Liver X receptors in cardiac hypertrophy: New insights into metabolic remodeling

The heart responds to pathological stress by shifting myocardial substrate metabolism toward a greater reliance on glucose. Liver X receptors (LXRs) are nuclear receptors that play a central role in lipid and glucose metabolism. Although it has been suggested that pharmacological LXR activation may protect the heart, lipogenic side effects of current LXR agonists preclude their clinical applicability, while the heart-specific effects of LXRs in cardiac pathophysiology and metabolism remain unknown. For this, we created transgenic mice with cardiac-specific LXRα overexpression, and demonstrate that the cardioprotective effects of LXRα are indeed heart-specific in the attenuation of cardiac hypertrophy, myocardial fibrosis, and dysfunction. This was also confirmed in pharmacological studies using a novel high affinity LXR agonist, AZ876. LXRα transgenic mice were protected from diverse hypertrophic perturbations, such as chronic pressure overload, angiotensin II stimulation, and obesity-induced diabetes. Gene profiling analyses uncovered novel roles for LXRα in the regulation of several metabolic pathways. In response to hypertrophic stress, LXRα overexpression markedly enhanced the capacity for glucose uptake, whereas this adaptation was impaired in LXRα-deficient mice. Further, we identified increased glucose-O-GlcNAc-dependent signalling and regulation of natriuretic peptide expression to be a major protective mechanism in this respect. Overall, we believe these findings advance our current understanding of myocardial glucose metabolism and its role in cardiac protection, and highlight the potential therapeutic value of LXRs as a target for metabolic intervention in cardiac hypertrophy and heart failure.