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Myocardial glycolysis and gene expression in the adult mouse heart

ABSTRACT: The heart uses primarily fatty acids and glucose for deriving energy. The majority of energy in the healthy heart derives from fat utilization, with the remainder coming primarily from the catabolism of glucose. Classical studies by Randle and colleagues describe the ability of the heart to switch its mode of utilization facilely and reversibly between glucose and fatty acids (myocardial glucose-fatty acid cycle or Randle cycle). However, under conditions of pathological stress, reliance of the heart on fatty acids decreases with a concomitant increase in reliance on glucose. It is unclear how such changes in metabolism regulate gene expression in the heart. Therefore, we examined how regulation of glycolysis at the level of phosphofructokinase modulates gene expression in the heart. We performed transcriptomic analysis of hearts from mice expressing either kinase-deficient phosphofructokinase 2 (GlycoLo) or phosphatase-deficient phosphofructokinase 2 (GlycoHi) under the control of the α-MHC promoter, which restricted expression of the transgenes to the heart. Phosphofructokinase 2 only controls the ability of the myocyte to regulate abundance of a single metabolite, F-2,6-P2, which is an allosteric regulator of the rate-limiting and committed step in glycolysis. Parallel radiometric and metabolomic studies showed the expected increases or decreases in glycolytic flux along with diametrically opposite changes in fat metabolism, which is consistent with the myocardial glucose-fatty acid cycle. Transcriptomic analyses showed remarkable changes in gene transcription in these hearts, which indicates that glucose and/or fatty acid metabolism is a driver of transcriptional programs in the heart. Furthermore, glycolytic activity coordinately regulated numerous genes in the heart, including genes important for cardiac remodeling as well as genes regulating gluconeogenic and ancillary biosynthetic pathway activity. These findings reveal that glycolytic rate is a critical regulator of gene expression in the heart and can coordinate programs that modulate cardiac metabolism, growth, and hypertrophy.

ORGANISM(S): Mus musculus

PROVIDER: GSE100176 | GEO | 2017/09/01

SECONDARY ACCESSION(S): PRJNA390925

REPOSITORIES: GEO

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Project description:Obesity is becoming increasingly widespread in developed countries, and is often associated with heart diseases and diabetes. Elevated levels of plasma free fatty acids are a biochemical hallmark of obesity. Unlike plants and bacteria, mammals cannot utilize fatty acids to generate glucose because of the lack of glyoxylate shunt enzymes. Instead, fatty acids are used for energy storage, and their utilization is regulated at multiple levels ranging from hormonal to metabolic ensuring that glucose is preferentially oxidized before fatty acids. Here we designed a synthetic gene-metabolic circuit to alter the intracellular signaling and metabolic pathways that control fatty acid metabolism. By introducing the Escherichia coli glyoxylate shunt enzymes, isocitrate lyase (AceA) and malate synthase (AceB), into the mitochondria of human hepatocytes, we demonstrated that fatty acid utilization is preferentially increased while glucose uptake is significantly reduced. This bacterial pathway diverts signal metabolites (citrate, acetyl-CoA, and malonyl-CoA) that inhibits fatty acid uptake and provides an additional channel for fatty acid utilization. Remarkably, the hepatocytes readily adapted to the synthetic circuit by a series of global transcriptional and post-translational changes in metabolic and signal transduction pathways that further advanced our design objective. This systems approach illustrates the logic of the synergistic interaction between metabolism and signal transduction. The ready acceptance of this non-native pathway by hepatocytes suggests the plasticity of liver metabolism and opens a possibility for the synthetic approach in regulating human metabolism. Experiment Overall Design: Wild type (WT) human hepatocyte HepG2 and HepG2 cells stably transfected with pBudaceAB (designated ACE), a vector containing isocitrate lyase and malate synthase from E. coli, were analyzed after 24hour exposure to palmitate. Cells were seeded at 70% confluency in 10cm plates with DMEM growth media augmented with 300uM palmitate. After 24hours, total RNA was harvested and hybrized to Affymetrix HG_U133A 2.0 GeneChips. Data was processed using GCOS 1.2 software. Experiment Overall Design: 2 WT biological replicates and 2 ACE biological replicates were analyzed. Experiment Overall Design:

Project description:Fatty acids comprise the primary energy source for the heart and are mainly taken up via hydrolysis of circulating triglyceride-rich lipoproteins. While most of the fatty acids entering the cardiomyocyte are oxidized, a small portion is involved in altering gene transcription to modulate cardiometabolic functions. So far, no in vivo model has been developed enabling study of the transcriptional effects of specific fatty acids in the intact heart. In the present study, mice were given a single oral dose of synthetic triglycerides composed of one single fatty acid. Hearts were collected 6h thereafter and used for whole genome gene expression profiling. Experiments were conducted in wild-type and PPARalpha-/- mice to allow exploration of the specific contribution of PPARalpha. It was found that: 1) linolenic acid (C18:3) had the most pronounced effect on cardiac gene expression. 2) The largest similarity in gene regulation was observed between linoleic acid (C18:2) and C18:3. Large similarity was also observed between the synthetic PPARalpha agonist Wy14643 and docosahexaenoic acid (C22:6). 3) Many genes were regulated by one particular treatment only. Genes regulated by one particular treatment showed large functional divergence. 4) The majority of genes responding to fatty acid treatment were regulated in a PPARalpha-dependent manner, emphasizing the importance of PPARalpha in mediating transcriptional regulation by fatty acids in the heart. 5) Several genes were robustly regulated by all or many of the fatty acids studied, mostly representing well-described targets of PPARs (e.g. Acot1, Angptl4, Ucp3). 6) Deletion and activation of PPARalpha had a major effect on expression of numerous genes involved in metabolism and immunity. Our analysis demonstrates the marked impact of dietary fatty acids on gene regulation in the heart via PPARalpha. To study the transcriptional effects of specific fatty acids in the intact heart, wild type and PPARalpha-/- mice were given a single oral dose of 4 synthetic triglycerides composed of one single fatty acid, as well as of the synthetic PPARalpha agonist Wy14,643. Hearts were collected 6h after gavag and used for whole genome gene expression profiling.

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Myocardial glycolysis and gene expression in the adult mouse heart

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