The North West of England Endocrinology, Diabetes and Obesity Newsletter

LDL metabolism in health and disease

Posted by Rahul Yadav on 24 December, 2013

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].


4. Durrington P N, Hyperlipidaemia: Diagnosis and Management. 2007, London: Hodder Arnold.
5. Bhatnagar D, Soran H,Durrington P N. Hypercholesterolaemia and its management. BMJ 2008; 337:a993
6. Walldius G J I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001; 358:2026-33
7. Sniderman A D, Williams K, Contois J H, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011; 4:337-45
8. Boekholdt S M, Arsenault B J, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012; 307:1302-9
9. Leiter L A, Bays H,Conrad S. Attainment of Canadian and European guidelines lipid targets with atorvastatin plus ezetimibe vs. doubling the dose of atorvastatin. Int J Clin Pract 2010; 64:1765-72
10. Austin M A, Hokanson J E,Brunzell J D. Characterization of low-density lipoprotein subclasses: methodologic approaches and clinical relevance. Curr Opin Lipidol 1994; 5:395-403
11. Chen G C, Liu W, Duchateau P, et al. Conformational differences in human apolipoprotein B-100 among subspecies of low density lipoproteins (LDL). Association of altered proteolytic accessibility with decreased receptor binding of LDL subspecies from hypertriglyceridemic subjects. J Biol Chem 1994; 269:29121-8
12. Galeano N F, Milne R, Marcel Y L, et al. Apoprotein B structure and receptor recognition of triglyceride-rich low density lipoprotein (LDL) is modified in small LDL but not in triglyceride-rich LDL of normal size. J Biol Chem 1994; 269:511-9
13. Scheffer P G, Bos G, Volwater H G, et al. Associations of LDL size with in vitro oxidizability and plasma levels of in vivo oxidized LDL in Type 2 diabetic patients. Diabet Med 2003; 20:563-7
14. Younis N N, Soran H, Sharma R, et al. Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes. Diab Vasc Dis Res 2010; 7:289-95
15. Younis N, Charlton-Menys V, Sharma R, et al. Glycation of LDL in non-diabetic people: Small dense LDL is preferentially glycated both in vivo and in vitro. Atherosclerosis 2009; 202:162-8
16. Tribble D L, Krauss R M, Lansberg M G, et al. Greater oxidative susceptibility of the surface monolayer in small dense LDL may contribute to differences in copper-induced oxidation among LDL density subfractions. J Lipid Res 1995; 36:662-71
17. Kritharides L, Jessup W, Gifford J, et al. A method for defining the stages of low-density lipoprotein oxidation by the separation of cholesterol- and cholesteryl ester-oxidation products using HPLC. Anal Biochem 1993; 213:79-89
18. Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 1998; 279:1955-61
19. Grundy S M. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997; 95:1-4
20. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation 1997; 95:69-75


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s