The Role Of Liver X Receptors In Cardiac Function And Metabolism Of Mice

Several members of nuclear receptor superfamily, including liver X receptors (LXRa and LXRP), have been shown to suppress inflammatory responses, but little is known about their effects in cardiomyocytes. We investigated LXR expression patterns in pressure overload-induced hypertrophic hearts and the hypertrophic growth of the LXRa-deficient hearts from mice (C57/B6) in response to pressure overload. The underlying mechanisms were also explored using cultured myocytes. We found that cardiac expression of LXRa was upregulated in pressure overload-induced left ventricular hypertrophy in mice. Transverse aorta coarctation-induced left ventricular hypertrophy was exacerbated in LXRa-null mice relative to control mice. A synthetic LXR ligand, T1317, suppressed cardiomyocyte hypertrophy in response to angiotensinⅡand lipopolysaccharide treatments. In addition, LXR activation suppressed NF-κB signalling and the expression of associated inflammatory factors. Overexpression of constitutively active LXRa and b in cultured myocytes suppressed NF-κB activity. LXRs are negative regulators of cardiac growth and inflammation via suppressing NF-κB signaling in cardiomyocytes. This should provide new insights into novel therapeutic targets for treating cardiac hypertrophy and heart failure. In addition to its important role in maintaining cholesterol homeostasis, LXRs is also essential in regulating lipid metabolism. Expression of LXRa has long been identified in adult heart, however, the role of LXRa in the transcriptional regulation of myocardial metabolism and cardiac pathophysiology remains obscure. To test the hypothesis that LXRa plays an important role in regulating lipid and glucose metabolism in the heart, Cardiomyocyte-restricted LXRa knockout were induced in mice treated with tamoxifen. After confirmation of LXRa knockout, LXRs target genes that were crucial in lipid and glucose metabolism were downregulated. Lipid and glucose metabolism were examined in ex vivo heart and in vitro cardiomyocytes. And in vivo and in vitro cardiac function was evaluated with echocardiography and isolated heart working system. Morphological and histological examinations of heart were also performed in transgenic mice. Fatty acid and glucose oxidation, as well as glucose uptake were both decreased in cardiomyocytes, followed by repressed cardiac function, cardiac hypertrophy and remodeling. Therefore, the present study demonstrated LXRa is essential in myocardial lipid and glucose metabolism, inducible cardiomyocyte-restricted LXRa knockout in adults leads to downregulation of related gene expression which regulates lipid and glucose metabolism, depressed ATP production, as well as cardiac dysfunction and remodeling.