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| Dr. Levinson |
It has long been known from epidemiological studies that elevated levels of high density lipoprotein cholesterol (HDLC) in serum or plasma are inversely associated with coronary heart disease (CHD), and a more powerful statistical predictor of CHD than low density lipoprotein cholesterol (LDL).
Each 10 mg/dL increase in HDLC translates into about a 23 percent decrease in risk for men and women. This inverse association has lead to the concept of reverse cholesterol transport (RCT), a process whereby cholesterol is thought to be removed from peripheral tissues by HDL and deposited in the liver for disposal in the bile.
It is thought accumulation of lipids in macrophages is an early event in arteriosclerosis, and RCT removes cholesterol from these cells. Over the past decade a goodly amount of new information regarding HDL species, receptors and transporters has accumulated. This has lead to a much better understanding of HDL metabolism.
It has also lead to the idea that therapeutic modifications facilitating RCT will reduce CHD, and several drugs are now in development or being tested in clinical trials. Nevertheless, several recent studies suggest increased levels of HDLC in plasma may not be a good marker for confirming therapeutic effects. Moreover, these studies allow room to question the RCT hypothesis as it currently stands itself.
According to the current hypothesis, it is thought the transporter ABCA1 is a first step that moves cholesterol and phospholipid from tissue to nascent lipid poor apo A-I, prebeta-migrating, so called short lived HDL. A mutation in this transporter is responsible for Tangier disease, where HDLC levels are very low. Lipid poor HDL takes up additional cholesterol from tissue probably by diffusion, facilitated by the phospholipid rich surface of HDL. With continuing lipid enrichment, apo A-I forms discoid particles, a process mediated through lecithin:cholesterol acyltransferase.
As more lipid accumulates in the particles, they become the predominant species of spherical, alpha-migrating HDL. Recent evidence indicates the transporter ABCG1 and possibly G4 can move cholesterol to mature spherical HDL and cholesterol in spherical HDL can be extracted by scavenger receptor (SR) -BI , found in the liver.
Also, it is thought cholesterol can be returned to the liver through the cholesteryl ester transfer protein (CETP) pathway, whereby cholesterol from HDL can be transferred to very low density lipoproteins (VLDL) in exchange for triglycerides, and the VLDL containing this cholesterol can be taken up by the liver LDL receptor and remnant receptors.
Clinical Trials
Nevertheless, some recent studies question these concepts. In preliminary studies, depending on dosage, the CETP inhibitor torcetrapib increased HDLC 16-106 percent and decreased LDLC by nine to 42 percent. Although there was a small increase in blood pressure, the positive modification of lipid profiles was thought to be more then enough to negate this detrimental effect.
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