title: PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid.
abstract: Obesity is a risk factor in the development of type 2 diabetes mellitus (DM2), which is associated with increased morbidity and mortality, predominantly as a result of cardiovascular complications. Increased adiposity is a systemic condition characterized by increased oxidative stress (ROS), increased inflammation, inhibition of anti-oxidant genes such as HO-1 and increased degradation of epoxyeicosatrienoic acids (EETs). We previously demonstrated that EETs attenuate mitochondrial ROS. We postulate that EETs increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which controls mitochondrial function, oxidative metabolism and induction of HO-1.
  
  
  
  Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess functional relationship between EETs, HO-1 and (PGC-1α) using an EET analogue (EET-A) and lentivirus to knock down the PPARGC1A gene.
  
  
  
  EET-A increased PGC-1α and HO-1 in cultured adipocytes and increased the expression of genes involved in thermogenesis and adipocyte browning (UCP1 and PRDM16, respectively). PGC-1α knockdown prevented EET-A-induced HO-1expression, suggesting that PGC-1α is upstream of HO-1. MRI data obtained from fat tissues showed that EET-A administration to mice on a HF diet significantly reduced total body fat content, subcutaneous and visceral fat deposits and reduced the VAT: SAT ratio. Moreover EET-A normalized the VO2 and RQ (VCO2/VO2) in mice fed a HF diet, an effect that was completely prevented in PGC-1α deficient mice. In addition, EET-A increased mitochondrial biogenesis and function as measured by OPA1, MnSOD, Mfn1, Mfn2, and SIRT3, an effect that was inhibited by knockdown of PGC-1α.
  
  
  
  Taken together, our findings show that EET-A increased PGC-1α thereby increasing mitochondrial viability, increased fusion potential thereby providing metabolic protection and increased VO2 consumption in HF-induced obesity in mice, thus demonstrating that the EET-mediated increase in HO-1 levels require PGC-1α expression.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States.
authors.forename: Shailendra P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schragenheim
authors.affiliation: First Geriatric Cardiology Division, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States; Department of Medicine, New York Medical College, Valhalla, NY 10595, United States; Department of Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, WV 25701, United States. Electronic address: Nader_Abraham@nymc.edu.
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States. Electronic address: Lars_bellner@nymc.edu.
authors.forename: Lars
authors.initials: L
authors.lastname: Bellner
mesh_terms: D041721:3T3-L1 Cells; D015126:8,11,14-Eicosatrienoic Acid / Q000737:chemistry / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D063154:Mitochondrial Dynamics / Q000187:drug effects; D001678:Organelle Biogenesis; D010101:Oxygen Consumption / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071256:Uncoupling Protein 1 / Q000378:metabolism
chemical_list: C577139:2-(11-(nonyloxy)undec-8-enamido)succinic acid; D052242:Adiponectin; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C521133:Prdm16 protein, mouse; D011506:Proteins; C525046:Sirt3 protein, mouse; D014157:Transcription Factors; D000071256:Uncoupling Protein 1; C103637:mesoderm specific transcript protein; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D001224:Aspartic Acid; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013482:Superoxide Dismutase; D056566:Sirtuin 3; D015126:8,11,14-Eicosatrienoic Acid
keywords: Epoxyeicosatrienoic acid; HO-1; Metabolic dysfunction