Correction: Hypoxic Regulation of Hand1 Controls the Fetal-Neonatal Switch in Cardiac Metabolism
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PROVIDER: S-EPMC3868671 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
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Project description:Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several "fetal" genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery.
| S-EPMC3782421 | biostudies-literature
Project description:Animals have evolved responses to low oxygen conditions to ensure their survival. Here, we have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial sugar metabolism enzyme. PQM-1 promotes hypoxic fat metabolism by maintaining the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity positively regulates fat transport to developing oocytes through vitellogenins under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, while pqm-1 mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.
| S-EPMC7532158 | biostudies-literature
Project description:IntroductionHypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury.ObjectivesIn this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs).MethodsImmunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of glucose transporter 5 (GLUT5), ketohexokinase (KHK)-A and KHK-C in miR-155-/- and miR-155wt CFs under normoxia or hypoxia. A microarray analysis of circRNAs was performed to identify circHIF1α. Then CoIP, RIP and mass spectrometry analysis were performed and identified SKIV2L2 (MTR4) and transformer 2 alpha (TRA2A), a member of the transformer 2 homolog family. pAd-SKIV2L2 was administrated after coronary artery ligation to investigate whether SKIV2L2 can provide a protective effect on the infarcted heart.ResultsWhen both miR-155-/- and miR-155wt CFs were exposed to hypoxia for 24 h, these two cells exhibited an increased glycolysis and decreased glycogen synthesis, and the expression of KHK-A and KHK-C, the central fructose-metabolizing enzyme, was upregulated. Mechanistically, miR-155 deletion in CFs enhanced SKIV2L2 expression and its interaction with TRA2A, which suppresses the alternative splicing of HIF1α pre-mRNA to form circHIF1α, and then decreased circHIF1α contributed to the activation of fructose metabolism through increasing the production of the KHK-C isoform. Finally, exogenous delivery of SKIV2L2 reduced myocardial damage in the infarcted heart.ConclusionIn this study, we demonstrated that miR-155 deletion facilitates the activation of fructose metabolism in hypoxic CFs through regulating alternative splicing of HIF1α pre-mRNA and thus circHIF1ɑ formation.
| S-EPMC9263644 | biostudies-literature
Project description:Fetal hemoglobin (HbF, α2γ2) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2β2) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in γ-globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.
| S-EPMC5889339 | biostudies-literature
Project description:Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.
| S-EPMC10561358 | biostudies-literature
Project description:Diverse sets of progenitors contribute to the development of the embryonic heart, but the mechanisms of their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation and identified transcription factors underpinning cell specification, identity and function. We discovered a concentration-dependent, fate determining function for the basic helix-loop-helix transcription factor HAND1 in mesodermal progenitors and uncovered its gene regulatory network. At low expression level, HAND1 directs differentiation towards multipotent juxta-cardiac field progenitors able to make cardiomyocytes and epicardial cells, whereas at high level it promotes the development of extraembryonic mesoderm. Importantly, HAND1-low progenitors can be propagated in their multipotent state. This detailed mechanistic insight into human development has the potential to accelerate the delivery of effective disease modelling, including for congenital heart disease, and cell therapy-based regenerative medicine.
| S-SCDT-10_1038-S44318-025-00409-0 | biostudies-other
Project description:Pathophysiologic mechanisms involved in neonatal hypoxic ischemic encephalopathy (HIE) are associated with complex changes of blood flow and metabolism. Therapeutic hypothermia (TH) is effective in reducing the extent of brain injury, but it remains uncertain how TH affects cerebral blood flow (CBF) and metabolism. Ten neonates undergoing TH for HIE and seventeen healthy controls were recruited from the NICU and the well baby nursery, respectively. A combination of frequency domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) systems was used to non-invasively measure cerebral hemodynamic and metabolic variables at the bedside. Results showed that cerebral oxygen metabolism (CMRO2i) and CBF indices (CBFi) in neonates with HIE during TH were significantly lower than post-TH and age-matched control values. Also, cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) were significantly higher in neonates with HIE during TH compared with age-matched control neonates. Post-TH CBV was significantly decreased compared with values during TH whereas SO2 remained unchanged after the therapy. Thus, FDNIRS-DCS can provide information complimentary to SO2 and can assess individual cerebral metabolic responses to TH. Combined FDNIRS-DCS parameters improve the understanding of the underlying physiology and have the potential to serve as bedside biomarkers of treatment response and optimization.
| S-EPMC3887346 | biostudies-literature
Project description:Accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and re-fed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.
| S-SCDT-10_15252-EMBR_202255981 | biostudies-other
Project description:Gestational hypoxia is a common stress to the fetal development and increases the risk of neonatal morbidity. The present study tested the hypothesis that fetal hypoxia results in heightened brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats via down-regulation of glucocorticoid receptor (GR) in the developing brain. Time-dated pregnant rats were exposed to hypoxia (10.5% O2) from days 15 to 21 of gestation. Brain HI injury was determined in day 10 pups. Maternal hypoxia resulted in asymmetric intrauterine growth restriction in the fetus. The brain HI injury was significantly increased in maternal hypoxia-treated pups as compared with the normoxia control in both males and females. Activation of brain GR by dexamethasone injection into the right lateral ventricle produced a concentration-dependent reduction of HI-induced brain injury in control pups. Maternal hypoxia significantly decreased GR mRNA and protein abundance in the fetal brain and neonatal hippocampus and abolished the dexamethasone-mediated neuroprotective effect in pup brains. This decreased GR expression was resulted from increased DNA methylation, decreased binding of transcription factors Egr-1 and Sp1 to GR gene exon 17 and 111 promoters, and reduced expression of GR exon 17 and 111 mRNA variants. The results demonstrate that gestational hypoxia causes epigenetic repression of GR gene expression in the developing brain resulting in the heightened brain vulnerability to HI injury in neonatal rats.
| S-EPMC3990589 | biostudies-literature
Project description:In the adult heart, regulation of fatty acid oxidation and mitochondrial genes is controlled by the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators. However, in response to pathological stressors such as hemodynamic load or ischemia, cardiac myocytes downregulate PGC-1 activity and fatty acid oxidation genes in preference for glucose metabolism pathways. Interestingly, despite the reduced PGC-1 activity, these pathological stressors are associated with mitochondrial biogenesis, at least initially. The transcription factors that regulate these changes in the setting of reduced PGC-1 are unknown, but Myc can regulate glucose metabolism and mitochondrial biogenesis during cell proliferation and tumorigenesis in cancer cells. Here we have demonstrated that Myc activation in the myocardium of adult mice increases glucose uptake and utilization, downregulates fatty acid oxidation by reducing PGC-1alpha levels, and induces mitochondrial biogenesis. Inactivation of Myc in the adult myocardium attenuated hypertrophic growth and decreased the expression of glycolytic and mitochondrial biogenesis genes in response to hemodynamic load. Surprisingly, the Myc-orchestrated metabolic alterations were associated with preserved cardiac function and improved recovery from ischemia. Our data suggest that Myc directly regulates glucose metabolism and mitochondrial biogenesis in cardiac myocytes and is an important regulator of energy metabolism in the heart in response to pathologic stress.
| S-EPMC2860901 | biostudies-literature