LDL metabolism in health and disease

1.2 Low density lipoprotein (LDL)
1.2.1 LDL metabolism in health (Figure 1.1)
Cholesterol is an important component of cell membranes as it provides stability/rigidity and reduces permeability of the membranes. It is also a precursor of steroid hormones. Cholesterol in the body either originates from the diet or is synthesised in the liver and gut. The liver is the most important site for cholesterol metabolism. After absorption from the gut, cholesterol is packed in chylomicrons and transported to the liver. Cholesterol is then packed in very low density lipoprotein (VLDL) along with triglycerides in the liver and released into the circulation. This VLDL converts into low density lipoprotein (LDL) as it loses its triglycerides by the action of lipoprotein lipase. LDL is rich in cholesterol and is the main source of cholesterol for various tissues. The uptake of LDL is facilitated by receptors present on the surface of cells needing the cholesterol. All excess LDL in the circulation is taken up by the liver via LDL receptor, scavenger receptor-BI (SR-BI), LDL receptor-related protein (LRP) and non-receptor medicated uptake. High density lipoprotein (HDL) transports the excess cholesterol from the tissues back to the liver either directly or via LDL [4].
Hypercholesterolemia is essential for the atheromatous process and lipid lowering is an most important step in management of atherosclerosis [5].
1.2.2 Apolipoprotein B 100
There is only one apolipoprotein B 100 (apoB) molecule in each LDL particle, therefore apoB concentration represents LDL particle numbers as opposed to LDL-cholesterol (LDL-C) which simply represents the amount of cholesterol in LDL particles [4]. The Apolipoprotein-related Mortality RISk Study (AMORIS) [6] was designed to compare LDL-C and apoB as markers of risk of fatal MI. (175,553 Swedes followed up for 6 years). Apo B was found to be superior in predicting events at all ages for both men and women compared to LDL-C. A meta-analysis based on epidemiological studies including 233,455 subjects and 22,950 events reported that in United States adult population over a 10-year period, a non-HDL-C strategy would prevent 300,000 more cardio-vascular (CV) events than an LDL-C strategy, whereas an apoB strategy would prevent 500 000 more CV events than a non-HDL-C strategy [7]. However, there is evidence from a recent meta-analysis that among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB [8]. Statins alone or in combination with ezetimibe are effective in significantly lowering apoB levels [9].
1.2.3 Small dense LDL
The role of small dense LDL (sdLDL) as a risk factor for coronary heart disease has been well established [10].Cholesteryl ester transfer protein (CETP), as a key enzyme in reverse cholesterol transport, mediates the transfer of cholesteryl esters (CE) from cholesterol-rich LDL to triglyceride (TG) rich VLDL in exchange for TGs. This lipid exchange promotes the generation of smaller LDL particles with higher density (sdLDL) [4] (Figure 1.1). There is a conformational change in the apoB present on sdLDL leading to a reduced affinity to hepatic LDL receptors [11, 12]. This increases the residence time of sdLDL in the circulation and makes it more susceptible to oxidative modification [4]. SdLDL preferentially undergoes atherogenic modifications like oxidation [13] and glycation [14, 15] in vivo. Small dense LDL has also been shown to preferentially undergo oxidation [16, 17] and glycation [15] in vitro.
Patients with metabolic syndrome or type 2 diabetes may have marginally higher LDL-C compared to the general population but their CV risk is much higher possibly because of higher sdLDL [4, 18, 19]. The proportionally high sdLDL in these patients is due to insulin resistance, delivery of excess non-esterified fatty acids (NEFA) to the liver, increased output of VLDL from the liver and higher CETP activity [4].The Quebec cardiovascular study showed that in patients with high ApoB levels but normal size LDL (i.e high LDL-C) there is twofold increase in CV risk compared to a six fold increase in CV risk in patients with high sdLDL levels [20].


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