Sci. Aging Knowl. Environ., 29 January 2003
Vol. 2003, Issue 4, p. nw18
[DOI: 10.1126/sageke.2003.4.nw18]


From Cheeseburgers to Chest Pains

Receptor might help fat clog arteries

Caroline Seydel;2003/4/nw18

Key Words: peroxisome proliferator-activated receptors • liver X receptors • orphan receptors • atherogenesis • lipoprotein lipase

Plaintiffs who sue burger joints might claim otherwise, but everyone knows that high-fat fare increases the risk of heart disease. Some secrets remain, however, about exactly how such a diet clogs arteries. Researchers investigating how the grease in that bacon double cheeseburger turns into artery-blocking gunk have discovered a pathway that allows an underappreciated lipid transporter to turn on genes, and it could explain how the transit vehicle fosters atherosclerosis.

Atherosclerosis results when white blood cells called macrophages gobble too many lipids and park in the blood vessel wall. These bloated macrophages trigger inflammation, which causes a debris pileup that blocks blood flow. Scientists have established that cholesterol-carrying low density lipoprotein (LDL) fosters plaque formation. Some studies, however, have shown that very low density lipoprotein (VLDL) and its main cargo, triglycerides, also contribute to the problem, although to what degree remains unclear. Macrophages respond to lipoproteins such as VLDL and LDL by activating nuclear receptor proteins called PPARs, which turn on genes to deal with the fatty molecules: PPAR{alpha} regulates oxidation and breakdown of fatty acids, whereas PPAR{gamma} directs lipid storage. Little was known about how a third protein, PPAR{delta}, responds to lipids.

Chawla and colleagues investigated whether lipoproteins activate PPAR{delta}. The researchers put a reporter gene into cultured cells that made them glow when PPAR{delta} became active; cells treated with VLDL shone brightly. Then, the researchers sought the genes that PPAR{delta} activates in response to VLDL. VLDL treatment turned on a gene called ADRP, whose protein product aids lipid storage in macrophages. Additional experiments suggest that VLDL activates ADRP through PPAR{delta}: Macrophages engineered to lack PPAR{delta} did not turn on ADRP in response to VLDL treatment. In addition, adding VLDL to cells that don't normally produce PPAR{delta} turned on ADRP only after the researchers engineered the cells to manufacture PPAR{delta}.

Activation of ADRP by VLDL might allow macrophages to store triglycerides, the researchers propose, contributing to the formation of artery-blocking plaques. Other evidence, however, suggests that the receptor could clear away triglyceride-rich lipoproteins, helping prevent plaque formation. Whether sucking up triglycerides is beneficial or harmful might hinge on the amount of triglycerides in the blood, says David Mangelsdorf of the University of Texas Southwestern Medical Center in Dallas: If PPAR{delta} can't keep up with the influx of triglycerides, plaques might result.

The paper is "a spectacular first step" in understanding how PPAR{delta} responds to lipids, says Mangelsdorf. Much more work lies ahead before VLDL's contribution to plaque formation is nailed down, cautions molecular biologist Gregory Shelness of Wake Forest University in Winston-Salem, North Carolina. Although identifying PPAR{delta} as a target for the triglyceride component of VLDL is a good start, he says, it doesn't explain how increased amounts of triglycerides in the blood help macrophages load up on vessel-blocking cholesterol. Filling in those greasy details might further demystify the dangers of a bacon double cheeseburger.

--Caroline Seydel

A. Chawla, C. H. Lee, Y. Barak, W. He, J. Rosenfeld, D. Liao, J. Han, H. Kang, R. M. Evans, PPAR{delta} is a very low-density lipoprotein sensor in macrophages. Proc. Natl. Acad. Sci. U.S.A., 22 January 2003 [e-pub ahead of print]. [Abstract] [Full Text]

January 29, 2003 Citation: C. Seydel, From Cheeseburgers to Chest Pains. Science's SAGE KE (29 January 2003),;2003/4/nw18

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