Cholesterol, as just about everyone now knows, wears two hats, blackand white. "Bad" cholesterol builds up atherosclerotic plaques in thearteries. These lead to atherosclerosis, the largest single cause ofdeath in the western world; a million a year in the U.S. alone.
"Cholesterol goes about its business in the body, mainly equippingcells with membranes, and synthesizing sex hormones. Only whenthere's too much of it does it go bad.
In pursuit of its metabolic activities, cholesterol hitches rides on afleet of common carriers, called apolipoproteins (apoLP). Like lawfulmedallion taxicabs in a big city, competing with less legal gypsycabs, some apoLP transporters cater to law-abiding cholesterol;others to the nefarious version.
Specifically _ if over-simply _ the good-guy proteins carry the label,"apolipoprotein A" (apo-A); the bad-guy jitneys, apo-B and apo-E.
On a police line-up, what marks the good from the bad apoLPs istheir molecular density. Low-density lipoproteins (LDL) are bad;very low-density lipoproteins (VLDL), very bad. Their passengersare the villainous cholesterols that deliver fatty substances to build upplaque in the hardening arteries.
The high-density lipoproteins (HDL) are the good-guy transporters.
When a molecule of white-hat cholesterol has finished its job, onecan picture it boarding an HDL for a trip to the liver, which breaks itdown and ships it out of the body.
"But things are not that straightforward," observed physician andclinical nutritionist Marie Lindner. "People talk about `good' and`bad' cholesterol, because it's a very simple way of dealing with it.Cholesterol that contains apo-B or E is called bad; apo-A, good.
"But in fact," she continued, "B plays a role in the artery as principalcholesterol transporter. If there's way too much low-densitylipoprotein, which is apo-B-carrying cholesterol, and VLDL, whichhas both B and E, you get negative consequences a high percent ofthe time. It's really the protein that's the atherogenic bad guy."
Scientists have, so far, discerned four distinct lipoproteins, numberedI, II, III and IV, in the apo-A molecule. Lindner explained: "Inprotecting against atherosclerosis, apo-A-I appears to be the criticalprotein, the one that makes up most of the protein in HDL-cholesterolparticles. The amount of HDL directly correlates with the amount ofapo-A-I."
Lately, the research spotlight has focused on apo-A-IV, which,Lindner added, "appears to have an important role in reversecholesterol transport. It may activate the enzyme that's thought to bepartly responsible for removing cholesterol, and returning it to theliver for breakdown and recycling. Apo-A-IV is not present inhumans in as high amounts as A-I and A-II."
Lindner, an atherosclerosis specialist, is director of strategic planningfor RPR Gencell, a division of Rhone-Poulenc Rorer Inc., inCollegeville, Pa.
This week's Science, dated Aug. 16, 1996, carries a paper by RPRGencell gene and cell therapy researchers in Vitry-sur-Seine, France,titled: "Protection against atherogenesis in mice mediated by humanapolipoprotein A-IV."
"That article," Lindner observed, "adds new knowledge to theprotective effect of apolipoprotein A-IV against atherosclerosis."
The authors generated two strains of transgenic mice, which expresshuman apo-A-IV specifically in the liver. Both are prone toatherosclerosis; one lacks the low-density apo-E transporter.
Their experiments showed that human apo-A-IV could substitute forthe mouse apo-A-I, form HDL-like particles and protect moreefficiently than the latter against atherogenesis.
They reported this effect in apo-E-deficient mice, which arespontaneously susceptible to the disease, as well as in the othertransgenic mice, fed on a cholesterol-rich diet that reliably producesatherosclerosis.
"Whenever you do a study with a transgenic animal," Lindnerpointed out, "you have very high amount of this apo-A-IV protein,where normally there would be very small amounts. It doesn't mimicthe human situation at all."
She suggested that "a lot of metabolic aspects need to be elucidated.For instance: If you excess amounts of apo-A-IV protein to animalsor people, and let it circulate, would you get the same effect?"
The French team concluded, "Our results also suggest possible newapproaches to the treatment of atherosclerosis that do not require anincrease in apo-A-I and HDL-cholesterol concentrations."
On this score, Lindner observed: "I can imagine several differentways of coming up with therapies in humans. The obvious one fromour standpoint of Gencell is gene therapy. But I think whenever youhave a good animal model like this for atherosclerosis, it's just asobvious to conceive of this as a potential small-molecule approach."n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.