Hyperlipidemia
The lipids in the body are mainly represented by cholesterol, triglycerides (TGs, also called triacylglycerides), and phospholipids. Lipids are transported in the blood as lipoproteins, which are mixed micellar-like particles with a central droplet contai
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Introduction to Hyperlipidemia The lipids in the body are mainly represented by cholesterol, triglycerides (TGs, also called triacylglycerides), and phospholipids. Lipids are transported in the blood as lipoproteins, which are mixed micellar-like particles with a central droplet containing their most hydrophobic components, cholesteryl esters and TGs, and an outer layer comprising amphiphilic phospholipid molecules interspersed with free (nonesterified) cholesterol, giving the particle a hydrophilic surface [1, 2]. The protein components of lipoproteins are mainly enzymes, such as lecithin-cholesterol acyltransferase (LCAT), and apolipoproteins. The latter play important roles in lipid and lipoprotein secretion by the liver and gut, transport in the lymph and blood, and uptake by various tissues, as they serve as receptor ligands. Also, they have structural and regulatory roles, modifying the activity of enzymes relevant to lipoprotein metabolism. They are oriented similarly to the lipids, with hydrophobic regions toward the P. Durrington (*) Cardiovascular Research Group, School of Biomedicine, University of Manchester, Manchester M13 9NT, UK e-mail: [email protected] H. Soran Department of Medicine, Central Manchester University Hospitals NHS Foundation Trust, Oxford road, Manchester M13 9WL, UK e-mail: [email protected]
core and polar regions outside. The lipoproteins are classified into four major classes (see below), which differ in size, density, composition, and function (Fig. 1). In this chapter, we will give an overview of lipoprotein physiology and metabolism followed by discussion of its major disturbances, the hyperlipidemias.
Physiological Lipoprotein Metabolism Chylomicrons The largest lipoproteins are the chylomicrons produced by the enterocytes of the small intestine carrying nutritional TGs and entering the blood circulation via the lymph. During tissue passage, TGs are hydrolyzed by lipoprotein lipase (LPL) located on capillary endothelium to fatty acids and glycerol, which are then used as respiratory substrates or reconstituted (into TGs) as an energy store. LPL has a binding site for sulfated glycosaminoglycans and another for apoCII. The former site allows it to be anchored to the capillary endothelium. LPL protrudes from that attachment into the current of circulating blood, where it comes into contact with apoCII-rich lipoproteins like chylomicrons and very-lowdensity lipoprotein (VLDL). LPL requires apoCII as a cofactor, if it is to be active. Its activity is greater for larger chylomicrons than for VLDL. Thus, chylomicrons are converted to TG-depleted
E. Lammert, M. Zeeb (eds.), Metabolism of Human Diseases, DOI 10.1007/978-3-7091-0715-7_43, © Springer-Verlag Wien 2014
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P. Durrington and H. Soran
296 (13 )
Food Nascent HDL
(1)
(10)
Small intestine
FC
Liver
ApoA1 [LCAT] (12) (4)
Enterocytes
(5) (2) ApoA1
CE
(8) VLDL
HDL
CE
LDL
ApoE
Chylomicrons
[CETP]
[CETP] (11) (6)
CE
LDL receptor TG [LPL]
Heparan sulphateLRP receptor
FA + Glycerol
[LCAT]
Sc
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