Genetic programs induced by the nuclear hormone receptor PPARdelta in muscle: control of lipid and energy homeostasis

脂类动态平衡受饮食摄入、从头合成和分解代谢的调节。脂类疾病与高胰岛素血症和脂三联体的异常水平有关，即低高密度脂蛋白-胆固醇、高低密度脂蛋白-胆固醇和甘油三酯升高。心血管疾病发病率的增加与饮食和生活方式相关的血脂异常有关。糖尿病、动脉粥样硬化和肥胖是这些脂质紊乱的共病。高密度脂蛋白通过调节组织中的胆固醇外流，在预防血脂异常方面起到防御作用。相反，低密度脂蛋白在动脉壁中积聚，导致动脉粥样硬化。生理上维持脂质稳态需要代谢信号级联、饮食、生活方式等之间的动态平衡。PPPAR是一种核激素受体，其功能是脂肪酸激活的转录因子，调节脂质和胆固醇的稳态。PPAR是开发用于治疗血脂紊乱的治疗化合物的真正靶点。PPAR Delta在骨骼肌中大量表达，骨骼肌是一种主要的周围组织，占总体重的40%左右。肌肉是葡萄糖代谢和脂肪酸氧化的主要场所。此外，它也是胆固醇稳态和高密度脂蛋白水平的重要调节因素。因此，它在胰岛素敏感性、血脂谱和脂代谢方面具有重要作用。了解PPAR Delta在骨骼肌中的功能作用对于了解全身脂肪动态平衡至关重要。骨骼肌是一种占总体重40%的外围组织。了解这些受体可能为预防高脂血症--胆固醇血症和动脉粥样硬化疾病提供一种药物解决方案。此外，它可能导致识别在脂肪吸收方面影响主要肿块组织的因素，并增加脂肪酸氧化，从而使血脂水平正常化。

Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of dyslipidemia by mediating cholesterol efflux from tissues. In contrast, the LDLs accumulate in the arterial wall leading to atherosclerosis. Physiological maintenance of lipid homeostasis requires a dynamic balance between metabolic signalling cascades, diet, lifestyle etc. PPPARs are nuclear hormone receptors that function as fatty acid activated transcription factors that regulate lipid and cholesterol homeostasis. PPARs are bona fide targets for the development of therapeutic compounds useful in the treatment of lipid disorders. PPAR delta is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight. Muscle is a major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile and lipid metabolism. Understanding the functional role of PPAR delta in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body lipid homeostasis. Understsanding these receptors may provide a pharmaceutical solution for the prevention of hyper-lipidemia--cholesterolemia, and atherogenic disease. Moreover, it may lead to the identification of agents that influence a major mass tissue in terms of lipid absorption, and increased fatty acid oxidation, and consequently normalize the blood lipid profile.