March 2009

 

OPHTHALMOLOGY NEWS

 

Zeroing in on a transport protein


by Maxine Lipner Senior EyeWorld Contributing Editor

 

 

Newly recognized protein may play a role in AMD development

Identification of a new protein may point the way to a better understanding of the role nutrition plays in the development of age-related macular degeneration (AMD). A study published in the August 2008 issue of Lipids showed that a transport protein known as SR-B1 may be linked to the development of AMD, according to Earl Harrison, Ph.D., Dean’s Distinguished Professor and chair of human nutrition, Ohio State University, Columbus, Ohio.

“It’s very interesting that the macular of the retina accumulates xanthophylls,” Dr. Harrison said. From a scientific point of view he finds that it begs the question of why this occurs. “If you had various carotenoids in the plasma, for example beta-carotene and lutein, and they’re present in a roughly equal amount, then it’s interesting that the macular seems to accumulate vastly more lutein than it does beta-carotene,” he said. “That implies that either lutein is taken up better than beta-carotene, or they’re both taken up the same but beta-carotene is put back out.”

In addition to this hint that there’s something unusual about the macular, there is also some epidemiological evidence that suggests a nutritional link to AMD centering on xanthophylls—a class of carotenoids that sometimes function as antioxidants. “It suggests some relationship between either the consumption of xanthophyll-rich food sources or plasma xanthophyll levels and risk for developing macular degeneration,” Dr. Harrison said. “That has led people in the nutrition community to wonder whether there is something about these xanthophylls accumulating in the macular that actually protects it from damage that might lead to macular degeneration.”

There is some thinking that the yellow pigments of the xanthophylls may have a protective effect. “In the nutrition community they think about these perhaps filtering out blue light or somehow protecting against photo damage to the retina,” Dr. Harrison said. “Obviously nobody knows what causes macular degeneration, but there is some evidence and a lot of interest in whether or not dietary factors including xanthophylls can somehow be related.”

Investigating SR-B1

Spurred by this, investigators launched an investigation centering on a line of human-derived cultured cells dubbed ARPE 19. “After a period of time these will differentiate into what look like retinal pigment epithelial cells,” Dr. Harrison said. “They are not primary cells – they are transformed.” This cell line has been used for many previous studies. “We have done a lot of studies with intestinal cells in culture. We found when we gave these cells either xanthophylls or beta-carotene that if you gave equal amounts of carotenoids, they took up more of the xanthophylls than they did of the beta-carotene by a three or four fold difference,” he said. In this most recent experiment, investigators treated the ARPE 19 cells with an antibody against this protein, called SR-B1. “When we treated the cells with that antibody, we were able to inhibit the uptake of both beta-carotene and zeaxanthin by the cells,” Dr. Harrison said.

In another kind of experiment using small inhibitory RNAs, investigators were able to block the expression of the SR-B1 protein. “When we treated under these conditions we got a 90% inhibition of the expression of that protein, and we got a 90% inhibition of the uptake of zeaxanthin and a 50% inhibition of the uptake of beta-carotene,” Dr. Harrison said. “So it seems that this transporter may be involved in the uptake of both.” Investigators were particularly intrigued by the fact that there appeared to be a direct correlation between the amount of the inhibition of the SR-B1 protein and the zeaxanthin uptake. “What was interesting was because there was a correspondence between the extent of inhibition of the protein expression and the extent of inhibition of zeaxanthin uptake, the simplest explanation would be that xanthophyll uptake, at least under the conditions that we studied it, was entirely dependent on that SR-B1 protein,” Dr. Harrison said.

“Working backward, one could speculate then that the extent or the efficiency of accumulation of xanthophylls in the eye or at least in the retinal pigment epithelium might somehow be related to the level of expression or the level of function of this protein called SR-B1.”

Clinical implications

The next step would be to look for differences in either the detail structure or the expression of SR-B1 in a group of people to see if this corresponds with the level of xanthophylls in the eye. Dr. Harrison thinks that if this proves true, it could have interesting clinical implications. “If in fact there was some relationship between polymorphisms and this gene and the accumulation of these pigments, then you might be able to identify persons who are at great risk for AMD development,” he said. In addition, it could potentially lead to new drug development. “If SR-B1 is the major factor involved in xanthophyll accumulation in the eye, the pharmaceutical person might say we could use that as a target for a drug to either enhance or block the function,” Dr. Harrison said.

Going forward, a better understanding of zeaxanthin and xanthophyll uptake could help to crystallize practitioners’ knowledge of AMD. “If we had a complete understanding of the trafficking of these molecules in the macular and why they accumulate there and what they do, that might shed some light on either the pathogenesis of macular degeneration or on some things related to protecting the macular from degeneration,” Dr. Harrison said. “But the state of the studies now is really far from drawing those connections.”

Editors’ note: Dr. Harrison has no financial interests related to his comments.

Contact information

Harrison: 614-292-8189, harrison.304@osu.edu

Zeroing in on a transport protein Zeroing in on a transport protein
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