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].


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

SCE Diabetes & Endocrine Revision Weekend: 1-2 Feb 2014

Specialty Certificate Examination Diabetes & Endocrine Revision Weekend

Dates: 1st and 2nd Feb 2014

Venue: Manchester Airport Marriott Hotel, Hale Road, Hale Barns, Manchester, WA15 8XW.

This two day revision course is intended to help diabetes specialist registrars prepare for the MRCP examination.

The Royal College of Physicians ran the first ever Endocrinology MRCP in May 2009. A Speciality Certificate Examination is now a compulsory component of assessment for Certificate of Completion of Training (CCT) for all UK trainees whose specialist training began in or after August 2007. The SCEs comprise of two 3-hour papers containing 100 best of five questions and are conducted as computer based tests. Each SCE is held once a year.

Candidates who pass the examination will be awarded a “Certificate” in the speciality concerned. All those with a Speciality Certificate and MRCP (UK) who are recommended to PMETB by the JRCPTB for a CCT, will be entitled to apply for the post nominal MRCP (Speciality).

The highly interactive programme will be chaired by Dr Moulinath Banerjee, Consultant in Diabetes & Endocrinology, who is the Course Director, developed the programme and has written the examination. The topics covered will be Neuroendocrine case presentations, Adrenal and Reproductive Endocrinology, Hot Topics in Diabetes and Calcium and Bone metabolic disorders, Lipid and Obesity. The speakers, who are all Consultants in Diabetes & Endocrinology, are listed separately with this invitation.


SCE Endocrinology and Diabetes Training Course: 14-15 Mar 2014

Specialty Certificate Examination in Endocrinology and Diabetes Training Course

Dates: 14th and 15th March 2014

Venue: Seminar Room A, 5th floor, St Marys Hospital, Central Manchester University Hospitals NHS Foundation Trust, M13 9WL

  • This is a two day intensive Endocrine and Diabetes SCE exam course delivered by expert consultants specialised in the field they cover.
  • 15 sessions aiming at covering the curriculum. More than 400 new questions will be discussed.
  • Mock exam will be e-mailed pre-course and answers will be provided and discussed.

To reserve your place please send a cheque for £100 (payable to University of Manchester-Lipid Research Fund AA09891 1831/Handrean Soran) with the registration form to: Debra Eccles (Secretary to Dr Handrean Soran) University Department of Medicine, 5th Floor St Mary’s Hospital, Central Manchester NHS Foundation Trust, Oxford Road, Manchester, M13 9WL)

Manchester Diabetes and Endocrine SCE Course 2014 Agenda

Course Organisers:

Dr Handrean Soran,  Consultant Physician & Endocrinologist, Central Manchester University Hospitals Foundation Trust

Dr Naveed Younis,  Consultant Physician & Endocrinologist, University Hospital South Manchester Foundation Trust

Registration fee does not include accommodation.

This is an independent educational meeting organised by the University of Manchester and has been supported by an unrestricted education grant from Bristol-Myers Squibb and AstraZeneca. BMS/AZ have not been involved with the agenda, content or selection of speakers.

The Sponsors had no input into speaker selection and content.

Joint endocrine/oncology update meeting 27.01.14.

Joint Endocrine/Oncology Update Meeting.

Christie Hospital auditorium, Wilmslow Rd Manchester

Manchester Centre for Endocrinology & Diabetes

Institute of Human Development

Manchester Clinical Endocrinology Symposium Series


27th January 2014

Joint endocrine/oncology update meeting



09.30-10.00                   Registration and coffee


10.00 -  11.00                 Prof Peter Clayton         RMCH

GH therapy in childhood brain cancer survivors          


11.00-  12.00               Dr Ed Smith                     Christie Hospital

Proton Beam therapy: current status


12.00 – 13.15                 Prof Peter Selby and Prof Judith Adams   MRI

Bone health in cancer and cancer survivors


13.15 – 14.15                Lunch


14.15- 15.15                Dr Daniela Montaldi        Manchester University

Hippocampal function following treatment for medulloblastoma


15.15 – 15.45                Tea/Coffee


15.45 – 16.30                 Professor Zulf Mughal  and   Dr Padidela  RMCH

Avascular necrosis in young adults with cancer


CME accreditation applied for

Christie Hospital auditorium, Wilmslow Rd Manchester

Sponsored by an educational grant from Pfizer

WHO Atlas on coronary heart disease world wide prevalence – a summary

 “Misfortunes always come in by a door that has been left open for them.” Czechoslovakian proverb

The World Health Organization’s Atlas for Heart Disease and Stroke illustrates that globally in 2002 coronary heart disease (CHD) accounted for 6.8% and 5.3% of Disability Adjusted Life Years (DALYs) in men and women respectively. DALYs are the same as years of life lost to disability and death, and therefore suggest a more meaningful way of projecting disease burden as opposed to simply the resulting death. The burden of CHD is expected to rise from 47 million DALYs in 1990 to 82 million DALYs in 2020 [1]. These figures are similar to HIV/AIDS and unipolar depressive disorders. CHD is now the leading cause of death worldwide and knows no borders. 3.8 million men and 3.6 million women die from CHD each year [2].

The basis of CHD is regarded to be atherosclerosis. Hypercholesterolemia is a major contributor to atherosclerosis. The incidence of CHD is much lower in rural China and Japan where average plasma cholesterol concentration is 4.0 mmol/l as compared to the United Kingdom where it is 5.9 mmol/l and CHD is a major cause of death [3].

1.            WHO. Global burden of coronary heart disease. Cardiovascular Disease, The Atlas of Heart Disease and Stroke  2011 2011 [cited 2011; Available from: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_13_coronaryHD.pdf.

2.            WHO. Deaths from coronary heart disease. Cardiovascular Disease, The Atlas of Heart Disease and Stroke  2011  [cited 2011; Available from: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_14_deathHD.pdf.

3.            Chaudhury M, Chapter 9. Risk factors for cardiovascular disease. Health Survey for England 2003, ed. Sproston K. Vol. 2. 2004, London: The Stationary Office.