Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics, Carbohydrate and Lipid Metabolism
Synthesis, Transport, and Excretion of Cholesterol
Cholesterol Transport - Transport of Cholesterol Between Tissues (Fig. 27.6)

In humans, the plasma Cholesterol level is approximately 200 mg/100 mL and tends to increase with age, showing significant individual variations. The majority of cholesterol exists in the esterified form and is transported in Blood Plasma as a component of Lipoproteins. Most of this cholesterol is associated with LDL (β-lipoproteins). However, if VLDL levels are quantitatively dominant, the cholesterol fraction of VLDL becomes predominant.

Radioactive tracer studies show that dietary cholesterol equilibrates with plasma cholesterol within a few days, and with tissue cholesterol within a few weeks. The half-life of cholesterol turnover is relatively short in the Liver, but spans several weeks for the body as a whole. Equilibrium between free cholesterol in blood plasma and the liver is achieved within a few hours.

Dietary cholesterol esters are hydrolyzed to free cholesterol, which then mixes with ingested free cholesterol and biliary cholesterol prior to absorption alongside other Lipids. Subsequently, it blends with cholesterol synthesized in the intestine and is incorporated into chylomicrons. In the intestinal mucosa, 80–90% of the absorbed cholesterol is esterified with long-chain Fatty acids. Plant sterols (phytosterols, such as sitosterol) are poorly absorbed. When chylomicrons are attacked by lipoprotein lipase to form chylomicron remnants, only 5% of the cholesterol esters are lost. Following interaction with apo-E receptors, chylomicron remnants enter the liver, where cholesterol esters are hydrolyzed back to free cholesterol. VLDL particles synthesized in the liver transport cholesterol into the blood plasma. In humans, however, due to low hepatic ACAT activity, cholesterol is secreted into plasma primarily as free cholesterol within VLDL. The cholesterol esters found in VLDL are formed mainly through the action of plasma LCAT. The majority of cholesterol residing in VLDL remains in VLDL remnants, which are either taken up by the liver or converted into LDL. The latter, in turn, bind to specific receptors in The Liver and extrahepatic Tissues.

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Fig. 27.6. Cholesterol transport between tissues in The Human Body. X — free cholesterol; CE — cholesterol esters; VLDL — very-low-density lipoproteins; IDL — intermediate-density lipoproteins; LDL — low-density lipoproteins; HDL — high-density lipoproteins; ACAT — acyl-CoA:cholesterol acyltransferase; LCAT — lecithin:cholesterol acyltransferase; A-I — apolipoprotein A-I; D — apolipoprotein D; LPL — lipoprotein lipase.

Role of LCAT

The activity of plasma LCAT in humans facilitates The formation of cholesterol esters. (A different pattern is observed in certain animals, such as rats, which possess highly active hepatic ACAT that ensures significant export of cholesterol esters within newly formed VLDL.) HDL containing apolipoprotein A-I exhibits LCAT activity. The Esterification of cholesterol within HDL establishes a free cholesterol concentration gradient, driving the influx of cholesterol from tissues and other lipoproteins into HDL (Fig. 27.6). The density of HDL decreases as it transforms into HDL₂, which subsequently delivers cholesterol to the liver (Fig. 26.6). Thus, HDL plays a crucial role in reverse cholesterol transport, meaning it mediates The transfer of cholesterol from peripheral tissues to the liver.

Role of Cholesterol Ester Transfer Protein (CETP)

This protein, present in human blood plasma (but absent in rats), is a component of HDL and appears to be identical to apolipoprotein D. It accelerates the transfer of cholesterol esters from HDL to VLDL, LDL, and, to a lesser extent, chylomicrons. Consequently, the cholesterol ester transfer protein helps alleviate product inhibition of LCAT associated with LDL. Thus, in humans, the majority of cholesterol esters generated by LCAT action in HDL reach the liver as part of VLDL remnants (IDL) or LDL (Fig. 26.6).

Ultimately, all cholesterol destined for elimination from the body reaches the liver and is excreted via Bile either as free cholesterol or as bile salts.