OR03-3 The ABC Transporter ABCC1 Exports Corticosterone but Not Cortisol from Human Adipocytes and is Upregulated in Subcutaneous but Not Visceral Adipose Tissue in Obesity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR03-Glucocorticoids & Glucocorticoid Actions
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:00 PM
Room 130 (Moscone Center)
Ash I Taylor*1, Lynne E Ramage1, Donald R Dunbar1, Mark Nixon2, Thomas M Stulnig3, Maximilian Zeyda3, Ruth Andrew1 and Brian R Walker1
1University of Edinburgh, Edinburgh, United Kingdom, 2University of Texas Health Science Centre, Houston, TX, 3Medical University of Vienna, Vienna, Austria
Human plasma contains both cortisol and corticosterone, the major glucocorticoid in rodents, at a ratio of ~10:1. Export of cortisol, but not corticosterone, from CNS by ABCB1 (MDR1, p-glycoprotein) explains lower cortisol:corticosterone ratios in cerebrospinal fluid than plasma and may allow corticosterone to exert disproportionate feedback on the HPA axis. Conversely, in cell models, corticosterone but not cortisol is transported by another ABC transporter, ABCC1 (MRP1). We hypothesised that tissue-specific distribution of ABCB1 and ABCC1 may render some tissues differentially sensitive to corticosterone or cortisol.

Using microarray, RT-PCR and qPCR in a library of human tissue cDNA samples, we showed similar expression of ABCB1 and ABCC1 in kidney, liver and thymus; however, ABCC1 was more highly expressed than ABCB1 in peripheral blood mononuclear cells, skeletal muscle and adipose tissue. In differentiated SGBS cells, a human adipocyte cell line, mRNA and protein for ABCC1 were present, and ABCB1 was not expressed. This contrasts with murine subcutaneous and visceral adipose tissue and differentiated 3T3-L1 cells in which both ABCB1 and ABCC1 are expressed. Influx of 3H-corticosterone and 3H-cortisol into the intracellular fraction in SGBS cells was similar over 24h, however, efflux of corticosterone from cells was faster than that of cortisol at 4h (2.3-fold; p<0.05), 8h (2.8-fold; p<0.01) and 24h (3.2-fold; p<0.01). Incubation with the ABCC1 inhibitor MK-571 for 24h increased intracellular accumulation of 3H-corticosterone (3.5-fold; p<0.001) to a greater extent than 3H-cortisol (1.2-fold; p<0.001). In human adipose biopsies, ABCC1 transcript levels were higher in subcutaneous (n=6) than visceral (n=8) adipose tissue (1.6-fold; p<0.01) in lean individuals, and higher in subcutaneous (1.5-fold; p<0.01) but not visceral adipose in obese (n=8) compared with lean subjects.

Thus, expression of ABCC1 may render human adipose tissue more responsive to variations in cortisol than corticosterone, in contrast with CNS where expression of ABCB1 confers differential sensitivity to corticosterone. This mechanism may have evolved in humans to exploit the presence of two endogenous glucocorticoids and increase the plasticity of tissue-specific glucocorticoid action. In obesity, up-regulation of ABCC1 may protect subcutaneous, but not visceral, adipose tissue from corticosterone and thereby contribute to glucocorticoid-dependent visceral fat accumulation.

Nothing to Disclose: AIT, LER, DRD, MN, TMS, MZ, RA, BRW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: British Heart Foundation, Programme Grant.