NR1 nuclear hormone receptors, and skeletal muscle metabolism: insights into dyslipidemia and metabolic disease.

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The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). Orphan NR1 receptors are abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight, and energy expenditure. Muscle is the 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, lipid metabolism and obesity. Understanding the functional role of the orphan NR1 receptors in skeletal muscle in the context of inflammation, lipid and energy homeostasis is of paramount importance in further understanding the mechanistic basis of dyslipidemia, chronic inflammation, insulin sensitivity, diabetes and obesity. Identification of novel NR1 targets that regulate metabolism in a major mass peripheral tissue, and positively influence the risk factors for cardiovascular disease, provides platforms for potential therapeutic intervention. Cardiovascular disease is the foremost cause of global mortality, and was responsible for >15 million deaths in 2003.