Genetic programs regulated by the nuclear hormone receptor, LXR, in muscle: control of cholesterol and lipid metabolism

心血管疾病的增加与脂类代谢紊乱有关。肥胖、胰岛素抵抗和动脉粥样硬化是与这些血脂异常相关的常见疾病。脂类动态平衡受饮食摄入、从头合成和分解代谢的调节。脂代谢紊乱与心血管疾病、胰岛素抵抗--糖尿病、肥胖和高血压有关。血清TGS水平升高和低高密度脂蛋白(HDL)胆固醇水平是脂中毒性疾病的特征。高密度脂蛋白通过激素依赖的三磷酸腺苷结合盒(ABC)转运体介导胆固醇从外周组织流出，回到肝脏排泄和消除，从而在预防动脉粥样硬化性血脂异常中起到防御作用。通过胆固醇外流提高高密度脂蛋白胆固醇(HDLc)水平的药物为预防高胆固醇血症、动脉粥样硬化和心血管疾病提供了一种药物解决方案。这些激素依赖的胆固醇和脂类外流蛋白由一种名为LXR的蛋白调节。了解LXR在骨骼肌中的功能作用对于了解全身胆固醇稳态和脂肪代谢至关重要。骨骼肌是一种外围组织，占总体重的40%。此外，LXR和LXR靶基因促进胆固醇外流，从而提高HDLc水平，是重要的药物靶点。在骨骼肌中识别新的LXR靶点，这在胰岛素敏感性和血脂谱中具有重要作用，为治疗干预提供了额外的平台。

The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholesterol levels are characteristic of lipotoxic diseases. HDLs have a defensive role in the prevention of atherogenic dyslipidemia by mediating cholesterol efflux from peripheral tissues through the hormone -dependent ATP-binding cassette (ABC) transporters back to the liver for excretion and elimination. Agents that raise the levels of high density lipoprotein cholesterol (HDLc) through cholesterol efflux provide a pharmaceutical solution for the prevention of hypercholesterolemia, atherogenic and cardiovascular disease. These hormone dependent cholesterol and lipid effluxing proteins are regulated by a protein named LXR. Understanding the functional role of LXR in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body cholesterol homeostasis and lipid metabolism. Furthermore, LXR and LXR target genes that facilitate cholesterol efflux and consequently raise HDLc levels are important pharmaceutical targets. Identification of novel LXR targets in skeletal muscle, which has a significant role in insulin sensitivity and the blood lipid profile provides an additional platform for therapeutic intervention.