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

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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.