Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals

Liu, Xiaojing; Cooper, Daniel E.; Cluntun, Ahmad A.; Warmoes, Marc O.; Zhao, Steven; Reid, Michael A.; Liu, Juan; Lund, Peder J.; Lopes, Mariana; García, Benjamin A.; Wellen, Kathryn E.; Kirsch, David G.; Locasale, Jason W.

doi:10.1016/j.cell.2018.08.040

Cited by 310 publications

(246 citation statements)

References 62 publications

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“…The current analysis considers two circulating metabolites as sources for the TCA cycle: glucose and lactate. However, many other metabolites circulate and are exchanged between tissue and plasma, such as acetate, alanine and pyruvate (Hui et al, 2017; Liu et al, 2018). Therefore, to investigate the applicability of this model, circulating pyruvate is introduced (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

Liu

Dai

Cooper

et al. 2019

Preprint

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The carbon source for catabolism in vivo is a fundamental question in metabolic physiology. Limited by data and rigorous mathematical analysis, controversy exists over the nutritional sources for carbon in the tricarboxylic acid (TCA) cycle under physiological settings. Using isotope-labeling data in vivo across several experimental conditions, we construct multiple models of central carbon metabolism and develop methods based on metabolic flux analysis (MFA) to solve for the preferences of glucose, lactate, and other nutrients used in the TCA cycle across many tissues. We show that in nearly all circumstances, glucose contributes more than lactate as a nutrient source for the TCA cycle. This conclusion is verified in different animal strains from different studies, different administrations of 13C glucose, and is extended to multiple tissue types. Thus, this quantitative analysis of organismal metabolism defines the relative contributions of nutrient fluxes in physiology, provides a resource for analysis of in vivo isotope tracing data, and concludes that glucose is the major nutrient used for catabolism in mammals.

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Section: Resultsmentioning

confidence: 99%

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

Liu

Dai

Cooper

et al. 2019

Preprint

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“…However, basal levels of these transcripts displayed marked variability and often trended higher in untreated Aldh2 −/− ESCs (Figs E and B ). Because cells produce and may accumulate 4‐HNE, AcH, and other RAS endogenously (Liu et al., ; LoPachin et al., ), it is tempting to speculate that ESCs that lack ALDH2 may be vulnerable to differentiation by endogenous aldehydes and therefore do not respond as robustly to external RAS insults as stem cells containing functional ALDH2. In this manner, a ceiling effect is possible whereby administering additional RAS does not increase transcript levels of differentiation‐association genes beyond those levels that are induced by endogenous RAS in the absence of ALDH2‐dependent metabolism.…”

Section: Discussionmentioning

confidence: 99%

Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation

Serio

Gross

et al. 2019

Alcoholism Clin & Exp Res

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Background: Ethanol (EtOH) is a teratogen that causes severe birth defects, but the mechanisms by which EtOH affects stem cell differentiation are unclear. Our goal here is to examine the effects of EtOH and its metabolites, acetaldehyde (AcH) and acetate, on embryonic stem cell (ESC) differentiation.Methods: We designed ESC lines in which aldehyde dehydrogenase (ALDH2, NCBI#11669) and acyl-CoA synthetase short-chain family member 2 (ACSS2, NCBI#60525) were knocked out by CRISPR-Cas9 technology. We selected these genes because of their key roles in EtOH oxidation in order to dissect the effects of EtOH metabolism on differentiation.Results: By using kinetic assays, we confirmed that AcH is primarily oxidized by ALDH2 rather than ALDH1A2. We found increases in mRNAs of differentiation-associated genes (Hoxa1, Cyp26a1, and RARb2) upon EtOH treatment of WT and Acss2 À/À ESCs, but not Aldh2 À/À ESCs. The absence of ALDH2 reduced mRNAs of some pluripotency factors (Nanog, Sox2, and Klf4). Treatment of WT ESCs with AcH or 4-hydroxynonenal (4-HNE), another substrate of ALDH2, increased differentiation-associated transcripts compared to levels in untreated cells. mRNAs of genes involved in retinoic acid (RA) synthesis (Stra6 and Rdh10) were also increased by EtOH, AcH, and 4-HNE treatment. Retinoic acid receptor-c (RARc) is required for both EtOH-and AcH-mediated increases in Hoxa1 and Stra6, demonstrating the critical role of RA:RARc signaling in AcH-induced ESC differentiation.Conclusions: ACSS2 knockouts showed no changes in differentiation phenotype, while pluripotency-related transcripts were decreased in ALDH2 knockout ESCs. We demonstrate that AcH increases differentiation-associated mRNAs in ESCs via RARc.

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“…Nevertheless, direct observations of cellular metabolism in vivo at the level of single cells is difficult. Most conclusions about the nature of the tumor microenvironment have relied on in vitro models such as co-culture systems [13][14][15] or measurements of single variables such as immunohistochemical staining for the expression of a metabolic enzyme 16 .…”

Section: Introductionmentioning

confidence: 99%

Metabolic landscape of the tumor microenvironment

Xiao

Dai

Locasale

2019

Preprint

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The tumor milieu consists of numerous cell types with each cell existing in a different nutritional environment. However, a characterization of intratumoral metabolic heterogeneity at the single-cell level in human cancer is not established. Here, we develop a computational pipeline to analyze metabolic gene expression programs of single cells within human tumors. In two representative cancer types, melanoma and head and neck, we apply this algorithm to define the single-cell metabolic landscape of human tumors. We find that malignant cells in general have higher metabolic activity and higher metabolic variation than previously observed from studies of bulk tumor comparisons. Indeed, most of the observed metabolic variation of single tumor and normal cells were found to be inconsistent with comparisons with bulk tumor samples. Variation in the expression of mitochondrial programs is the major contributor to intratumoral metabolic heterogeneity. Surprisingly, the expression of both glycolytic and mitochondrial programs strongly correlates with hypoxia in almost all cell types. Immune and stromal cells could also be distinguished by their metabolic features.Taken together this analysis establishes a computational framework for characterizing metabolism using single cell expression data and defines principles of intratumoral metabolic heterogeneity.

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Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals

Cited by 310 publications

References 62 publications

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation

Metabolic landscape of the tumor microenvironment

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