title: LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes.
abstract: OBJECTIVE
  Diabetic cardiomyopathy is a myocardial disease triggered by impaired insulin signalling, increased fatty acid uptake and diminished glucose utilisation. Liver X receptors (LXRs) are key transcriptional regulators of metabolic homeostasis. However, their effect in the diabetic heart is largely unknown.
  
  
  METHODS
  We cloned murine Lxrα (also known as Nr1h3) behind the α-myosin heavy chain (αMhc; also known as Myh6) promoter to create transgenic (Lxrα-Tg) mice and transgene-negative littermates (wild-type [WT]). A mouse model of type 2 diabetes was induced by a high-fat diet (HFD, 60% energy from fat) over 16 weeks and compared with a low-fat diet (10% energy from fat). A mouse model of type 1 diabetes was induced via streptozotocin injection over 12 weeks.
  
  
  RESULTS
  HFD manifested comparable increases in body weight, plasma triacylglycerol and insulin resistance per OGTT in Lxrα-Tg and WT mice. HFD significantly increased left ventricular weight by 21% in WT hearts, but only by 5% in Lxrα-Tg. To elucidate metabolic effects in the heart, microPET (positron emission tomography) imaging revealed that cardiac glucose uptake was increased by 1.4-fold in WT mice on an HFD, but further augmented by 1.7-fold in Lxrα-Tg hearts, in part through 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and restoration of glucose transporter 4 (GLUT4). By contrast, streptozotocin-induced ablation of insulin signalling diminished cardiac glucose uptake levels and caused cardiac dysfunction, indicating that insulin may be important in LXRα-mediated glucose uptake. Chromatin immunoprecipitation assays identified natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as potential direct targets of cardiac LXRα overexpression.
  
  
  CONCLUSIONS
  Cardiac-specific LXRα overexpression ameliorates the progression of HFD-induced left ventricular hypertrophy in association with increased glucose reliance and natriuretic peptide signalling during the early phase of diabetic cardiomyopathy. These findings implicate a potential protective role for LXR in targeting metabolic disturbances underlying diabetes.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Megan V
authors.initials: MV
authors.lastname: Cannon
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Herman H W
authors.initials: HH
authors.lastname: Silljé
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Jürgen W A
authors.initials: JW
authors.lastname: Sijbesma
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Mohsin A F
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. r.a.de.boer@umcg.nl.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000628:therapy*; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D000071518:Liver X Receptors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000150:complications*
chemical_list: D000071518:Liver X Receptors
keywords: Diabetic cardiomyopathy; Left ventricular hypertrophy; Liver X receptor; Natriuretic peptides