IMPROVING ENERGY SUPPLY TO MEND A SICK HEART
Qinglin Yang, M.D., Ph.D.,
University of Alabama at Birmingham, Birmingham, AL, USA
Substrate supply to the heart plays an essential role in maintaining cardiac performance. Perturbations in energy metabolism have been linked to pathological cardiac hypertrophy and failure. However, our understanding of the regulation of substrate utilization in the adult heart remains poor. Liver X Receptors (LXRα and β ) are members of the nuclear receptor superfamily that play roles in transcriptional regulation of lipid and cholesterol metabolism. Our previous study showed that LXRα is a negative regulator of cardiac hypertrophy via its anti-inflammatory effect. However, it remains unclear if LXRα may protect the heart through transcriptional regulation of myocardial energy supply. The current study on a mouse line of tamoxifen inducible, cardiomyocyte-restricted knockout of the LXRα further uncovers the essential role of this nuclear receptor in the cardiac pathophysiology via regulating energy metabolism. LXRα deficiency in adult hearts led to cardiac dysfunction and myocardial hypertrophic remodeling. Moreover, LXRα deficiency in cardiomyocytes attenuated expression of genes for fatty acid and glucose metabolism, and cholesterol efflux. Consequently, LXRα deficiency perturbed myocardial energy metabolism and mitochondrial oxidative function due to diminished fatty acid and glucose utilization, elevated cholesterol, and especially mitochondrial membrane cholesterol content. As a result, LXRα deficient hearts showed increased cell death, and subsequent cardiac hypertrophy and remodeling. Interestingly, endoplasmic reticulum (ER) stress and autophagic flux were upregulated, preventing the LXRα deficient heart from further pathological development. On the other hand, treatment of T1317, a dual ligand, not only activates LXRα but also LXRβ , could at least partially rescue the above metabolic defects in cultured cardiomyocytes from LXRα deficient hearts. Therefore, these results indicate that LXRα plays an essential role in the heart for fuel utilization and cholesterol efflux. Cardiac selective LXRα activation may help improve energy substrate supply to the heart and rescue cardiac function.