Cholesterol, Lipoproteins and the Liver


Lipids are transported in the circulation packaged in lipoproteins. The clinical relevance of blood lipid levels is that abnormal levels of lipids in certain lipoproteins are linked to an increase risk of atherosclerosis. Atherosclerosis is a cardiovascular disease in which lipids and inflammatory cells accumulate in plaques within the walls of blood vessels. As a result, vessel walls are narrowed and clots may form, impeding blood flow and oxygen delivery and causing tissue injury. Heart disease occurs because the coronary arteries supplying the heart are a major site where atherosclerotic plaques form.

The liver is central to the regulation of cholesterol levels in the body. Not only does it synthesize cholesterol for export to other cells, but it also removes cholesterol from the body by converting it to bile salts and putting it into the bile where it can be eliminated in the feces. Furthermore, the liver synthesizes the various lipoproteins involved in transporting cholesterol and other lipids throughout the body. Cholesterol synthesis in the liver is under negative feedback regulation.  Increased cholesterol in a hepatocyte leads to decreased activity of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis.


Many important molecules in the body are lipids. But transporting these molecules around the body through the blood presents an obvious problem, because, by definition, lipids are nonpolar and thus not very soluble in water. Small amounts of fatty acids are transported in the blood bound to blood proteins. These are called free fatty acids (despite the binding). Beyond this, however, other lipids are transported in special particles called lipoproteins.

To emphasis, lipoproteins are not molecules, but rather particles comprised of several thousand molecules. These particles solve the problem of lipid/water incompatibility via the amphipathic nature of phospholipids. One end of these molecules is polar and the other end nonpolar.

Lipoproteins have a single layer of phospholipid molecules on their outside, surrounding a central core. (By contrast, plasma membranes are comprised of a BILAYER.) Since the polar part of each phospholipid faces out, the outside of the phospholipid molecule is polar and thus compatible with the surrounding water environment. On the other hand, the nonpolar portion of each phospholipid faces inward, and thus is compatible with the very nonpolar ingredients of the core of the lipoprotein. In addition, some cholesterol is found in the outer layer of phospholipid.

As shown in the figure, the outer layer of the lipoprotein also has a protein molecule called an apolipoprotein. Like phospholipids, this protein is amphipathic and helps stabilize the particle. But even more important, the protein serves to identify the specific lipoprotein. For example, some lipoproteins transport dietary lipids from the small intestine to adipocytes and the liver. Other lipoproteins transport cholesterol between different part of the body. Each type of lipoprotein can be identified because it has a different apolipoprotein.

At the target cell, in some cases, the apolipoprotein binds to a receptor and then the lipoprotein is then taken up by receptor mediated endocytosis. In other cases, an enzyme on the capillary wall, termed lipoprotein lipase, unloads triacylglycerol from the lipoprotein by breaking triacylglycerol into fatty acids and glycerol.

(The terminology here often confuses students. Remember the lipoprotein is a particle, the apolipoprotein is a protein that is part of the particle.

The core of the lipoprotein contains the most nonpolar substances. A lipoprotein formed in the small intestine, for example, would have much triacylglycerol (triglyceride) derived from the diet. Esterified cholesterol is also found in the core. ( "Esterified" means that a fatty acid is combined with the cholesterol at its one vaguely polar spot to make an even more nonpolar molecule.) A small amount of ordinary cholesterol is also found in the phospholipid outer layer.