Abstract 16335: Metabolic Reprogramming From Glycolysis to Amino Acid Utilization in Cardiac Hif1 Alpha Deficient Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Manuel J Gómez ◽  
Teresa Albendea-Gomez ◽  
Beatriz Palacios ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Alternative Fuels ◽  
Cardiac Injury ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Structural Defects ◽  
Acid Oxidation ◽  
Cardiac Progenitors ◽  
Knock Out

Introduction: Hypoxia is an important environmental cue implicated in several physiopathological processes, including cardiac development. Several gain of function models described before indicate that HIF1 signaling needs to be tightly regulated to ensure proper heart formation. However, there is lack of consensus about the functional outcomes of cardiac HIF1 elimination. We have previously reported that HIF1alpha expression is spatiotemporally regulated along cardiogenesis, establishing metabolic territories in the embryonic myocardium and controlling a switch from glycolysis to fatty acid oxidation (FAO) essential for chamber formation and cardiomyocyte maturation. Objectives and Hypothesis: We aim to assess the consequences of cardiac deletion of HIF1alpha during heart development and identify the adaptations to HIF1 signaling loss. Based on the tight regulation of HIF1alpha expression during cardiogenesis, we anticipated significant alterations of cardiac metabolism as well as functional and structural defects in HIF1alpha mutants. Methods and Results: A new conditional Hif1alpha knock out was generated in NKX2.5 cardiac progenitors. By means of histology, electron microscopy and high-throughput genomics, proteomics and metabolomics, we found that deletion of Hif1alpha leads to impaired embryonic glycolysis without influencing cardiomyocyte size or proliferation and results in increased mitochondrial number, transient activation of amino acid response and upregulation of HIF2alpha and ATF4. HIF1alpha mutants display normal FAO metabolic profile and do not show cardiac dysfunction in the adulthood. Conclusions: We demonstrated that HIF1 signaling is dispensable for heart development and uncovered the metabolic flexibility of the mammalian embryonic myocardium, able to utilize alternative fuels to carbohydrates in contrast to other vertebrates like zebrafish. This data highlights the importance of HIF in cardiac metabolic programing and could explain the distinct proliferative and regenerative capacity of cardiomyocytes from different species in response to cardiac injury.

scholarly journals Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice

2019 ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Beatriz Palacios ◽  
Manuel J. Gomez ◽  
Elena Bonzon ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Cardiac Development ◽  
Building Blocks ◽  
Embryonic Heart ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Cardiac Growth ◽  
Cardiac Progenitors

AbstractRationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1α loss.ObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1α during heart development and identify the cardiac adaptations to HIF1 loss.Methods and ResultsHere, we used a conditional deletion model ofHif1ain NKX2.5+cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1α is dispensable for cardiac development.Hif1aloss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover,Hif1aloss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.ConclusionsOur data indicate that HIF1α is not required for normal cardiac development and suggest that additional mechanisms can compensateHif1aloss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

scholarly journals Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice

2020 ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Manuel J. Gomez ◽  
Teresa Albendea-Gomez ◽  
Beatriz Palacios ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Alternative Energy ◽  
Therapeutic Interventions ◽  
Acid Oxidation ◽  
Normal Fatty Acid ◽  
Loss Of Function ◽  
Cardiac Progenitors ◽  
Knock Out ◽  
The Impact

ABSTRACTHypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1α elimination in cardiac tissue. Here, we used a new conditional knock out of Hif1a in NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1α loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2α and ATF4 by E12.5. Hif1a mutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.

β-catenin-activated hepatocellular carcinomas are addicted to fatty acids

Gut ◽  
2018 ◽  
Vol 68 (2) ◽  
pp. 322-334 ◽  
Author(s):  
Nadia Senni ◽  
Mathilde Savall ◽  
David Cabrerizo Granados ◽  
Marie-Clotilde Alves-Guerra ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Target Therapy ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Primary Hepatocytes ◽  
Knock Out ◽  
Metabolic Fluxes ◽  
Hepatocellular Carcinomas ◽  
Knock Out Mice

ObjectivesCTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC.DesignWe used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.Resultsβ-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα.ConclusionsFAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.

scholarly journals p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1

PLoS Biology ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. e3001447
Author(s):  
Ayelén M. Santamans ◽  
Valle Montalvo-Romeral ◽  
Alfonso Mora ◽  
Juan Antonio Lopez ◽  
Francisco González-Romero ◽  
...  
Keyword(s):  
Heart Development ◽  
Glycogen Synthase ◽  
Maternal Diet ◽  
Cardiac Metabolism ◽  
Whole Body ◽  
Acid Oxidation ◽  
Metabolic Shift ◽  
Heart Metabolism ◽  
Metabolic Switch ◽  
Newborn Mice

During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.

scholarly journals Amino Acid Metabolism in Lupus

2021 ◽  
Vol 12 ◽  
Author(s):  
Michihito Kono ◽  
Nobuya Yoshida ◽  
George C. Tsokos
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Activation ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Cell Metabolism ◽  
Cell Subset ◽  
Metabolic Reprogramming ◽  
Acid Oxidation

T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases. Besides glycolysis and fatty acid oxidation/synthesis, amino acid metabolism is also crucial in T cell metabolism. It appears that each T cell subset favors a unique metabolic process and that metabolic reprogramming changes cell fate. Here, we review the mechanisms whereby amino acid transport and metabolism affects T cell activation, differentiation and function in T cells in the prototype systemic autoimmune disease systemic lupus erythematosus. New insights in amino acid handling by T cells should guide approaches to correct T cell abnormalities and disease pathology.

scholarly journals Gender differences in the regulation of amino acid metabolism

2003 ◽  
Vol 95 (3) ◽  
pp. 1259-1265 ◽  
Author(s):  
Linda S. Lamont ◽  
Arthur J. McCullough ◽  
Satish C. Kalhan
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Alternative Fuels ◽  
Acid Metabolism ◽  
Placebo Control ◽  
Acid Oxidation ◽  
Dietary Control ◽  
Adrenergic Blockade ◽  
Leucine Oxidation

Exercising men, compared with women, have a greater increase in leucine oxidation but not lysine rate of appearance. The cause for this sexual dimorphism is unknown; however, an inhibition of β-adrenoreceptor activity has previously been shown to mediate amino acid metabolism (Lamont LS, McCullough AJ, and Kalhan SC. Am J Physiol Endocrinol Metab 268: E910-E916, 1995; Lamont LS, Patel DG, and Kalhan SC. J Appl Physiol 67: 221-225, 1989). This study was a gender comparison of leucine and lysine kinetics during a β-adrenoreceptor blockade (β1,β2-blockade) and a placebo control by using a double-blind crossover protocol. Subjects exercised at 50% of their trial-specific maximal O2 consumption (1 h) after 7 days of dietary control. During exercise with β-blockade, men had an increased nonprotein respiratory exchange ratio ( P < 0.001), whereas women had an increased circulation of free fatty acids ( P < 0.001). The genders also displayed distinct differences in exercise amino acid kinetics. The men, but not the women, increased leucine oxidation ( P < 0.005) and lysine rate of appearance ( P < 0.009) when exercising during β-adrenergic blockade. This study indicates that during β-blockade, exercising men increase their need for amino acids (and carbohydrate) to fuel energy needs, whereas women increase their mobilization of fat, thereby requiring less alternative fuels such as carbohydrate and amino acids. Gender-specific fuel preferences during exercise are regulated by β-adrenergic-receptor activity. Substrate availability during exercise appears to modulate the amino acid oxidation differences between genders.

scholarly journals Amino Acid Transporters on the Guard of Cell Genome and Epigenome

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 125
Author(s):  
Uğur Kahya ◽  
Ayşe Sedef Köseer ◽  
Anna Dubrovska
Keyword(s):  
Amino Acid ◽  
Cancer Metabolism ◽  
Tumor Imaging ◽  
Redox Homeostasis ◽  
Amino Acid Uptake ◽  
Metabolic Reprogramming ◽  
Tumor Evolution ◽  
Amino Acid Transporters ◽  
Acid Uptake ◽  
Growth And Survival

Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.

scholarly journals Identifying Personalized Metabolic Signatures in Breast Cancer

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 20
Author(s):  
Priyanka Baloni ◽  
Wikum Dinalankara ◽  
John C. Earls ◽  
Theo A. Knijnenburg ◽  
Donald Geman ◽  
...  
Keyword(s):  
Drug Targets ◽  
Metabolic Networks ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Estrogen Metabolism ◽  
Acid Oxidation ◽  
A Genome ◽  
Context Specific

Cancer cells are adept at reprogramming energy metabolism, and the precise manifestation of this metabolic reprogramming exhibits heterogeneity across individuals (and from cell to cell). In this study, we analyzed the metabolic differences between interpersonal heterogeneous cancer phenotypes. We used divergence analysis on gene expression data of 1156 breast normal and tumor samples from The Cancer Genome Atlas (TCGA) and integrated this information with a genome-scale reconstruction of human metabolism to generate personalized, context-specific metabolic networks. Using this approach, we classified the samples into four distinct groups based on their metabolic profiles. Enrichment analysis of the subsystems indicated that amino acid metabolism, fatty acid oxidation, citric acid cycle, androgen and estrogen metabolism, and reactive oxygen species (ROS) detoxification distinguished these four groups. Additionally, we developed a workflow to identify potential drugs that can selectively target genes associated with the reactions of interest. MG-132 (a proteasome inhibitor) and OSU-03012 (a celecoxib derivative) were the top-ranking drugs identified from our analysis and known to have anti-tumor activity. Our approach has the potential to provide mechanistic insights into cancer-specific metabolic dependencies, ultimately enabling the identification of potential drug targets for each patient independently, contributing to a rational personalized medicine approach.

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