|Budget Amount *help
¥3,300,000 (Direct Cost : ¥3,300,000)
Fiscal Year 2000 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1999 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1998 : ¥1,700,000 (Direct Cost : ¥1,700,000)
In order to search new therapeutic strategies for autoimmune thyroid diseases, we have worked on adipose differentiation-related protein (ADRP), which was originally identified as an early marker of adipose cell differentiation program. This protein is ubiquitously expressed and is involved in lipid storage as well as long chain fatty acid uptake. Since free fatty acid could be a mediator of inflammatory response, we aimed to disclose the regulatory mechanism of the ADRP gene expression. In the present study, we disclosed that the mouse ADRP gene expression is regulated by PPARg. Thus, PPARg ligands, troglitazone, pioglitazone and 1 5 -deoxy-D12,14-prostaglandin J2, increased ADRP mRNA levels in NMuLi mouse liver cells and J774.1 mouse macrophages in vitro. This increase was completely inhibited by actinomycin D.On the contrary, PPARa ligands, fenofibrate and bezafibrate, failed to increase the mRNA levels. In order to delineate the promoter region responsible for this PPARg-induced stimulation, we cloned an approximately 2.8kb 5'-flanking region of the mouse ADRP gene, and constructed luciferase reporter plasmids for the assessment of promoter activity. All chimeric constructs containing the promoter region, when transfected into NMuLi cells, exhibited significant luciferase activity by comparison to a control plasmid. Troglitazone or troglitazone plus 9 -cis-RA significantly stimulated promoter activity expressed by the promoter containing a fragment of-2090bp or longer, but not -2005bp or shorter, indicating that the region between -2090 and -2006bp is responsible for the PPARg action. These results will facilitate understanding of the mechanism of PPARg action on ADRP expression. We are currently examining physiological significance of ADRP in thyrocytes and regulation of autoimmune thyroid diseases.