Cholesterol

Dietary sources of cholesterol are limited to foods of animal origin. Cholesterol is an amphipathic molecule that is composed of a steroid nucleus and a branched hydrocarbon tail (Figure 6). Cholesterol occurs naturally in two forms, either as free (nones-terified) cholesterol or esterified to a fatty acid (cho-lesteryl ester). If esterified, the fatty acid is linked to cholesterol at the number 3 carbon of the sterol ring.

Cholesterol serves a number of important functions in the body. Free cholesterol is a component of cell membranes and along with the fatty acid profile of the phospholipid bilayer determines membrane fluidity. The intercalation of free cholesterol into the phospho-lipid bilayer restricts motility of the fatty acyl chains and hence decreases fluidity. Free cholesterol is critical for normal nerve transmission. It makes up approximately 10% (dry weight) of total brain lipids. Cholesterol is a precursor of steroid hormones (i.e., estrogen and testosterone), vitamin D, adrenal steroids (i.e., hydrocortisone and aldosterone), and bile acids. This latter property is exploited in certain approaches to decrease plasma cholesterol levels by preventing the resorption of bile acids (recycling) and hence forcing the liver to use additional cholesterol for bile acid synthesis and in so doing creating an alternate mechanism for cholesterol excretion.

The receptor-mediated cellular uptake of cholesterol from lipoprotein particles is critical to maintaining intracellular and whole body cholesterol homeostasis. Once internalized, lipoprotein-associated cholesterol that is released from lyso-somes has three major effects in the cell. The free cholesterol inhibits the activity of 3-hydroxy 3-methylglutaryl CoA reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis. This property serves to decrease cholesterol biosynthesis commensurate with the uptake of cholesterol from circulating lipoprotein particles and

H3C H3C

H3C H3C

Figure 6 Cholesterol.

hence protects the cell from accumulating excess intracellular cholesterol. Free cholesterol inhibits the synthesis of receptors that mediate the uptake of lipoproteins from the bloodstream, thereby limiting the amount of additional cholesterol taken up by the cell. Free cholesterol increases the activity of acyl CoA cholesterol acyltransferase (ACAT), the intracellular enzyme that converts free cholesterol to cholesteryl ester. A high level of intracel-lular free cholesterol is cytotoxic, whereas cholesteryl ester is a highly nonpolar molecule and coalesces into a lipid droplet within the cell, preventing interaction with intracellular components. Increased ACAT activity is an important mechanism in preventing the accumulation of intracellular free cholesterol.

Cholesterol can be esterified intracellularly, as previously indicated, by ACAT. ACAT uses primarily oleoyl CoA as substrate and the resulting product is primarily cholesteryl oleate. Cholesterol can also be esterified in plasma by lecithin cholesterol acyl-transferase (LCAT). LCAT uses phosphotidylcholine as substrate; the resulting products are primarily cholesteryl linoleate and lysolecithin. Cholesteryl ester is less polar than free cholesterol and this difference dictates how the two forms of cholesterol are handled—intracellularly and within lipoprotein particles.

Approximately one-third of cholesterol in plasma circulates as free cholesterol and approximately two-thirds as cholesteryl ester. Cholesterol in circulation is carried on all the lipoprotein particles (both intest-inally derived chylomicrons and hepatically derived very low-density lipoprotein) or those generated during the metabolic cascade (intermediate-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)). Free cholesterol is sequestered on the surface of lipoprotein particles within the phospholipid monolayer, whereas choles-teryl ester resides in the core of the lipoprotein particle. The majority of the cholesterol in circulation is carried on LDL particles. Cholesteryl ester is the major component of atherosclerotic plaque. In the arterial wall, cholesteryl ester is derived from the infiltration of lipoprotein-associated cholesteryl ester resulting from LCAT activity or is synthesized in situ as a result of ACAT activity. The fatty acid profile of the cholesteryl ester in arterial plaque can provide some indication of its source.

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