Lecture 9: Cholestrol

important aspect of cell membranes, has a rigid ring system and a short branched hydrocarbon tail. Cholesterol is largely hydrophobic. But it has one polar group, a hydroxyl, making it amphipathic

Cholesterol inserts into bilayer membranes with its hydroxyl group oriented toward the aqueous phase & its hydrophobic ring system adjacent to fatty acid chains of phospholipids. The OH group of cholesterol forms hydrogen bonds with polar phospholipid head groups.

Cholesterol: In the absence of cholesterol, such membranes would crystallize at physiological temperatures. The inner mitochondrial membrane lacks cholesterol but includes many phospholipids whose fatty acids have one or more double bonds, which lower the melting point to below physiological temperature.

are esters of long chain fatty acids and glycerol sometimes called triacylglycerol.

particles found in plasma that transport lipids including cholesterol

chylomicrons: take lipids from small intestine through lymph cells very low density lipoproteins (VLDL) intermediate density lipoproteins (IDL) low density lipoproteins (LDL) high density lipoproteins (HDL)

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major components of lipoproteins responsible for recognition of particle by receptors

spherical particles with a hydrophobic core apolipoproteins on the surface Large: apoB (b-48 and B-100) smaller: apoA-I, apoC-II, apoE classified on the basis of density and electrophoretic mobility

A-I (28,300) • principal protein in HDL • activate LCAT A-II (8,700) • occurs as dimer mainly in HDL • enhance hepatic activity B-48 (240,000) – found only in chylomicron B-100 (500,000) – principal protein in LDL - binds to LDL receptor C-I (7,000) – found in chylomicron, VLDL, HDL -activate LCAT C-II (8,800) • found in chylomicron, VLDL, HDL • activate lipoprotein lipase C-III (8,800) • found in chylomicron, VLDL, IDL, HDL • inhibits lipoprotein lipase D (32,500) - found in HDL E (34,100) • found in chylomicron, VLDL, IDL HDL • Binds to LDL receptor H (50,000) – found in chylomicron

lipoprotein is an assembly of molecules whose function is to transport hydrophobic lipids in watery media including water and extracellular fluid whereas apolipoprotein is a protein bound to lipids in order to form lipoproteins.

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formed through extrusion of resynthesized triglycerides from the mucosal cells into the intestinal lacteals flow through the thoracic ducts into the suclavian veins degraded to remnants by the action of lipoprotein lipase (LpL) which is located on capillary endothelial cell surface remnants are taken up by liver parenchymal cells due to apoE-III and apoE-IV isoform recognition sites

density >1.006 diameter 30 - 80nm endogenous triglycerides apoB-100, apoE, apoC-II/C-III prebeta in electrophoresis formed in the liver as nascent VLDL (contains only triglycerides, apoE and apoB) nascent VLDLs then interact with HDL to generate mature VLDLs (with added cholesterol, apoC-II and apoC-III) mature VLDLs are acted upon by LpL to generate VLDL remnants (IDL) IDL are further degraded by hepatic triglyceride lipase (HTGL) to generate LDLs

density: 1.006 - 1.019 diameter: 25 - 35nm cholesteryl esters and triglycerides apoB-100, apoE, apoC-II/C-III slow pre-beta

density: 1.019 - 1.063 diameter: 18-25nm cholesteryl esters apoB-100 beta (electrophoresis) < 130 LDL cholesterol is desirable, 130-159 is borderline high and >160 is high

density: 1.063-1.210 diameter: 5-12nm cholesteryl esters and phospholipids apoA-I, apoA-II, apoC-II/C-III and apoE alpha (electrophoresis)

contains cholesterol, phospholipid, apoA-I, apoA-II, apoE and is disc shaped; it is formed in liver and intestine

transfers proteins to other lipoproteins picks up lipids from other lipoproteins picks up cholesterol from cell membranes converts cholesterol to cholesterol esters via the LCAT reaction transfers cholesterol esters to other lipoproteins, which transport them to the liver (referred to as “reverse cholesterol transport)

they consist of LDL and a protein designated as (a) the apoA is covalently linked to apoB- 100 by a disulfide linkage high risk association with premature coronary artery disease and stroke

Dietary TGs are digested in the stomach and duodenum into monoglycerides (MGs) and FFAs by gastric lipase, emulsification from vigorous stomach peristalsis, and pancreatic lipase. Once absorbed into enterocytes, they are reassembled into TGs and packaged with cholesterol into chylomicrons, the largest lipoproteins Chylomicrons transport dietary TGs and cholesterol from within enterocytes through lymphatics into the circulation. In the capillaries of adipose and muscle tissue, apoprotein C-II (apo C-II) on the chylomicron activates endothelial lipoprotein lipase (LPL) to convert 90% of chylomicron triglyceride to fatty acids and glycerol, which are taken up by adipocytes and muscle cells for energy use or storage.

the liver assembles and secretes triglyceride-rich very low-density lipoprotein (VLDL) particles, which transport triglycerides from the liver to peripheral tissues. hydrolysis of the triglycerides by LPL, the VLDL particles are reduced to intermediate-density lipoproteins (IDL), which can be taken up by the liver or can be further hydrolysed to LDL particles. LDL transports cholesterol primarily to hepatocytes but also to peripheral tissues. ApoB-100 is responsible for the recognition and uptake of LDL by the LDL receptor High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport, which shuttles cholesterol from peripheral cells to the liver

Lecture Slide

Dyslipidemia: abnormal lipid levels causes: defective synthesis/transport/catabo lism of lipoproteins hyperlipoproteinemia: elevated lipoprotein levels - hypercholesterolemia - hypertriglyceridemia - combined hyperlipidemia hypolipoproteinemia: decreased lipoprotein levels