving BCAA dietary interventions (normal or high BCAA diet) was employed to idenfity the enrichment of histone acetylation on the promoter of FASN and ACLY.

2023-10-10 | GSE240663 | GEO

ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate

Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.

2015-12-10 | GSE61286 | GEO

Characterization of genome-wide transcriptional changes in liver and adipose tissues of ZDF (fa/fa) rats fed R-Î±-lipoic acid by next-generation sequencing

Project description:We report on the characterization of lipogenic tissue transcriptional networks that support physiological responses of obese rats to a lipid-lowering bioactive food compound, R-a-lipoic acid (LA). Nine-week old male ZDF (fa/fa) rats were fed a chow diet supplemented with 3 g LA per kg diet or pair fed for two weeks. At the end of the trial, high-quality RNA was extracted from the liver and epididymal fat and subjected to transcriptome analysis using RNA-Seq technology. Results showed a substantially higher number of differentially expressed genes (DEG, q â¤ 0.05 and absolute log2(fold change) â¥ 1) in liver (110 genes) vs. epididymal fat (10 genes). Most epididymal fat DEG were also differentially expressed in liver and shared directionality of change. Gene Ontology (GO) analysis of these transcripts revealed significant enrichment of GO categories related to immune response, stress response, lipid metabolism, and carboxylic acid metabolic processes. Of interest interferon-related genes involved in defense against microorganism and innate immune response were induced by LA. Lipid metabolism-related transcript changes observed in LA-fed animals included downregulation of lipogenic genes (Pnpla3, Pnpla5, Elov6, Acly, Gpam, and Aacs) and concomitant upregulation of short-, medium- and long-chain fatty acid metabolic processes (Acot1, Acot2, Acsf2, and Crat). Transcriptional changes were accompanied by the lowering of abdominal adiposity and blood triacylglycerol levels. We conclude that LA dietary supplementation induces prominent gene expression changes in liver in support of significant improvement of whole-body lipid status For each tissue and feed combination (liver/LA+, liver/LA-, adipose/LA+, and adipose/LA-) the transcriptome was sequenced with 4 biological replicates.

2014-01-08 | E-GEOD-50424 | biostudies-arrayexpress

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