Abstract 15617: Liver X Receptor α is essential for myocardial fatty acid and glucose metabolism
Liver X receptors (α and β) are nuclear receptors and ligand-dependent transcription factors. LXRs have been recognized as key transcriptional regulators of lipid and glucose metabolism, as well as anti-inflammation factors. It has been documented that LXRα is expressed in cardiomyocytes, and activation of LXRs suppresses inflammation and cardiac hypertrophy. However, the role of LXRα in the transcriptional regulation of myocardial metabolism and cardiac function remain unclear. To test the hypothesis that LXRα plays an important role in regulating lipid and glucose metabolism in the heart, we investigated a tamoxifen-inducible, cardiomyocyte-restricted LXRα knockout mouse model. We found that LXRα knockout (TMLA) in the adult heart led to depressed expression of several key proteins involved in fatty acid and glucose metabolism, and cholesterol efflux compared with littermate controls (TMCM). In isolated working heart studies, TMLA hearts showed significantly decreased myocardial fatty acid oxidation, glucose oxidation, and glucose uptake, together with impaired contraction and oxygen consumption (n=6, p<0.05). Echocardiography assessment confirmed cardiac dysfunction and increased mass of left ventricular in the TMLA relative to TMCM. The ratio of heart weight to tibia length in TMLA mice was also increased. Treatment of T1317, a dual synthetic ligand of LXRα and LXRβ, on cultured adult cardiomyocytes isolated from TMCM and TMLA mice recovered depressed gene expression and the rates of fatty acid and glucose metabolism (n=4, p<0.05). Moreover, the TMLA hearts showed fibrosis, cholesterol accumulation and apoptosis compared with controls. Therefore, this present study uncovers an important transcriptional regulator in the heart that plays an essential role in governing cardiac metabolism and function.
- © 2011 by American Heart Association, Inc.