Sci. Aging Knowl. Environ., 16 March 2005
Vol. 2005, Issue 11, p. nf20
[DOI: 10.1126/sageke.2005.11.nf20]


How Low Can You Go?

Molecule might improve statins' cholesterol-depleting power

R. John Davenport

Efforts to lower cholesterol can backfire, but new work suggests a route for attaining that goal. Cholesterol-abating drugs spur production of an enzyme that helps manufacture the fatty compound, undermining their effectiveness. The results suggest that a cholesterol-like molecule helps eliminate the enzyme. Tapping into this mechanism might aid efforts to improve the drugs.

Too many bacon double cheeseburgers--or an unlucky genetic draw--can elevate cholesterol quantities in the blood, inducing plaques in vessels and increasing the risk of a heart attack or stroke. Millions of people take statins to reduce the burden. These drugs cripple HMG CoA reductase, an enzyme that makes mevalonate, which in turn becomes cholesterol through a series of transformations. Statins trim cholesterol production, but their real power comes because cells respond by churning out the LDL receptor. This molecule grabs and disposes of LDL--so-called "bad cholesterol"--and thus quantities of the lipid drop dramatically. However, cells also respond to declining cholesterol by generating more HMG CoA reductase, counteracting the beneficial effects of statins. To improve on these drugs, researchers want to understand how cells control HMG CoA reductase amounts.

Previous studies revealed that dosing cells with lanosterol--an intermediate compound between mevalonate and cholesterol--reduces HMG CoA reductase activity. Now, biochemist Russell DeBose-Boyd of the University of Texas Southwestern Medical Center in Dallas and colleagues have examined how lanosterol influences HMG CoA reductase.

To investigate, the team added different amounts of lanosterol to cultured human connective tissue cells. Cells treated with more lanosterol made less HMG CoA reductase, the researchers found. In treated cells, HMG CoA reductase molecules accumulated ubiquitin, a tag that sends proteins to the cellular incinerator. Doses of lanosterol enhanced HMG CoA reductase breakdown only when cells carried particular proteins known to help stitch ubiquitin onto the enzyme. In addition, lanosterol accelerated ubiquitin attachment to HMG CoA reductase in a test tube experiment, indicating that lanosterol itself--and not a derivative that cells create--was responsible. Together, the findings suggest that lanosterol prompts cells to dismantle HMG CoA reductase.

Reducing HMG CoA reductase output prompts LDL receptor production by urging cells to send a gene-activating molecule called SREBP to the nucleus, where it activates the LDL receptor gene. The researchers found that SREBP doesn't flock to the nucleus when cells are treated with lanosterol, but it does when they're exposed to other cholesterol-like compounds. That result suggests that lanosterol depletes HMG CoA reductase without altering LDL receptor amounts.

"The study really gets at where the action is," says biochemist Gene Ness of the University of South Florida in Tampa. Statins can only reduce cholesterol so far, and higher doses might come with side effects. Drugs that mimic lanosterol might lower cholesterol amounts further and enhance statins' effectiveness, he says. However, Ness notes that cell lines that are amenable to culturing lose the feedback mechanism that ramps up HMG CoA reductase, and further studies will need to verify that lanosterol affects normal cells in the same way. If so, drugs based on the molecule might bring lower cholesterol within reach.

March 16, 2005
  1. B.-L. Song, N. B. Javitt, R. A. DeBose-Boyd, Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol. Cell Metab. 1, 179-189 (2005). doi:10.1016/j.cmet.2005.01.001 [CrossRef][Medline]
Citation: R. J. Davenport, How Low Can You Go? Sci. Aging Knowl. Environ. 2005 (11), nf20 (2005).

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