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

肌肉中核激素受体 PPARδ 诱导的遗传程序：控制脂质和能量稳态

• 批准号: nhmrc : 301041
• 负责人: Prof George Muscat
• 金额: $ 28.86万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/genetic-programs-induced-energy-homeostasis/96653
• 关键词: Genetic; programs; induced; nuclear; hormone

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.

脂质稳态受饮食摄入、从头合成和代谢的调节。脂质疾病与高胰岛素血症和脂质三联体的异常水平相关，即低HDL-胆固醇、高LDL-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合并症。HDL通过介导胆固醇从组织流出而在预防血脂异常中具有防御作用。相反，LDL在动脉壁中积累，导致动脉粥样硬化。脂质稳态的生理维持需要代谢信号级联、饮食、生活方式等之间的动态平衡。PPPAR是核激素受体，其作为调节脂质和胆固醇稳态的脂肪酸激活的转录因子起作用。PPARs是用于开发可用于治疗脂质紊乱的治疗性化合物的真正靶标。PPAR δ在骨骼肌中大量表达，骨骼肌是占总体重~40%的主要外周组织。肌肉是葡萄糖代谢和脂肪酸氧化的主要场所。此外，它是胆固醇稳态和HDL水平的重要调节剂。因此，它在胰岛素敏感性、血脂谱和脂质代谢中具有重要作用。了解PPARdelta在骨骼肌（占总体重40%的外周组织）中的功能作用对于了解全身脂质稳态至关重要。了解这些受体可能为预防高胆固醇血症和动脉粥样硬化疾病提供药物解决方案。此外，它可能导致识别在脂质吸收方面影响主要肿块组织的试剂，并增加脂肪酸氧化，从而使血脂谱正常化。