title: Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1.
abstract: OBJECTIVE
  Alterations in cardiac energy and substrate metabolism play a critical role in the development and clinical course of heart failure. We hypothesized that the cardioprotective role of the breast cancer 1, early onset (BRCA1) gene might be mediated in part by alterations in cardiac bioenergetics.
  
  
  METHODS
  We generated cardiomyocyte-specific BRCA1 homozygous and heterozygous knockout mice using the Cre-loxP technology and evaluated the key molecules and pathways involved in glucose metabolism, fatty acid metabolism, and mitochondrial bioenergetics.
  
  
  RESULTS
  Cardiomyocyte-specific BRCA1-deficient mice showed reduced cardiac expression of glucose and fatty acid transporters, reduced acetyl-coenzyme A carboxylase 2 and malonyl-coenzyme A decarboxylase (key enzymes that control malonyl coenzyme A, which in turn controls fatty acid oxidation), and reduced carnitine palmitoyltransferase I, a rate-limiting enzyme for mitochondrial fatty acid uptake. Peroxisome proliferator-activated receptor α and γ and carnitine palmitoyltransferase I levels were also downregulated in these hearts. Rates of glucose and fatty acid oxidation were reduced in the hearts of heterozygous cardiomyocyte-restricted BRCA1-deficient mice, resulting in a decrease in the rate of adenosine triphosphate production. This decrease in metabolism and adenosine triphosphate production occurred despite an increase in 5'-adenosine monophosphate-activated protein kinase and AKT activation in the heart.
  
  
  CONCLUSIONS
  Cardiomyocyte-specific loss of BRCA1 alters critical pathways of fatty acid and glucose metabolism, leading to an energy starved heart. BRCA1-based cell or gene therapy might serve as a novel target to improve cardiac bioenergetics in patients with heart failure.
authors: Division of Cardiac Surgery and Endocrinology, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors: Krishna K
authors: KK
authors: Singh
authors: Praphulla C
authors: PC
authors: Shukla
authors: Bobby
authors: B
authors: Yanagawa
authors: Adrian
authors: A
authors: Quan
authors: Fina
authors: F
authors: Lovren
authors: Yi
authors: Y
authors: Pan
authors: Cory S
authors: CS
authors: Wagg
authors: Hwee
authors: H
authors: Teoh
authors: Gary D
authors: GD
authors: Lopaschuk
authors: Subodh
authors: S
authors: Verma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase; D005947:Glucose
keywords: 29; 31.2; 5′-adenosine monophosphate-activated protein kinase; ACC; AMPK; ATP; BRCA1; CPT1; CoA; GLUT; MCD; PGC1α; PPARs; acetyl-coenzyme A carboxylase; adenosine triphosphate; breast cancer 1, early onset; carnitine palmitoyltransferase 1; coenzyme A; glucose transporter; malonyl-CoA decarboxylase; peroxisome proliferator-activated receptor-γ coactivator 1α; peroxisome proliferator-activated receptors