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(NaturalNews) Cardiovascular disease is the leading cause of death in North America and other parts of the world with a western diet and lifestyle. High cholesterol levels have taken most of the blame, and statin drugs to lower LDLs ("bad cholesterol") are among the most lucrative pharmaceuticals on the market. Statins are quite effective at lowering LDL levels, but this is not what matters. What matters of course is the prevention of heart disease, and statins certainly haven't dislodged cardiovascular disease from its position as the leading cause of death. In fact, they have created problems of their own.

Yet there is a connection between cholesterol and heart disease. It has been known for some time now that there is a strong inverse correlation between HDL ("good cholesterol") levels and cardiovascular events, i.e. the higher the HDL level, the lower the risk of heart disease. This protective effect of HDL was observed even in patients whose LDL levels were lowered to < 70mg/dL with statins (1).

This protective effect has made HDL a tempting target for pharmaceutical intervention. HDLs pick up waste cholesterol from tissues and transfer most of it to LDL particles. This transfer is catalyzed by an enzyme called cholesteryl ester transfer protein (CETP). It was reasoned that inhibition of this protein, and therefore the suppression of cholesterol transfer to LDLs, should keep HDL levels high and protect against atherosclerosis and heart disease.

In late 2006 phase 3 clinical trials of one such CETP inhibitor, torcetrapib, were halted. The drug did increase HDL levels by 72.1% and decrease LDL levels by 24.9%. Unfortunately, it also increased the risk of cardiac events by 25%, death from vascular causes by 40%, and death from all causes by 58%(2). It had no effect on the progression of atherosclerosis. As the authors put it: "Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition" (2).

First, a little background (3):

Lipids - free fatty acids, triglycerides, free and esterified cholesterol and the fat-soluble vitamins A, D, E, and K - are hydrophobic, and special carriers are needed to transport them in the blood. Free fatty acids are carried by albumin; the remaining lipids are transported in water-miscible containers called lipoproteins.

Lipoproteins are micellar structures. Think of the lipid bilayer of a cellular membrane, but with the inner layer missing. The remaining outer monolayer again consists of phospholipids and cholesterol, with the hydrophilic surface facing outward, but the inward facing hydrophobic (lipophilic) surface is now exposed. In other words, elimination of the inner layer of the lipid bilayer creates a water-miscible container for lipids. The phospholipid/cholesterol micelle is only the container. Proteins called apolipoproteins have to be added to the surfaces of these lipoproteins to give them functionality.

Our cells make three types of lipoproteins: chylomicrons deliver dietary lipids, very low density lipoproteins (VLDLs) distribute hepatic lipids, and high density lipoproteins (HDLs) collect surplus tissue cholesterol. As they discharge their lipid cargo, chylomicrons change into chylomicron remnants; VLDLs change into VLDL remnants, also called intermediate density lipoproteins (IDLs), which can further change to become low density lipoproteins (LDLs). Chylomicrons and VLDLs distribute only triglycerides to the tissues, a subject that doesn't concern us here. Cholesterol trafficking is controlled by HDLs and LDLs.

Since VLDLs are the precursors of LDLs, let's start here. VLDLs are created in the liver and deliver lipids from the liver to the tissues. These are lipids that were either synthesized by the liver or recovered from recycled lipoprotein remnants. The properties and fate of VLDLs are determined by three different apolipoproteins on their surfaces: apo B100, apo C-II and apo E.

Apo B100 defines a VLDL particle; it remains fixed to the particle throughout its life cycle and gets passed on to its descendants, IDLs and LDLs. Apo C-II is required for unloading the triglyceride cargo by binding to, and acting as cofactor for, an enzyme called lipoprotein lipase displayed on capillary walls. The triglycerides are hydrolyzed and the free fatty acids are taken up by the tissues. Apo E is needed for the disposal of the remnant lipoprotein. The lipoprotein binds to an hepatic apo E receptor, is taken up whole and degraded.

Both apo C-II and apo E are labile; they can be transferred from and to HDLs. A triglyceride-depleted VLDL particle loses its apo C-IIs and is ready for elimination via apo E binding in the liver. However, it can additionally lose its apo Es and be left only with a copy of apo B100. Such a particle is called LDL. It can now only bind, via apo B100, to LDL receptors in the liver or on cholesterol-starved tissues.

Most tissues are able to synthesize all the cholesterol they need and do not rely on the liver or on dietary sources. However, growing tissues and organs synthesizing steroidal hormones require large amounts of cholesterol. Cells in those tissues display LDL receptors on their plasma membranes; the number of LDL receptors is related to a cell's need for cholesterol. When an LDL particle binds to an LDL receptor via the apo B100 protein, the whole lipoprotein is taken up by the cell.

Liver cells also express LDL receptors, and LDL particles that weren't taken up by extra-hepatic tissues are removed in this way.

HDLs are synthesized in the liver and, to a lesser extent, the small intestine. They have two functions. First, HDLs are involved in triglyceride transport by supplying apo C-II and apo E proteins to chylomicrons and VLDLs. Secondly, they collect excess cholesterol from tissues and transfer it either to cholesterol-hungry cells for use or to the liver for disposal in the bile.

HDLs are excreted empty or in a lipid-poor form as collapsed disk-shaped bags. Apo A-I is the defining HDL protein. It is its only apolipoprotein at the initial stage and present throughout the particle's life cycle. Apo A-I binds to hepatic HDL receptors and serves as cofactor for an enzyme catalyzing cholesterol esterification.

Excess cholesterol mainly comes from cellular debris, including damaged lipoproteins. Cellular waste is taken up by macrophages and the recovered cholesterol is displayed on the plasma membranes for pick-up by HDLs. Lipoproteins can suffer oxidative damage to the lipid or protein components. In addition, elevated blood glucose levels can damage the apolipoproteins by glycating lysyl residues. Damaged lipoproteins are dysfunctional and are quickly eliminated by macrophages.

The uptake of cholesterol by HDLs requires its conversion to cholesteryl esters; this esterification is catalyzed by the HDL-bound enzyme lecithin: cholesterol acyltransferase (LCAT). As the name of the enzyme implies, the source of the fatty acid used to esterify cholesterol is the lecithin part of a phospholipid.

The collection and disposal of surplus cholesterol by HDLs is called reverse cholesterol transport (RCT), and it can occur directly or indirectly.

In the direct route, the HDLs themselves deliver the cholesterol to the target cells. Either they bind to a so-called scavenger receptor class B type I (SR-BI) on extra-hepatic tissue and transfer their cholesterol load, or they bind via apo A-I to an hepatic HDL receptor and are taken up whole and dismantled.

In the indirect route, the HDLs transfer cholesterol to VLDLs, many of which become LDLs. The LDLs in turn can either be broken down in the liver or taken up by extra-hepatic tissues. In the latter case, the LDL apo B-100 binds to an LDL receptor on a cell that needs cholesterol; the cell then takes up the whole lipoprotein.

The transfer of cholesteryl esters between HDLs and apo B10-carrying lipoproteins, like VLDLs or LDLs, is catalyzed by the HDL-bound enzyme cholesteryl ester transfer protein (CETP), which gets us back to the inhibition of CETP by torcetrapib. The drug was meant to suppress the HDL to LDL cholesterol transfer, the indirect route of reverse cholesterol transport.

The failure of torcetrapib is undoubtedly a combination of off-target and on-target effects, i.e. side effects specific to this particular CETP inhibitor and unintended consequences of CETP inhibition itself (4). The off-target effects included an elevation in blood pressure as well as more direct vascular effects like impaired endothelial function and increased inflammation, which are thought to be responsible for the observed increase in the number of deaths from cancer and infection in the treatment group.

There is also the more fundamental problem that the intended effect itself, namely CETP inhibition, may impair reverse cholesterol transport. In other words, the very concept of targeting HDL cholesterol therapeutically may be flawed. Still, the torcetrapib failure isn't likely to end attempts to target HDL. Other avenues of attack are already considered, particularly the possibility of up-regulating the expression of apolipoprotein A-I transcription to increase the number of HDL particles (4). Yet there seems something wrong with the whole approach.

First, cholesterol is clearly more than just a risk factor for atherosclerosis and cardiovascular disease. It is a vital substance, an integral component of cell membranes, and the starting material for all other steroids. While most cells can synthesize their own cholesterol, growing tissues and those synthesizing steroidal hormones need extra cholesterol. Those cells express LDL receptors to bind and take up cholesterol-rich lipoproteins. Clearly, cholesterol transport is at least in part responsible for supplying cholesterol, not just for disposing of it. If fact, the term reverse cholesterol transport wouldn't make any sense if there weren't a forward cholesterol transport to extra-hepatic tissues as well. Any interference in cholesterol cycling must affect cholesterol delivery to tissues that need it.

Secondly, the severity of atherosclerosis isn't simply proportional to the amount of circulating cholesterol. In fact, a significant percentage of patients with cardiovascular disease have normal cholesterol levels. Nor is cholesterol deposition randomly or uniformly distributed throughout the arteries. Attempts to prevent or reduce atherosclerosis by merely mainpulating cholesterol levels, without addressing other risk factors like oxidative stress and inflammation, would seem to be doomed to failure.

Torcetrapib may well have had unintended consequences (which drug doesn't?), but one has to wonder about the wisdom of interfering in a control system like the cholesterol distribution system without a clear understanding of the workings of that system and the consequences of interference. A statistical correlation was found between HDL levels and the degree of atherosclerosis. On this empirical basis, it was decided that raising HDL levels would reduce the risk of cardiovascular disease. Apparently no thought was given to the mechanism by which that was to be accomplished, or how high HDL levels actually have to be to keep atherosclerosis at bay. Hardly what one might call rational drug design.

References:

1. Philip Barter, Antonio M. Gotto,, John C. LaRosa, Jaman Maroni, Michael Szarek, Scott M. Grundy, John J.P. Kastelein, Vera Bittner, and Jean-Charles Fruchart. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N. Engl. J. Med. 2007;357(13):1301-1310.

2. Philip J. Barter, Mark Caulfield, Mats Eriksson, Scott M. Grundy, John J.P. Kastelein, Michel Komajda, Jose Lopez-Sendon, Lori Mosca, Jean-Claude Tardif, David D. Waters, Charles L. Shear, James H. Revkin, Kevin A. Buhr, Marian R. Fisher, Alan R. Tall, and Bryan Brewer. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 2007; 357(21):2109-2122.

3. Harper's Biochemistry, 25th Edition, Appleton & Lange 2000.

4. Daniel J. Rader. Illuminating HDL - is it still a viable therapeutic target? N. Engl. J. Med. 2007; 357(21): 2180-2183.

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