The genomic analysis of the impact of steroid receptor coactivators ablation on hepatic metabolism.
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.
Jeong
Jae-Wook
JW
Department of Molecular and Cellular Biology, Microarray Core Facility, Baylor College of Medicine, Houston, Texas 77030, USA.
Kwak
Inseok
I
Lee
Kevin Y
KY
White
Lisa D
LD
Wang
Xiao-Ping
XP
Brunicardi
F C
FC
O'Malley
Bert W
BW
DeMayo
Francesco J
FJ
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D023281:Genomics; D006003:Glycogen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D056921:Nuclear Receptor Coactivator 3; D020411:Oligonucleotide Array Sequence Analysis; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D005227:Fatty Acids; D051958:Nuclear Receptor Coactivator 2; D015534:Trans-Activators; D014157:Transcription Factors; D006003:Glycogen; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; C538867:Ncoa3 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3