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White hearted

When a geneticist first spotted mutant white-eyed flies among his red-eyed fruit-flies in the early years of the 20th century, he launched the gene '_white_' on a career that is still going strong, as Eleanor Lawrence explains.

When the geneticist Thomas Hunt Morgan first spotted mutant white-eyed flies among his red-eyed fruit-flies in the early years of the 20th century, he launched the gene white on a career that is still going strong. Almost 90 years later, biomedical scientists investigating the causes of atherosclerosis, or fatty deposition in arteries, have discovered a function for the human counterpart of the white gene. And it's nothing to do with eye colour.

As Jochen Klucken of the University of Regensburg, Germany, and colleagues from Germany and the United States report in the Proceedings of the National Academy of Sciences 1, the protein produced by the human white gene, known as '_ABCG1_', is involved in preventing cells from accumulating too much cholesterol.

Although all cells need cholesterol to build healthy cell membranes, its chronic over-accumulation in cells within artery walls produces fatty deposits, which can lead to blocked arteries and, eventually, heart failure.

In atherosclerosis, accumulation of excess cholesterol as droplets in the specialized scavenger 'macrophages' that are common in blood vessel walls turns them into 'foam cells' -- a critical first step in the formation of fatty deposits, or 'atheromas'.

Macrophages in healthy blood vessel walls are continually importing and exporting cholesterol. To try and find components of the export pathways, Klucken's group grew macrophages in the lab, made them load and unload cholesterol, and identified those genes that were switched on and off during these activities. '_ABCG1_' was one such gene.

It is switched on as soon as cells start to load cholesterol and switched off once the cells have started to unload. If the production of ABCG1 protein is blocked, cells can import cholesterol as normal, but its export is very much reduced.

Cholesterol enters cells in the form of 'low-density lipoproteins' or 'LDLs' which are taken up into the cell by specialized receptors. Excess cholesterol is exported as free cholesterol, apparently with the help of membrane transporters such as ABCG1, which starts to be produced as soon as the cell is in danger of cholesterol overload. The released cholesterol then assembles outside the cell into high-density lipoprotein - 'HDL' - particles that would, in the body, be carried to other cells by the blood.

ABCG1, and the original fruit-fly white gene, encode transport proteins belonging to the large ABC protein family. These proteins sit in the cell membrane and transport a wide variety of substances across the otherwise impassable membrane. The original fly protein is involved in transporting compounds required for pigment formation; ABCG1 can export cholesterol, and probably other lipids.

Another related cholesterol-exporting protein identified by the same team is ABCA1; mutations in this protein are the cause of the rare inherited 'Tangier disease' as the Nature News Service reported last year: see 'Transport in Tangier', 30 July-5 August, 1999, in which certain cells cannot export cholesterol.

ABCG1 and ABCA1 are by no means the end of the story. They are only 2 of some 20 proteins identified by Klucken's team that are regulated in response to cholesterol uptake and release in macrophages. Any one of these could turn out to be a useful target for drugs aimed at preventing atherosclerosis.

References

  1. Klucken,J., Büchler, C., Orsó, E., Kaminski, W. E., Porsch-Özcürümez, M., Liebisch, G., Kapinsky, M., Diederich, W., Drobnik, W., Dean, M., Allikmets, R. & Schmitz, G. ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport PNAS 97, 817 - 822 2000.

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Lawrence, E. White hearted. Nature (2000). https://doi.org/10.1038/news000127-3

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  • DOI: https://doi.org/10.1038/news000127-3

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