Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Rev-erbβ is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-α (RORα). RORα has been implicated in the regulation of high density lipoprotein cholesterol, lipid homeostasis, and inflammation. Reverbβ and RORα are expressed in similar tissues, including skeletal muscle; however, the pathophysiological function of Rev-erbβ has remained obscure. We hypothesize from the similar expression patterns, target genes, and overlapping cognate sequences of these nuclear receptors that Rev-erbβ regulates lipid metabolism in skeletal muscle. This lean tissue accounts for >30% of total body weight and 50% of energy expenditure. Moreover, this metabolically demanding tissue is a primary site of glucose disposal, fatty acid oxidation, and cholesterol efflux. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. We utilize ectopic expression in skeletal muscle cells to understand the regulatory role of Rev-erbβ in this major mass peripheral tissue. Exogenous expression of a dominant negative version of mouse Rev-erbβ decreases the expression of many genes involved in fatty acid/lipid absorption (including Cd36 , and Fabp-3 and - 4 ). Interestingly, we observed a robust induction (>15-fold) in mRNA expression of interleukin-6, an “exercise-induced myokine” that regulates energy expenditure and inflammation. Furthermore, we observed the dramatic repression (>20-fold) of myostatin mRNA, another myokine that is a negative regulator of muscle hypertrophy and hyperplasia that impacts on body fat accumulation. This study implicates Rev-erbβ in the control of lipid and energy homoeostasis in skeletal muscle. In conclusion, we speculate that selective modulators of Rev-erbβ may have therapeutic utility in the treatment of dyslipidemia and regulation of muscle growth.