Thursday, December 17, 2009

3. Cholesterol and Lipid Management

In addition to some knowledge about the brain, you will also need to know something about the processes that deliver fats and cholesterol to all the tissues of the body, with a special focus on the brain. Most cell types can use either fats or glucose (a simple sugar derived from carbohydrates) as a fuel source to satisfy their energy needs. However, the brain is the one huge exception to this rule. All cells in the brain, both the neurons and the glial cells, are unable to utilize fats for fuel. This is likely because fats are too precious to the brain. The myelin sheath requires a constant supply of high quality fat to insulate and protect the enclosed axons. Since the brain needs its fats to survive long-term, it is paramount to protect them from oxidation (by exposure to oxygen) and from attack by invasive microbes.

Fats come in all kinds of shapes and sizes. One dimension is the degree of saturation, which concerns how many double bonds they possess, with saturated fats possessing none, monounsaturated fats having only one, and polyunsaturated fats having two or more. Oxygen breaks the double bond and leaves the fat oxidized, which is problematic for the brain. Polyunsaturated fats are thus the most vulnerable to oxygen exposure, because of multiple double bonds.

Fats are digested in the intestine and released into the blood stream in the form of a relatively large ball with a protective protein coat, called a chylomicron. The chylomicron can directly provide fuel to many cell types, but it may also be sent to the liver where the contained fats are sorted out and redistributed into much smaller particles, which also contain substantial amounts of cholesterol. These particles are called "lipoproteins," (henceforth, LPP's) because they contain protein in the spherical shell and lipids (fats) in the interior. If you've had your cholesterol measured, you've probably heard of LDL (low density LPP) and HDL (high density LPP). If you think these are two different kinds of cholesterol, you would be mistaken. They are just two different kinds of containers for cholesterol and fats that serve different roles in the body. There are actually several other LPP's, for example, VLDL (very-high) and IDL (intermediate), as shown in the accompanying diagram. VLDL,IDL,LDL,HDL In this essay I will refer to these collectively as the XDL's. As if this weren't confusing enough, there is also another unique XDL that is found only in the cerebrospinal fluid, that supplies the nutritional needs of the brain and nervous system. This one doesn't seem to have a name yet, but I will call it "B-HDL," because it is like HDL in terms of its size, and "B" is for "brain [13]"

An important point about all the XDL's is that they contain distinctly different compositions, and each is targeted (programmed) for specific tissues. A set of proteins called "apolipoproteins" or, equivalently, "apoproteins" ("apo's" for short) figure strongly in controlling who Chylomicron Structure gets what. As you can see from the schematic of the chylomicron shown at the right, it contains a rainbow of different apo's for every conceivable application. But the XDL's are far more specific, with HDL containing "A," LDL containing "B," VLDL containing "B" and "C," and IDL containing only "E." The apo's have special binding properties that allow the lipid contents to be transported across cell membranes so that the cell can gain access to the fats and choleseterol contained inside.

The only apo that is of concern to us in the context of this essay is apoE. ApoE is very important to our story because of its known link with Alzheimer's disease. ApoE is a protein, i.e., sequence of amino acids, and its specific composition is dictated by a corresponding DNA sequence on a protein-coding gene. Certain alterations in the DNA code lead to defects in the ability of the transcribed protein to perform its biological roles. ApoE-4, the allele associated with increased risk to Alzheimer's, is presumably unable to perform its tasks as efficiently as the other alleles. By understanding what apoE does, we can better infer how the consequences of doing it poorly might impact the brain, and then observe experimentally whether the features of the Alzheimer's brain are consistent with the roles played by apoE.

A strong clue about apoE's roles can be deduced from where it is found. As I mentioned above, it is the only apo in both B-HDL in the cerebrospinal fluid and IDL in the blood serum. Only selected cell types can synthesize it, the two most significant of which for our purposes are the liver and the astrocytes in the brain. Thus the astrocytes provide the linkage between the blood and the cerebrospinal fluid. They can usher lipids and cholesterol across the blood-brain barrier, via the special key which is apoE.

It turns out that, although apoE is not found in LDL, it does bind to LDL, and this means that astrocytes can unlock the key to LDL in the same way that they can gain access to IDL, and hence the cholesterol and fatty acid contents of LDL are accessible to astrocytes as well, as long as apoE is functioning properly. The astrocytes reshape and repackage the lipids and release them into the cerebospinal fluid, both as B-HDL and simply as free fatty acids, available for uptake by all parts of the brain and nervous system [13].

One of the critical reshaping steps is to convert the fats into types that are more attractive to the brain. To understand this process you need to know about another dimension of fats besides their degree of saturation, which is their total length. Fats have a chain of linked carbon atoms as their spine, and the total number of carbons in a particular fat characterizes it as short, medium length, or long. The brain works best when the constituent fats are long, and, indeed, the astrocytes are able to take in short chain fats and reorganize them to make longer chain fats [24].

A final dimension of fats that plays a role is where the first double bond is located in a polyunsaturated fat, which distinguishes omega-3 from omega-6 fats (position 3; position 6). Omega-3 fats are very common in the brain. Certain ones of the omega-3 and omega-6 fats are essential fatty acids, in that the human body is unable to synthesize them, and therefore depends upon their supply from the diet. This is why it is claimed that fish "makes you smart": because cold water fish is the best source of essential omega-3 fats.

Now I want to return to the subject of the XDL's. It is a dangerous journey from the liver to the brain, as both oxygen and microbes are found in abundance in the blood stream. The XDL's protective shell contains both LPP's and unesterified cholesterol, as well as the signature apo that controls which cells can receive the contents, as shown in the accompanying schematic. lipoprotein schematic The internal contents are esterified cholesterol and fatty acids, along with certain antioxidants that are conveniently being transported to the cells packaged in the same cargo ship. Esterification is a technique to render the fats and cholesterol inert, which helps protect them from oxidation [50]. Having the antioxidants (such as vitamin E and Coenzyme Q10) along for the ride is also convenient, as they too protect against oxidation. The cholesterol contained in the shell, however, is intentionally not esterified, which means that it is active. One of its roles there is to guard against invasive bacteria and viruses [54]. Cholesterol is the first line of defense against these microbes, as it will alert the white blood cells to attack whenever it encounters dangerous pathogens. It has also been proposed that the cholesterol in the XDL's shell itself acts as an antioxidant [48].

HDL's are mostly depleted of the lipid and cholesterol content, and they are tasked with returning the empty shell back to the liver. Once there, cholesterol will be recommissioned to enter the digestive system as part of the bile, which is produced by the gall bladder to help digest ingested fats. But the body is very careful to conserve cholesterol, so that 90% of it will be recycled from the gut back into the blood stream, contained in the chylomicron that began our story about fats.

In summary, the management of the distribution of fats and cholesterol to the cells of the body is a complex process, carefully orchestrated to assure that they will have a safe journey to their destination. Dangers lurk in the blood stream, mostly in the form of oxygen and invasive microbes. The body considers cholesterol to be precious cargo, and it is very careful to conserve it, by recycling it from the gut back to the liver, to be appropriately distributed among the XDL's that will deliver both cholesterol and fats to the tissues that depend upon them, most especially the brain and nervous system.