Hepatic ACLY deficiency and bempedoic acid drive divergent responses to dietary lipid
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ABSTRACT:
PROVIDER: PRJNA1037152 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26735818_1.fastq.gz | Fastqsanger.gz | |||
| SRR26735818_2.fastq.gz | Fastqsanger.gz | |||
| SRR26735819_1.fastq.gz | Fastqsanger.gz | |||
| SRR26735819_2.fastq.gz | Fastqsanger.gz | |||
| SRR26735820_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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: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 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 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
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 the modulation of wound healing processes. In vivo, potassium hydroxycitrate modulated locomotor function toward increased wire hang performance and reduced rotarod performance in healthy-fed mice, and improved locomotion in mice exposed to cardiotoxin-induced muscle atrophy. Our findings implicate ACLY and ACLY inhibitors in different aspects of aging and muscle regeneration.
2024-05-16 | GSE232837 | 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:Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
2023-08-09 | GSE240406 | GEO
Project description:Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
2023-08-09 | GSE240409 | 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