The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

An Introduction to Lipid Metabolism
Fig. 4.2. Cholesterol.
because it can be used as fuel for the TCA cycle (which is always needed), so homeostasis is
achieved by regulating the uptake and storage of the TCA cycle’s other main fuel, glucose.
4.3. Good and Bad LDL
The blood stream is used as a transporter not only of cholesterol but of all nutrients, so
it is not an especially predictable environment. LDL and HDL particles can, in particular,
suffer chemical changes during their journey which can, potentially, render them toxic to
the cells that are their intended destination. The main such modification is oxidation. In the
case of HDL, this is not much of a problem, because the destination cells (in the liver) are
purpose-built to deal with all manner of toxins and are not likely to suffer unduly. The
situation with LDL is much more serious. We know that LDL particles can undergo
modifications that make them toxic to most cells, not only because of in vitro experiments 9
but also because of the extreme care that the body takes to avoid this damage. Firstly, the
intracellular machinery that imports LDL specifically rejects (fails to bind) LDL that has
been significantly oxidized. 10 Secondly, a certain type of white blood cell called a monocyte
has the potential to turn into a vacuum cleaner for oxidized LDL, by attaching itself to the
artery wall and expressing a different type of surface protein that imports oxidized LDL
even more assiduously than unoxidized. 11 (We will consider a highly deleterious side-effect
of this process—atherosclerosis—in Section 5.1.) Thirdly, the blood contains high levels of
various chemicals that limit the rate at which LDL oxidation occurs in the first place; these
will also be discussed in detail later.
There is, however, a major paradox concerning the presence of oxidized LDL in the
blood stream. It was shown in 1984 12 that the oxidation of LDL by cultured cells is totally
abolished by the addition to the culture medium of antioxidants such as vitamin E, and
moreover that the concentration one needed to add was a good deal less than is present in
the blood stream. The same is true of the arterial intima. 13 Thus, ostensibly, LDL oxidation
should not be happening in the body at all! The only way out of this is to presume the
existence of oxidation “hot spots” in the extracellular medium, in which the concentration
of toxins (such as LECs) is much higher than average and/or that of antioxidants is much
lower. No such non-uniformity has been identified experimentally, but a possible one will
be described in Chapter 9; see also Section 10.13.
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