title: FXR activation improves myocardial fatty acid metabolism in a rodent model of obesity-driven cardiotoxicity.
abstract: OBJECTIVE
  Obesity-driven lipotoxicity is a risk factors for cardiovascular disease. The Farnesoid X Receptor (FXR) is a bile acids sensor and member of the nuclear receptor superfamily. Activation of FXR lowers plasma triacylglycerols and glucose levels through a mechanism that involves both the repression of key regulatory genes in the liver and the modulation of insulin sensitivity in peripheral tissues. In the present study we have investigated whether administering obese (fa/fa) Zucker rats, a genetic model of obesity associated with dyslipidemia and insulin resistance, with an FXR ligand protects against lipid-induced cardiomyopathy.
  
  
  RESULTS
  FXR is expressed in neonatal cardiomyocytes and the treatment with FXR agonists, chenodeoxycholic acid (CDCA), and GW4064, increased the mRNA expression of FXR and its canonical target gene, the small heterodimer partner (SHP), as well as proliferator-activated receptor alpha PPARα, acyl-CoA oxidase (AOX) and pyruvate dehydrogenase kinase (PDK-4). Feeding obese fa/fa rats with CDCA, 12 weeks, reduced hyperinsulinemia and hyperlipidaemia. The histological-pathological analysis of hearts demonstrated that treatment with the FXR ligand reduced lipid heart content decreased the rate of apoptosis, fibrosis scores and restored heart insulin signalling. Chronic CDCA administration, in the heart, induced PPARα and PPARα-regulated genes involved in β-oxidation.
  
  
  CONCLUSIONS
  FXR agonism exerts beneficial effects in a genetic model of lipid-induced cardiomyopathy. The striking benefit of this therapy on cardiac function in this model warrants an effort to determine whether a counterpart of this activity translates in human settings.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1, S. Andrea delle Fratte, 06132 Perugia, Italy. andrea.mencarelli@unipg.it
authors.forename: A
authors.initials: A
authors.lastname: Mencarelli
authors.forename: S
authors.initials: S
authors.lastname: Cipriani
authors.forename: B
authors.initials: B
authors.lastname: Renga
authors.forename: C
authors.initials: C
authors.lastname: D'Amore
authors.forename: G
authors.initials: G
authors.lastname: Palladino
authors.forename: E
authors.initials: E
authors.lastname: Distrutti
authors.forename: F
authors.initials: F
authors.lastname: Baldelli
authors.forename: S
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D050171:Dyslipidemias / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy; D006946:Hyperinsulinism / Q000188:drug therapy; D006949:Hyperlipidemias / Q000188:drug therapy; D007333:Insulin Resistance; D007555:Isoxazoles / Q000494:pharmacology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D042962:Acyl-CoA Oxidase; D001647:Bile Acids and Salts; D001786:Blood Glucose; D002635:Chenodeoxycholic Acid; D007555:Isoxazoles; D047493:PPAR alpha; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C412815:GW 4064