Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging
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PROVIDER: PRJNA807590 | ENA |
REPOSITORIES: ENA
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Project description: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.
2023-03-06 | GSE196853 | GEO
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
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.
2014-04-13 | GSE37243 | GEO
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
2012-11-07 | GSE42062 | GEO
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. 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
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
Project description:ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in non-alcoholic fatty liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol lowering drug bempedoic acid (BPA), which has been shown to improve steatosis in mice. However, the acetyl-CoA synthetase ACSS2 can compensate for ACLY deficiency to support DNL, potentially complicating the targeting of ACLY. We show that hepatic loss of both ACLY and ACSS2 reduces DNL. Nevertheless, even when ACSS2 is suppressed by dietary or genetic means, we find that steatosis is counterintuitively exacerbated with hepatic ACLY deficiency in mice fed a Western diet (WD), linked to reduced expression of PPARa target genes controlling fatty acid oxidation. Conversely, BPA treatment increased fat catabolism and ameliorated WD-mediated lipid accumulation in both WT and liver ACLY knockout mice. Thus, hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation, and BPA improves steatosis independent of ACLY.
2024-08-01 | GSE247358 | GEO
Project description:Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with a potential anti-tumor phenotype in vivo, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells.
2021-06-30 | GSE169187 | GEO
Project description:To investigate the regulatory role of ACLY activation in EC functions, we treated HUVEC with ACLY inhibitor BMS-303141 before LPS stimuli. We then performed gene expression profiling analysis using data obtained from RNA-seq of HUVEC lysates.
2023-09-11 | GSE216178 | GEO
Project description:RNA-sequencing from Aclyf/f and Acly-/- preadipocytes generated from Aclyf/f mice and induced to differentiate to adipocytes.
2019-05-08 | GSE120504 | GEO