LXR? improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes.

ABSTRACT:

Aims/hypothesis

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 Lxr? (also known as Nr1h3) behind the ?-myosin heavy chain (?Mhc; also known as Myh6) promoter to create transgenic (Lxr?-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 Lxr?-Tg and WT mice. HFD significantly increased left ventricular weight by 21% in WT hearts, but only by 5% in Lxr?-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 Lxr?-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 LXR?-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 LXR? overexpression.

Conclusions/interpretation

Cardiac-specific LXR? 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.

SUBMITTER: Cannon MV 

PROVIDER: S-EPMC4742491 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature