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.

Types of Lipoproteins

Lipoproteins are particles that contain triacylglycerol (TAG), cholesterol, phospholipids and amphipathic proteins called apolipoproteins. (You can refresh your memory about the structure of lipoproteins by visiting the webpage Lipoproteins from fall quarter). Lipoproteins can be differentiated on the basis of their density, but also by the types of apolipoproteins they contain. The degree of lipid in a lipoprotein affects its density—the lower the density of a lipoprotein, the more lipid it contains relative to protein. The four major types of lipoproteins are chylomicrons, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).

The figure below summarizes the fates of the various lipoproteins. Refer to it as you read about the different lipoproteins.

Disorders and Drug Treatments

The link between cholesterol and heart disease was recognized through the study of individuals with familial hypercholesterolemia. Individuals with this disorder have several-fold higher levels of circulating LDL due to a defect in the function of their LDL receptors. Without functioning LDL receptors, LDL is not cleared from the circulation. As well, because cholesterol cannot get into cells efficiently, there is no negative feedback suppression of cholesterol synthesis in the liver.  Individuals with familial hypercholesterolemia may have strokes and heart attacks starting in their 30's.

More common in the general population is dyslipidemia, which is the term that is used if lipid levels are outside the normal range.  In a typical lipid profile, the fasting levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides are determined. High levels of LDL cholesterol (the so-called “bad cholesterol”) greatly increase the risk for atherosclerosis because LDL particles contribute to the formation of atherosclerotic plaques. Low levels of HDL cholesterol (the so-called "good cholesterol") are an independent risk factor, because reverse cholesterol transport works to prevent plaque formation, or may even cause regression of plaques once they have formed. HDL may also have anti-inflammatory properties that help reduce the risk of atherosclerosis.  Fasting triglyceride levels are used to estimate the level of VLDL. High levels of triglycerides are also associated with an increased risk for atherosclerosis, although the mechanism is not entirely clear.

The most important drugs for the treatment of dyslipidemia are by far, the statins. Statins have been shown in multiple clinical trials to reduce cardiovascular events and mortality.

In the past, several different drugs have been used to treat dyslipidemia, however the most recent treatment guidelines recommend mainly statin therapy at different intensities according to the patient's risk for cardiovascular disease. However, statins may cause adverse effects in some patients, or in others, statins by themselves may not provide sufficient lowering of LDL cholesterol.  These patients may benefit from the use of the other two drugs listed below.