title: TXNIP regulates myocardial fatty acid oxidation via miR-33a signaling.
abstract: Myocardial fatty acid β-oxidation is critical for the maintenance of energy homeostasis and contractile function in the heart, but its regulation is still not fully understood. While thioredoxin-interacting protein (TXNIP) has recently been implicated in cardiac metabolism and mitochondrial function, its effects on β-oxidation have remained unexplored. Using a new cardiomyocyte-specific TXNIP knockout mouse and working heart perfusion studies, as well as loss- and gain-of-function experiments in rat H9C2 and human AC16 cardiomyocytes, we discovered that TXNIP deficiency promotes myocardial β-oxidation via signaling through a specific microRNA, miR-33a. TXNIP deficiency leads to increased binding of nuclear factor Y (NFYA) to the sterol regulatory element binding protein 2 (SREBP2) promoter, resulting in transcriptional inhibition of SREBP2 and its intronic miR-33a. This allows for increased translation of the miR-33a target genes and β-oxidation-promoting enzymes, carnitine octanoyl transferase (CROT), carnitine palmitoyl transferase 1 (CPT1), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase-β (HADHB), and AMPKα and is associated with an increase in phospho-AMPKα and phosphorylation/inactivation of acetyl-CoA-carboxylase. Thus, we have identified a novel TXNIP-NFYA-SREBP2/miR-33a-AMPKα/CROT/CPT1/HADHB pathway that is conserved in mouse, rat, and human cardiomyocytes and regulates myocardial β-oxidation.
authors.affiliation: Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Junqin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.affiliation: Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: John C
authors.identifier: 0000-0001-7180-9948
authors.initials: JC
authors.lastname: Chatham
authors.affiliation: Bioinformatics; Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: David K
authors.initials: DK
authors.lastname: Crossman
authors.affiliation: Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
authors.affiliation: Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; shalev@uab.edu.
authors.forename: Anath
authors.initials: A
authors.lastname: Shalev
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D002333:Carnitine Acyltransferases / Q000235:genetics / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006801:Humans; D000067268:Isolated Heart Preparation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D063993:Mitochondrial Trifunctional Protein, beta Subunit / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D023081:CCAAT-Binding Factor; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005227:Fatty Acids; C580642:MIRN33 microRNA, rat; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; C492060:Nfya protein, mouse; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C486715:TXNIP protein, human; C493796:TXNIP protein, rat; C445672:Txnip protein, mouse; D013879:Thioredoxins; D002333:Carnitine Acyltransferases; C030162:carnitine octanoyltransferase; C576207:Hadhb protein, mouse; D063993:Mitochondrial Trifunctional Protein, beta Subunit; D002334:Carnitine O-Palmitoyltransferase; D055372:AMP-Activated Protein Kinases
keywords: heart; microRNA; nuclear factor Y; thioredoxin-interacting protein; β-oxidation