Abstract
Rev-erbbeta is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-alpha (RORalpha). RORalpha has been implicated in the regulation of high density lipoprotein cholesterol, lipid homeostasis, and inflammation. Reverbbeta and RORalpha are expressed in similar tissues, including skeletal muscle; however, the pathophysiological function of Rev-erbbeta has remained obscure. We hypothesize from the similar expression patterns, target genes, and overlapping cognate sequences of these nuclear receptors that Rev-erbbeta 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-erbbeta in this major mass peripheral tissue. Exogenous expression of a dominant negative version of mouse Rev-erbbeta 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-erbbeta in the control of lipid and energy homoeostasis in skeletal muscle. In conclusion, we speculate that selective modulators of Rev-erbbeta may have therapeutic utility in the treatment of dyslipidemia and regulation of muscle growth.
Highlights
Members of the nuclear receptor (NR)1 superfamily bind to specific DNA elements and function as transcriptional regulators (1, 2)
Our recent studies demonstrate that ROR␣ regulates the expression of genes involved in lipid homeostasis and energy balance in skeletal muscle cells (16)
We have utilized the C2C12 in vitro cell culture model system and ectopic overexpression of dominant negative Rev-erb to investigate the role of this orphan receptor in skeletal muscle lipid, and energy homeostasis
Summary
Members of the nuclear receptor (NR) superfamily bind to specific DNA elements and function as transcriptional regulators (1, 2). Rev-erb␣, Rev-erb, and ROR bind as monomers to the nuclear receptor half-site motif, PuGGTCA flanked 5Ј by an ATrich sequence ((A/T)6PuGGTCA). These receptors are closely related, and bind to the same motif, they function in an opposing manner. The inter-relationship between these nuclear receptors is underscored by the evidence that demonstrates ROR␣ trans-activates the Rev-erb␣ promoter (13). Our recent studies demonstrate that ROR␣ regulates the expression of genes involved in lipid homeostasis and energy balance in skeletal muscle cells (16)
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