Abstract 15845: Improved Myocardial Glucose Tolerance by Cardiac-Specific Overexpression of Liver X Receptor-a Prevents Cardiac Hypertrophy in Obesity-Induced Type II Diabetic Mice
Objectives: Diabetic cardiomyopathy is a myocardial disease triggered by metabolic derangements. In diabetes, impaired insulin signaling leads to increased fatty acid (FA) uptake and oxidation with diminished glucose utilization, resulting in myocardial lipotoxicity, left ventricular (LV) hypertrophy and dysfunction. Liver X receptors (LXR) are key transcriptional regulators of glucose and lipid metabolism. However, their effect in the diabetic heart has not been described. We therefore investigated the metabolic and functional consequences of myocardial LXRα activation in response to a metabolic challenge imposed by high fat-induced obesity.
Methods: We cloned murine LXRα behind the α-myosin heavy chain promoter to create transgenic (TG) mice and transgene-negative littermates (CON). TG mice exhibited a 9-fold increase in myocardial LXRα protein expression. Type II diabetes was induced by high fat diet (HFD, 60 kcal% fat) over 16 weeks and compared to low fat diet (LFD, 10 kcal% fat).
Results: HFD manifested comparable increases in body weight, plasma triglycerides, and insulin resistance per oral glucose tolerance test in TG and CON. HFD significantly increased LV weight by 21% in CON mice, but only 5% in TG (P<0.01). This was further associated with stronger induction of hypertrophic gene markers in CON versus TG, where elevated βMHC and Rcan1 expression and αMHC downregulation were observed (P<0.05). Functionally, HFD intervention did not alter systolic or diastolic parameters as assessed by echocardiography. Further experiments were performed to elucidate myocardial glucose uptake using 18F-FDG and PET. TG mice fed either LFD or HFD displayed enhanced FDG-glucose uptake levels of 1.5- and 1.7-fold compared to respective CON (P<0.05). In addition, Oil red O staining revealed increased lipid deposition in CON hearts fed HFD, whereas in TG mice, transcriptional analysis confirmed a shift away from FA uptake and oxidation pathways (P<0.05).
Conclusion: Cardiac-specific LXRα overexpression ameliorates the progression of HFD-induced LV hypertrophy largely in part due to enhanced glucose reliance. Herein, our findings implicate an important therapeutic role for LXR in targeting metabolic disturbances underlying diabetic cardiomyopathy.
- © 2013 by American Heart Association, Inc.