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

Abstract

Rev-erb␤ is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-␣ (ROR␣). ROR␣ has been implicated in the regulation of high density lipoprotein cholesterol, lipid homeostasis, and inflammation. Reverb␤ and ROR␣ are expressed in similar tissues, including skeletal muscle; however, the pathophysiological function of Rev-erb␤ has remained obscure. We hypothesize from the similar expression patterns, target genes, and overlapping cognate sequences of these nuclear receptors that Rev-erb␤ 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-erb␤ in this major mass peripheral tissue. Exogenous expression of a dominant negative version of mouse Rev-erb␤ 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 "exerciseinduced 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-erb␤ in the control of lipid and energy homoeostasis in skeletal muscle. In conclusion, we speculate that selective modulators of Rev-erb␤ may have therapeutic utility in the treatment of dyslipidemia and regulation of muscle growth. Members of the nuclear receptor (NR)1 superfamily bind to specific DNA elements and function as transcriptional regulators (1, 2). In addition to the ligand-activated NRs, many members within this superfamily have no known ligand, and are referred to as "orphan NRs" (3). The orphan receptor Rev-erb␤ (NR1D2, also known as Rev-erb␣-related receptor, RVR) belongs to the family of "Reverbs" that also contain Rev-erb␣ (4, 5). The primary structure of these two receptors together with retinoic acid-related orphan receptor-␣ (ROR␣) and the Drosophila orphan receptor, E75A, is very similar especially in the DNA-binding domain and the putative ligand-binding domain (6).Two Rev-erb␤ genes have been identified; Rev-erb␤1 and Rev-erb␤2, which are alternatively spliced products of the Reverb␤ gene (7). The mRNA expression data shows that Rev-erb␤ is abundantly expressed in most tissues, although higher levels of expression are observed in skeletal muscle, brain, kidney, and liver (Refs. 4 and 8 and references therein).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) 6 PuGGTCA). Although...

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