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Aug 16, 2007

Researchers Find Evidence Refuting ABCA1’s Role in Cholesterol Transport

  • A team of researchers at Penn State University and Amherst College say they have data that casts doubt on the dominant hypothesis of how the body rids its cells of LDL cholesterol and increases HDL cholesterol.

    The most popular hypothesis for ABCA1 was put forth in 2000 by researchers at the Centre d'Immunologie Marseille-Luminy in France. They suggested that the ABCA1 enzyme plays a major role in the transfer of a phospholipid called phosphatidylserine (PS) from the inside of the cell across the cell membrane to the outer surface of the cell. This is a crucial first step in the mechanism by which excess lipids and cholesterol are eliminated from the body.

    “This work really changes our understanding of the mechanics of cholesterol metabolism,” remarks Robert A. Schlegel, Ph.D., professor of biochemistry and molecular biology at Penn State. “We can't find any evidence whatsoever to support the popular hypothesis that the ABCA1 enzyme catalyzes the movement of PS across the cell membrane to the outer surface of the cell.

    “Since none of our experimental results were consistent with the hypothesis that ABCA1 influences the first step in the process, we think that ABCA1 must operate in the second step, when the phospholipids are loaded onto the apoA1.”

    The researchers performed their experiments using cells from people with Tangier disease who lack the ABCA1 gene and mice in which this gene has been knocked out. They report being able to refute theories that suggest the direct and indirect role of ABCA1 enzyme on the expression of PS on the cell's surface. They also presented data that disqualifies the hypotheses on process of apoptosis and macrophage activity in PS expressing cells.

    Exacting measurements of the movement of various phospholipids across the membrane of normal cells showed that the rate of phospholipid transport into the cell is not affected by the presence or absence of the ABCA1 gene and its corresponding enzyme, the scientists report. Similar experiments with Tangier cells or knock-out mouse cells produced the same results.

    “This showed us that the ABCA1 enzyme was not involved in the transport of phospholipids across the cell membrane under normal conditions,” says Dr.  Schlegel.

    The team then looked at scramblase, an enzyme thought to be activated by ABCA1 causing PS and other phospholipids to redistribute until there are equal amounts inside and outside the cell membrane. Scramblase was triggered in some cells in the laboratory by increasing the concentration of calcium ions. In these cells neither the presence nor the absence of ABCA1, however, changed phospholipids transport. In cells that cannot be activated by adding calcium ions, adding ABCA1 as well, does not induce activation. The experiments have the same outcome whether the team used cells from Tangier individuals or knock-out mice. This suggests that ABCA1 does not code for scramblase and is not required for its activation.

    The team then turned to the function of ABCA1 in apoptosis. “We could not demonstrate that the addition or deletion of ABCA1 had any effect on the movement of PS to the cell surface in apoptotic cells,” says Dr. Schlegel.

    Another possibility was that ABCA1 functioned only in macrophages to cause the expression of PS on the cell surface. The absence of ABCA1, however, did not prevent macrophages from expressing PS on their surfaces. Further, the rate at which macrophages recognized and engulfed their target apoptotic cells remained constant whether ABCA1 was present in the macrophages or not.

    The study is published online in PLoS One.



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