Rev-erbbeta regulates the expression of genes involved in lipid absorption in skeletal muscle cells: evidence for cross-talk between orphan nuclear receptors and myokines.

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.

• Authors: Sathiya N Ramakrishnan, Patrick Lau, Les J Burke, George E O Muscat
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 10 Pg. 8651-9 (Mar 11 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15623503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• DNA-Binding Proteins
• Fatty Acids
• Nr1d2 protein, mouse
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Recombinant Proteins
• Repressor Proteins
• Cholesterol
• Glucose

Topics

• Animals
• Biological Transport
• Cell Line
• Cholesterol (metabolism)
• DNA Primers
• DNA-Binding Proteins (genetics, metabolism)
• Fatty Acids (metabolism)
• Gene Expression Regulation
• Glucose (metabolism)
• Lipid Metabolism
• Mice
• Muscle, Skeletal (physiology)
• RNA, Messenger (genetics)
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
• Recombinant Proteins (metabolism)
• Repressor Proteins (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection