title: Tauroursodeoxycholic acid mitigates high fat diet-induced cardiomyocyte contractile and intracellular Ca2+ anomalies.
abstract: OBJECTIVE
  The endoplasmic reticulum (ER) chaperone tauroursodeoxycholic acid (TUDCA) has exhibited promises in the treatment of obesity, although its impact on obesity-induced cardiac dysfunction is unknown. This study examined the effect of TUDCA on cardiomyocyte function in high-fat diet-induced obesity.
  
  
  METHODS
  Adult mice were fed low or high fat diet for 5 months prior to treatment of TUDCA (300 mg/kg. i.p., for 15d). Intraperitoneal glucose tolerance test (IPGTT), cardiomyocyte mechanical and intracellular Ca(2+) property, insulin signaling molecules including IRS-1, Akt, AMPK, ACC, GSK-3β, c-Jun, ERK and c-Jun N terminal kinase (JNK) as well as ER stress and intracellular Ca(2+) regulatory proteins were examined. Myocardial ultrastructure was evaluated using transmission electron microscopy (TEM).
  
  
  RESULTS
  High-fat diet depressed peak shortening (PS) and maximal velocity of shortening/relengthenin as well as prolonged relengthening duration. TUDCA reversed or overtly ameliorated high fat diet-induced cardiomyocyte dysfunction including prolongation in relengthening. TUDCA alleviated high-fat diet-induced decrease in SERCA2a and phosphorylation of phospholamban, increase in ER stress (GRP78/BiP, CHOP, phosphorylation of PERK, IRE1α and eIF2α), ultrastructural changes and mitochondrial permeation pore opening. High-fat diet feeding inhibited phosphorylation of AMPK and promoted phosphorylation of GSK-3β. TUDCA prevented high fat-induced dephosphorylation of AMPK but not GSK-3β. High fat diet promoted phosphorylation of IRS-1 (Ser(307)), JNK, and ERK without affecting c-Jun phosphorylation, the effect of which with the exception of ERK phosphorylation was attenuated by TUDCA.
  
  
  CONCLUSIONS
  These data depict that TUDCA may ameliorate high fat diet feeding-induced cardiomyocyte contractile and intracellular Ca(2+) defects through mechanisms associated with mitochondrial integrity, AMPK, JNK and IRS-1 serine phosphorylation.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, Division of Pharmaceutical Sciences, University of Wyoming College of Health Sciences, Laramie, Wyoming, United States of America.
authors.forename: Subat
authors.initials: S
authors.lastname: Turdi
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D059305:Diet, High-Fat; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005951:Glucose Tolerance Test; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D007328:Insulin; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000263:Adenylate Kinase; D002118:Calcium