This Figure shows the pathways by which excess cholesterol is removed from macrophages in the arterial walls by a process mediated by HDL particles. It is a simplified version, but it is not wrong. In the bottom right-hand corner of the Figure there is cholesterol in extra-hepatic tissues (ie, the macrophages and plaques), and this can’t be broken down; it has to be removed from the cell. It is removed by being picked up by HDL particles, and from there it can be delivered back to the liver.
There are three arrows for delivery of the cholesterol from the HDL particles: 2 of them return cholesterol directly to the liver. One of these pathways is direct movement of the free cholesterol, the other is movement of cholesterol ester that has been formed from the free cholesterol in the HDL particles, and both pathways deliver cholesterol to the liver by binding of the HDL cholesterol to a receptor called the scavenger receptor B1, or SRB1.
However, cholesterol can also be delivered to the liver indirectly by a third pathway, via transfer to the VLDL and LDL particles, and then taken up by the liver via binding to the LDL receptor. The mechanism by which the first step in this transfer, from HDL particles to VLDL and LDL particles, occurs is via the protein cholesterol ester transfer protein, or CETP.
CETP is not present in most species, but it is present in humans, nonhuman primates, and rabbits (for some reason that nobody quite understands), and these are the species that turn out to be more susceptible to development of atherosclerotic CHD.
In some senses this pathway could be regarded as advantageous, because it delivers cholesterol to lipoprotein particles, ultimately the LDL particles, that physiologically deliver that cholesterol to where it is needed for building cellular structures – and where it is needed, there are LDL receptors to bind and transport the cholesterol. If a cell needs cholesterol, it up-regulates the LDL receptor, and this targets the cholesterol to be extracted for that tissue.
The only problem with a “cholesterol-preserving” CETP pathway is that human beings in the 20th and 21st centuries do not need to conserve cholesterol. Humans, especially humans in economically advanced societies today, consume a diet and live a lifestyle in which the LDL level is high, and therefore the LDL receptor is chronically down-regulated. Thus, although this CETP pathway had potential benefits in early evolution, ultimately what it is doing now is delivering cholesterol from a harmless lipoprotein, the HDL particle, to a lipoprotein like LDL that causes atherosclerosis.
J Clin Lipidol. 2011; 5(6).