scholarly journals mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Martinez Calejman ◽  
S. Trefely ◽  
S. W. Entwisle ◽  
A. Luciano ◽  
S. M. Jung ◽  
...  
Keyword(s):  
De Novo ◽  
Ppar Gamma ◽  
Akt Signaling ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Brown Adipocytes ◽  
Glucose And Lipid Metabolism ◽  
Citrate Lyase ◽  
Acetyl Coa Synthesis

Abstract mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.

scholarly journals mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (18) ◽  
pp. 25224-25240 ◽  
Author(s):  
Yaqing Chen ◽  
Jianchang Qian ◽  
Qun He ◽  
Hui Zhao ◽  
Lourdes Toral-Barza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

scholarly journals Author Correction: mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Martinez Calejman ◽  
S. Trefely ◽  
S. W. Entwisle ◽  
A. Luciano ◽  
S. M. Jung ◽  
...  
Keyword(s):  
De Novo ◽  
Akt Signaling ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Citrate Lyase ◽  
Brown Adipogenesis

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

2020 ◽  
Vol 21 (4) ◽  
pp. 1206 ◽  
Author(s):  
Luisa Siculella ◽  
Laura Giannotti ◽  
Mariangela Testini ◽  
Gabriele V. Gnoni ◽  
Fabrizio Damiano
Keyword(s):  
Lipid Accumulation ◽  
De Novo ◽  
Cell Model ◽  
Mrna Translation ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Entry Site ◽  
Alcoholic Fatty Liver ◽  
Citrate Lyase ◽  
Independent Mechanism

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5′ untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed.

scholarly journals Exploring the Role of ATP-Citrate Lyase in the Immune System

2021 ◽  
Vol 12 ◽  
Author(s):  
Monica Dominguez ◽  
Bernhard Brüne ◽  
Dmitry Namgaladze
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Histone Acetylation ◽  
Epigenetic Regulation ◽  
De Novo ◽  
Regulation Of Gene Expression ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

Studies over the past decade have revealed that metabolism profoundly influences immune responses. In particular, metabolism causes epigenetic regulation of gene expression, as a growing number of metabolic intermediates are substrates for histone post-translational modifications altering chromatin structure. One of these substrates is acetyl-coenzyme A (CoA), which donates an acetyl group for histone acetylation. Cytosolic acetyl-CoA is also a critical substrate for de novo synthesis of fatty acids and sterols necessary for rapid cellular growth. One of the main enzymes catalyzing cytosolic acetyl-CoA formation is ATP-citrate lyase (ACLY). In addition to its classical function in the provision of acetyl-CoA for de novo lipogenesis, ACLY contributes to epigenetic regulation through histone acetylation, which is increasingly appreciated. In this review we explore the current knowledge of ACLY and acetyl-CoA in mediating innate and adaptive immune responses. We focus on the role of ACLY in supporting de novo lipogenesis in immune cells as well as on its impact on epigenetic alterations. Moreover, we summarize alternative sources of acetyl-CoA and their contribution to metabolic and epigenetic regulation in cells of the immune system.

Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase

2021 ◽  
Author(s):  
Kenneth Verstraete ◽  
Koen H. G. Verschueren ◽  
Ann Dansercoer ◽  
Savvas N. Savvides
Keyword(s):  
Citrate Synthase ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase ◽  
Homology Module

Abstract 15978: Acetyl-coa Catalysis by Atp-citrate Lyase is Essential for Myofibroblast Differentiation and Persistence

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael P Lazaropoulos ◽  
Andrew A Gibb ◽  
Anh Huynh ◽  
Kathryn Wellen ◽  
John W Elrod
Keyword(s):  
Histone Acetylation ◽  
Transcriptional Activation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Metabolic Reprogramming ◽  
Myofibroblast Differentiation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Matrix Deposition ◽  
Citrate Lyase

A feature of heart failure (HF) is excessive extracellular matrix deposition and cardiac remodeling by a differentiated fibroblast population known as myofibroblasts. Identifying mechanisms of myofibroblast differentiation in cardiac fibrosis could yield novel therapeutic targets to delay or reverse HF. Recent evidence suggests that myofibroblast differentiation requires metabolic reprogramming for transcriptional activation of the myofibroblast gene program by chromatin-dependent mechanisms. We previously reported that inhibition of histone demethylation blocks myofibroblast formation, however, whether histone acetylation (e.g., H3K27ac, a prominent mark associated with gene transcription) is involved in fibroblast reprogramming remains unclear. ATP-citrate lyase (ACLY) synthesizes acetyl-CoA and therein supplies acetyl-CoA to the nucleus, where it is used as a substrate by histone acetyltransferases (HATs). To define the role of acetyl-CoA metabolism in myofibroblast differentiation, we stimulated differentiation in mouse embryonic fibroblasts (MEFs) and adult mouse cardiac fibroblasts (ACFs) with the pro-fibrotic agonist transforming growth factor β (TGFβ) and treated cells with a pharmacological inhibitor of ACLY. ACLY inhibition decreased myofibroblast gene expression in ACF and MEFs in TGFβ-stimulated myofibroblast differentiation, in addition to decreasing the population of αSMA positive MEFs. Genetic deletion of ACLY in MEFs recapitulated the results observed with pharmacological inhibition. Encouragingly, the ACLY inhibitor was sufficient to revert fully differentiated myofibroblasts under continuous TGFβ stimulation to a quiescent, non-fibrotic phenotype. Altogether, our data indicate that ACLY activity is necessary for myofibroblast differentiation and persistence. We hypothesize that ACLY-dependent acetyl-CoA synthesis is necessary for histone acetylation and transcriptional activation of the myofibroblast gene program. Currently, we are examining mechanisms of ACLY-dependent chromatin remodeling in fibroblasts and the in vivo relevance of this mechanism in mutant mice. In summary, ACLY is a potential target to reverse cardiac fibrosis and lessen HF.

scholarly journals Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects

2018 ◽  
Vol 315 (3) ◽  
pp. E386-E393 ◽  
Author(s):  
Corin O. Miller ◽  
Xiaodong Yang ◽  
Ku Lu ◽  
Jin Cao ◽  
Kithsiri Herath ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
De Novo ◽  
Liver Weight ◽  
De Novo Lipogenesis ◽  
Chow Diet ◽  
Fructose Metabolism ◽  
Metabolic Defects ◽  
Glucose And Lipid Metabolism ◽  
High Fructose ◽  
Altered Glucose

Fructose consumption in humans and animals has been linked to enhanced de novo lipogenesis, dyslipidemia, and insulin resistance. Hereditary deficiency of ketohexokinase (KHK), the first enzymatic step in fructose metabolism, leads to essential fructosuria in humans, characterized by elevated levels of blood and urinary fructose following fructose ingestion but is otherwise clinically benign. To address whether KHK deficiency is associated with altered glucose and lipid metabolism, a Khk knockout (KO) mouse line was generated and characterized. NMR spectroscopic analysis of plasma following ingestion of [6-13C] fructose revealed striking differences in biomarkers of fructose metabolism. Significantly elevated urine and plasma 13C-fructose levels were observed in Khk KO vs. wild-type (WT) control mice, as was reduced conversion of 13C-fructose into plasma 13C-glucose and 13C-lactate. In addition, the observation of significant levels of fructose-6-phosphate in skeletal muscle tissue of Khk KO, but not WT, mice suggests a potential mechanism, whereby fructose is metabolized via muscle hexokinase in the absence of KHK. Khk KO mice on a standard chow diet displayed no metabolic abnormalities with respect to ambient glucose, glucose tolerance, body weight, food intake, and circulating trigylcerides, β-hydroxybutyrate, and lactate. When placed on a high-fat and high-fructose (HF/HFruc) diet, Khk KO mice had markedly reduced liver weight, triglyceride levels, and insulin levels. Together, these results suggest that Khk KO mice may serve as a good model for essential fructosuria in humans and that inhibition of KHK offers the potential to protect from diet-induced hepatic steatosis and insulin resistance.

scholarly journals Quantifying carbon sources for de novo lipogenesis in wild-type and IRS-1 knockout brown adipocytes

2004 ◽  
Vol 45 (7) ◽  
pp. 1324-1332 ◽  
Author(s):  
Hyuntae Yoo ◽  
Gregory Stephanopoulos ◽  
Joanne K. Kelleher
Keyword(s):  
De Novo ◽  
Carbon Sources ◽  
De Novo Lipogenesis ◽  
Wild Type ◽  
Brown Adipocytes

scholarly journals RNA-seq reveals novel mechanistic targets of withaferin A in prostate cancer cells

2020 ◽  
Vol 41 (6) ◽  
pp. 778-789 ◽  
Author(s):  
Su-Hyeong Kim ◽  
Eun-Ryeong Hahm ◽  
Krishna B Singh ◽  
Sruti Shiva ◽  
Jacob Stewart-Ornstein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Rna Seq ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

Abstract Withaferin A (WA) is a promising phytochemical exhibiting in vitro and in vivo anticancer activities against prostate and other cancers, but the mechanism of its action is not fully understood. In this study, we performed RNA-seq analysis using 22Rv1 human prostate cancer cell line to identify mechanistic targets of WA. Kyoto Encyclopedia of Genes and Genomes pathway analysis of the differentially expressed genes showed most significant enrichment of genes associated with metabolism. These results were validated using LNCaP and 22Rv1 human prostate cancer cells and Hi-Myc transgenic mice as models. The intracellular levels of acetyl-CoA, total free fatty acids and neutral lipids were decreased significantly following WA treatment in both cells, which was accompanied by downregulation of mRNA (confirmed by quantitative reverse transcription-polymerase chain reaction) and protein levels of key fatty acid synthesis enzymes, including ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase and carnitine palmitoyltransferase 1A. Ectopic expression of c-Myc, but not constitutively active Akt, conferred a marked protection against WA-mediated suppression of acetyl-CoA carboxylase 1 and fatty acid synthase protein expression, and clonogenic cell survival. WA was a superior inhibitor of cell proliferation and fatty acid synthesis in comparison with known modulators of fatty acid metabolism including cerulenin and etomoxir. Intraperitoneal WA administration to Hi-Myc transgenic mice (0.1 mg/mouse, three times/week for 5 weeks) also resulted in a significant decrease in circulating levels of total free fatty acids and phospholipids, and expression of ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase and carnitine palmitoyltransferase 1A proteins in the prostate in vivo.

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