Mechanism of SR-BI-Mediated Macular Carotenoid Transport
Supplementation of macular carotenoids can protect human retina against age-related macular degeneration (AMD), a leading cause of blindness in the USA. Carotenoids are a class of mainly yellow, orange, or red pigments that provide color to plants and natural organisms, and serve as vital nutrients for human vision. Humans do not synthesize carotenoids and have to obtain them from diets; therefore, it is important to understand the relevant mechanism of macular carotenoid transport. However, that is still unknown because there has been no appropriate small animal model that is capable of accumulating carotenoid in their retinas. Recently, we discovered that mice deficient in β-carotene oxygenase 2 (BCO2), a carotenoid cleavage enzyme, can deposit carotenoid in their retinas, and we plan to use this mouse model to study the biochemical mechanism underlying macular carotenoid transport mediated by a protein known as scavenger receptor B1 (SR-B1) a critical carotenoid transporter. The results may lead to new treatments and therapies to prevent AMD using carotenoid supplementation.
Carotenoids can reduce approximately 40 percent of the risk of AMD, but humans do not synthesize carotenoids and have to obtain them from diets. Therefore, it is important to understand the mechanism of macular carotenoid transport.
Our goal is to understand the mechanism of scavenger receptor BI (SR-BI)-mediated macular carotenoid transport.SR-BI has long been thought to be the critical protein responsible for the uptake of macular carotenoids from the bloodstream to the retina; however, until now, this biochemical pathway has been difficult to approach because there have been no appropriate animal models for this study. Our recent discovery of “macular pigment mice” that can reproducibly take up carotenoids into the retina finally allows investigation into this problem.
In Specific Aim I, using our unique macular pigment mice which can accumulate carotenoids in their retinas, we are defining whether SR-BI is the critical protein to transport carotenoids from the bloodstream to the retina. The SR-BI gene is deleted specifically from the retinal pigmented epithelium (RPE) cells of the macular pigment mice. Once we have these knockout mice, we will feed them carotenoids for one month. If no carotenoid is detected in the retina, it will demonstrate that SR-BI is the critical carotenoid transporter.
In Specific Aim II, we are investigating the molecular mechanism of SR-BI- mediated carotenoid transport. Using cell culture assays, we are exploring whether carotenoids enter RPE cells through a cholesterol tunnel found in the SR-BI protein, and we also are testing whether SR-BI needs a protein partner to facilitate carotenoid transport.
In Specific Aim III, we are examining if there are additional proteins involved in macular carotenoid transport. Using surface plasmon resonance (SPR) spectroscopy, we are screening the potential protein candidates. They should be able to bind the macular carotenoids lutein and zeaxanthin more tightly than other carotenoids.
Completion of our proposed research will facilitate our understanding of macular carotenoid transport, offering new treatments and therapies to prevent AMD and other human eye disease using carotenoids.
About the Researcher
Dr. Li is a research assistant professor in the Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, at the University Of Utah School Of Medicine. He received his PhD degree from the Chinese Academy of Sciences, Beijing, China, in 2005. He then began his postdoctoral training and research associate work at the Moran Eye Center. Subsequently, in 2015, he became a research faculty member in the department. His research is focused on the role of carotenoids in retinal disease prevention by studying the relevant metabolism, transport pathways, and physiological functions of xanthophyll carotenoids in the human eye. Dr. Li’s work has resulted in more than 30 publications in PNAS, Biochemistry, Biophysical J., and other leading journals.
I was trained as a plant biochemist, and my PhD thesis was about the structure and function of a photosynthetic membrane protein, cytochrome b6f, which was isolated from a green algae living in the East China Sea (Bryopsis corticulans). Cytochrome b6f is a carotenoid protein complex. After graduation, I tried very hard but still could not get a post-doc offer to continue working on this protein. One day, I thought, why not to look for a job related to carotenoids in other organisms? I googled “carotenoid” and found a post-doc position to study the carotenoid-binding proteins in the human macula! Several months later, I joined Dr. Paul S. Bernstein’s lab at Moran Eye Center, University of Utah, accomplishing my research transition from plants to medicine. Since then, I have begun studying the function and mechanism of carotenoids as high-efficacy natural antioxidants for the prevention of age-related macular degeneration (AMD) and other human eye diseases.
First published on: August 15, 2017
Last modified on: June 30, 2019