Lipoproteins Seminar No. 3 A.1 - Lipids of Blood Plasma Q.2 A.2 - FFA transport • FFA are non-polar species, insoluble in water • they always need transport systems • In blood plasma - bound to albumin • In cytoplasm – Z protein ^• Across cell membrane – protein transporter, cotransport with Na^+ • Across mitochondrial membrane – ester with carnitine Q.3 A.3 FFA come predominantly from adipose tissues Q.4 A.4 • Fasting state – action of glucagon – FFA are released from adipose tissues – 0.8 mmol/l • Postprandial state – 0.4 mmol/l Q. 5 A.5 - Lipoprotein particle • Polar surface monolayer contact with polar aqueous environment • Non-polar core completely separated from aqueous environment Components of Surface Layer Components of Surface Layer Non-polar core of lipoprotein Non-polar core of lipoprotein Q. 8 Draw formula of cholesterol Describe the structure Structure of cholesterol Draw formula of lecithin Structure of lecithin Draw formula of triacylglycerol Q.9 + Q.12 A.9,12 - Lipoproteins: Density vs. Composition Q. 10 A. 10 CM contain predominantly TAG = neutral molecules (without charge) TH they do not move in electric field Q. 11 A. 11 - The Composition of Lipoproteins Apoproteins Complete the table Functions of apoproteins the completion of the table A-I LCAT activator B-100 structure of VLDL, ligand for LDL receptor B-48 structure of CM C-II LPL activator Transport functions of lipoproteins Q.14 A.14 Liver receptors have greater affinity to IDL to remove them from circulation because of apo E receptors Q.15 A.15 LDL because: • Long half-life (2-4 days) !! • They are stationary (no remodelling in contrast to HDL) • Contain a big portion of CE with PUFA Enzymes in lipoprotein metabolism Q. 16 A. 16 • Elevated CM and VLDL in serum – chylous serum Q. 17 Write the equation of reaction catalyzed by LCAT (lecithin cholesterol acyltransferase) What is acyl? Acyl LCAT reaction Metabolism of chymomicrons (CM) • CM are produced in enterocytes, apo B-48 • They carry dietary TAG and CE to periph. tissues • In plasma, CM receive apo E and apo C-II from HDL • Apo C-II activates lipoprotein lipase (LPL) • LPL is attached to capillary surface in adipose, cardiac and muscle tissues • TAG are hydrolysed, apo C-II is returned to HDL • CM particles begin to shrink – remnants • Remnants bind to apo E receptors in liver, where they are hydrolytically degraded in lysosomes Q. 20 What is the result of deficient synthesis of apo B-48? A. 20 No CM will be produced, dietary fat remains in stool (steatorrhoea) Lipophilic vitamins and essential FA will be deficient. Q. 21 A. 21 Metabolism of VLDL • VLDL are made in liver, they transport endogenous TAG to periph. tissues • In plasma they take apo C-II from HDL (LPL activ.) • TAG are removed by LPL action – VLDL become smaller and more densed = IDL • IDL take some CE from circulating HDL • IDL are transformed into LDL by hepatic lipase Q. 24 A. 24 Food rich in lipids (fat) and saccharides (sugars) Q. 27 Three pathways of LDL • LDL provide cholesterol to peripheral tissues via LDL receptors • The rest of LDL is taken up by liver and degraded • Small amount of LDL (chemically modified by oxidative stress) enters to some cells (endothelial) by non-specific endocytosis and alters them to „foam cells“ Q. 28 A. 28 • Apo B-100 is structural protein of VLDL • If absent, VLDL cannot be made in liver • TAG remain and accumulate in liver • Liver steatosis Q. 30 A. 30 Metabolism of HDL • HDL particles are made in liver • Nascent HDL are disc-shaped (bilayer of PL + proteins) • HDL take free cholesterol (C) from cell membranes • Once C is taken up, it is esterified by LCAT • After this process HDL becomes spherical • Spherical HDL are taken up by liver and CE are degraded Q. 32 A. 32 • Apo A-I • ABC transporter A1 • LCAT • CETP • SR-B1 • HL Q. 34 A. 34 • LCAT • Made in liver • Acts on HDL • Activated by apo A-I Q. 35 A. 35 • During digestion: Pancreatic lipase, LPL • In fasting: HSL Cellular uptake of LDL • LDL receptors are in clathrin-coated pits • After binding, LDL+receptor are internalized by endocytosis • Vesicle loses its clathrin coat and becomes endosome • Receptor is removed and recycled • LDL is hydrolyzed after fusing with lysosome • Free cholesterol is released to make cholesterol pool Intracellular cholesterol • Free cholesterol (C) is immediately esterified by ACAT* to make intracellular storage • Small amounf of C is incorporated into cell membrane • Some C is converted into hormones (in some tissues) • Some C is converted into bile acids (in liver) Intracellular cholesterol regulates three processes • Decreases activity of HMG-CoA reductase (= synthesis of cholesterol) • Decreases synthesis of new LDL receptors (to block intake of LDL) • Enhances activity of ACAT (to make storage) Q. 37 A. 37 • They are not recognized by LDL receptors in tissues • They are taken by scavenger receptors in macrophages – and make foam cells • The aggregation of foam cells – atherogenic plaques Q.45 The Balance of Cholesterol Which food is the main source of cholesterol? Q. A. only animal fats (including fish): lard, butter, bacon, egg yolk, mayonnaise, fat meat, fat cheese plant oils and margarines are cholesterol free The next seminar you will write the revision test (15 Q) from • Seminar chapters 1-3 • Practical chapters 1-2