Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease

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dc.contributor.advisorEssop, Mohammed Faadielen_ZA
dc.contributor.authorMakaula, Siyanda S Sen_ZA
dc.date.accessioned2014-07-29T09:07:09Z
dc.date.available2014-07-29T09:07:09Z
dc.date.issued2006en_ZA
dc.descriptionIncludes bibliographical references (leaves 130-173).
dc.description.abstractMetabolic remodeling is thought to be an important contributor towards the development of various cardiac pathophysiologic conditions. Therefore, studies attempting to delineate undenying mechanisms driving cardiac metabolic remodeling represent an important initiative toward the development of novel therapeutic interventions. To further investigate the role of metabolic substrate switches in the heart, we focused on a pivotal, rate-limiting step of cardiac fatty acid metabolism i.e. an upstream modulator of long-chain fatty acid importation into the mitochondrion. In the heart, long-chain fatty acids are transported into the mitochondrion by the rate-limiting enzyme, carnitine palmitoyl transferase 1 (CPT1). CPT1 is potently inhibited by malonyl-CoA, the product of the acetylCoA carboxylation reaction that is catalyzed by acetyl-CoA carboxylase (ACC). Recent studies have demonstrated that metabolic fuels such as fatty acids and glucose can function as signaling ligands, directing transcriptional regulation of numerous metabolic genes. However, transcriptional mechanisms directing the gene expression of the cardiac isoform of acetyl-CoA carboxylase (ACCβ) are less well understood. Previously, four E-box (CANNTG) sequence motifs were identified on the human ACCβ promoter. Since E-boxes act as binding sites for upstream stimulatory factors (US F), putative glucose-responsive transcriptional modulators, we hypothesized that ACCβ is induced by USF1 in a glucosedependent manner. To investigate this, we began by acutely fasting and subsequently refeeding Balb/C mice with a carbohydrate-enriched diet. Here, high carbohydrate feeding resulted in elevated systemic glucose levels associated with increased cardiac ACCβ gene and protein expression. To further explore these interesting findings, we tranSiently cotransfected neonatal card iom yocytes , H9C2 myoblasts, CV-1 fibroblasts and HepG2 hepatocytes with the full-length and deletion constructs of the human ACC[3 gene promoter together with a putative activator and repressor expression vector, respectively: a) USF1 (glucose-responsive transcription factor) - the rationale that it should elevate ACCβ gene promoter activity in accordance with the glucose-fatty acid cycle, and b) nuclear respiratory factor 1(NRF1) - the hypothesis being that this mitochondrial biogenesis and β-oxidation enhancing modulator would be expected to attenuate ACCβ promoter activity in order to increase fatty acid oxidation capacity.en_ZA
dc.identifier.apacitationMakaula, S. S. S. (2006). <i>Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/3423en_ZA
dc.identifier.chicagocitationMakaula, Siyanda S S. <i>"Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2006. http://hdl.handle.net/11427/3423en_ZA
dc.identifier.citationMakaula, S. 2006. Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Makaula, Siyanda S S AB - Metabolic remodeling is thought to be an important contributor towards the development of various cardiac pathophysiologic conditions. Therefore, studies attempting to delineate undenying mechanisms driving cardiac metabolic remodeling represent an important initiative toward the development of novel therapeutic interventions. To further investigate the role of metabolic substrate switches in the heart, we focused on a pivotal, rate-limiting step of cardiac fatty acid metabolism i.e. an upstream modulator of long-chain fatty acid importation into the mitochondrion. In the heart, long-chain fatty acids are transported into the mitochondrion by the rate-limiting enzyme, carnitine palmitoyl transferase 1 (CPT1). CPT1 is potently inhibited by malonyl-CoA, the product of the acetylCoA carboxylation reaction that is catalyzed by acetyl-CoA carboxylase (ACC). Recent studies have demonstrated that metabolic fuels such as fatty acids and glucose can function as signaling ligands, directing transcriptional regulation of numerous metabolic genes. However, transcriptional mechanisms directing the gene expression of the cardiac isoform of acetyl-CoA carboxylase (ACCβ) are less well understood. Previously, four E-box (CANNTG) sequence motifs were identified on the human ACCβ promoter. Since E-boxes act as binding sites for upstream stimulatory factors (US F), putative glucose-responsive transcriptional modulators, we hypothesized that ACCβ is induced by USF1 in a glucosedependent manner. To investigate this, we began by acutely fasting and subsequently refeeding Balb/C mice with a carbohydrate-enriched diet. Here, high carbohydrate feeding resulted in elevated systemic glucose levels associated with increased cardiac ACCβ gene and protein expression. To further explore these interesting findings, we tranSiently cotransfected neonatal card iom yocytes , H9C2 myoblasts, CV-1 fibroblasts and HepG2 hepatocytes with the full-length and deletion constructs of the human ACC[3 gene promoter together with a putative activator and repressor expression vector, respectively: a) USF1 (glucose-responsive transcription factor) - the rationale that it should elevate ACCβ gene promoter activity in accordance with the glucose-fatty acid cycle, and b) nuclear respiratory factor 1(NRF1) - the hypothesis being that this mitochondrial biogenesis and β-oxidation enhancing modulator would be expected to attenuate ACCβ promoter activity in order to increase fatty acid oxidation capacity. DA - 2006 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2006 T1 - Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease TI - Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease UR - http://hdl.handle.net/11427/3423 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/3423
dc.identifier.vancouvercitationMakaula SSS. Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2006 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/3423en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherMedicineen_ZA
dc.titleMolecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular diseaseen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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