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The Genomic Analysis of the Impact of Steroid Receptor Coactivators Ablation on Hepatic Metabolism

Molecular and Cellular Biology (J.-W.J., I.K., K.Y.L., B.W.O’M., F.J.D.), Microarray Core Facility Department of Molecular and Human Genetics (L.D.W.), and Michael E. DeBarkey Department of Surgery (X.-P.W., F.C.B.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to Francesco J. DeMayo, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. E-mail: fdemayo{at}bcm.tmc.edu.

Members of the steroid receptor coactivator (SRC) family, which include SRC-1 (NcoA-1/p160), SRC-2(TIF2/GRIP1/NcoA-2) and SRC-3(pCIP/RAC3/ACTR/pCIP/ AIB1/TRAM1), are critical mediators of steroid receptor action. Gene ablation studies previously identified SRC-1 and SRC-2 as being involved in the control of energy homeostasis. A more precise identification of the molecular pathways regulated by these coactivators is crucial for understanding the role of steroid receptor coactivators in the control of energy homeostasis and obesity. A genomic approach using microarray analysis was employed to identify the subsets of genes that are altered in the livers of SRC-1^–/–, SRC-2^–/–, and SRC-3^–/– mice. Microarray analysis demonstrates that gene expression changes are specific and nonoverlapping for each SRC member in the liver. The overall pattern of altered gene expressions in the SRC-1^–/– mice was up-regulation, whereas SRC-2^–/– mice showed an overall down-regulation. Several key regulatory enzymes of energy metabolism were significantly altered in the liver of SRC-2^–/– mice, which are consistent with the prior observation that SRC-2^–/– mice have increased energy expenditure. This study demonstrates that the molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway, whereas fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated.

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Coregulators:   SRC-1  |  GRIP1  |  AIB1

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