All-trans-retinoic acid regulates vitamin A homeostasis
Open Access
- Author:
- Cifelli, Christopher John
- Graduate Program:
- Nutrition
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 27, 2006
- Committee Members:
- A Catharine Ross, Committee Chair/Co-Chair
John Elliot Beard, Committee Member
Ronald Scott Kensinger, Committee Member
Michael Henry Green, Committee Member - Keywords:
- vitamin A
retinoic acid
CYP26
compartmental analysis - Abstract:
- All-trans-retinoic acid (RA) is the active metabolite of vitamin A (VA; retinol) that mediates the majority of VA-dependent functions, such as embryonic development, cellular proliferation and differentiation, testicular function, and immune function. Because of the clinical impact of RA on different disease conditions, it is important to delineate the affects of acute and chronic RA administration on both whole-body and tissue specific VA and RA utilization and kinetics. The present study was conducted to better understand the regulation of RA in vivo and expand the current model that describes VA regulation. The results of this thesis show that chronic RA administration altered VA kinetics, acute RA rapidly increased CYP26 expression, and RA metabolism is maintained during physiological stress. Moreover, this work shows that the distribution and metabolism of RA are adjusted in response to changes in dietary VA intake and retinol supplementation. Together, the results presented here suggest that VA homeostasis is maintained through an autoregulatory process, with RA acting as the principle messenger that enables the liver to sense VA status. Based the observation that increased RA levels, whether administered through diet or intravenous injection, directly affect retinol and RA homeostasis, it is proposed that tissue and plasma RA levels are homeostatically maintained within a narrow range thus allowing the liver to respond to minor changes in VA status. In addition, RA homeostasis was apparently maintained despite nutritional and physiological stress, thus enabling the body to preserve VA homeostasis. In sum, the results demonstrate that RA is the signal that enables the body to “sense” VA status and that molecular mechanisms regulating RA levels adjust rapidly in response to different physiological, nutritional, and metabolic states to preserve RA homeostasis.