lip synth transport NAM 2023 - Tagged.pdf

Lipid synthesis and transport in the blood Dr Despo Papachristodoulou  Storage of fuel energy providing foods consumed in quantities greater than needed at the time fuel is stored Carbohydrate stored as glycogen store is limited long term reserve is lipi...

Lipid synthesis and transport in the blood Dr Despo Papachristodoulou  Storage of fuel energy providing foods consumed in quantities greater than needed at the time fuel is stored Carbohydrate stored as glycogen store is limited long term reserve is lipid (fat) as Triacylglycerol (TAG)  Fed state liver TAG muscle oxidation TAG TAG TAG small intestine adipose tissue  Fatty acid synthesis from acetyl Co A. Stimulated by insulin in the fed state oxaloacetate acetyl CoA mitochondrion oxaloacetate acetyl CoA citrate  Fatty acid synthesis from acetyl Co A. Stimulated by insulin in the fed state oxaloacetate acetyl CoA mitochondrion oxaloacetate acetyl CoA citrate citrate  First step in Fatty acid synthesis acetyl CoA to malonyl CoA catalysed by acetyl CoA carboxylase this is the rate limiting step. Malonyl CoA signifies the fed state. The enzyme is activated by insulin. Malonyl CoA inhibits carnitine transferase and so inhibits the entry of the FA into the mitochondrion and subsequent oxidation  Fatty acid synthesis acetyl CoA CO2 malonyl CoA NADPH is needed for fatty acid synthesis. provided by the hexose monophosphate shunt Fatty acid synthetase  acetyl CoA CO2 malonyl CoA + = malonyl CoA + = + + = + NADPH is needed for fatty acid synthesis  TAG synthesis: glycerol phosphate +3 fatty acids LIVER CELL from glycolysis  apoproteins p p TAG TAG plp c other lipids VLDL  LIPOPROTEIN STRUCTURE inner core triglycerides & cholesterol esters outer shell single layer of phospholipids & cholesterol & apoproteins  Lipoproteins Lipid is insoluble in water needs to be transported as a lipid-protein complex Apoproteins: structural role recognised by receptors activate certain enzymes in lipid metabolism  Classes of lipoproteins Chylomicrons – largest and of lowest density carry mainly dietary TAG Very Low Density Lipoprotein (VLDL) – carries mainly endogenous TAG Low Density Lipoprotein (LDL) – carries mainly cholesterol to the tissues High Density Lipoprotein (HDL) – carries mainly cholesterol from the tissues to the liver Cholesterol controls its own synthesis and the number of LDL receptors on the cell surface  Cholesterol synthesis: Acetyl CoA + Acetoacetyl CoA ↓ HMG-CoA rate limiting step ↓ HMG-CoA reductase mevalonate ↑ I ↓ STATINS INHIBIT HMG CoA reductase cholesterol  LDL receptors LDL receptors are very important recognise B-100 remove LDL from the circulation (receptor mediated endocytosis) deficiency of LDL receptors (familial hypercholesterolaemia) very high blood cholesterol levels premature death from atherosclerosis  Hyperlipidaemias (hyperlipoproteinaemias) Hypercholesterolaemia Hypertriglyceridaemia Genetic disposition Environment (diet,lifestyle)  Examples of genetic Hyperlipoproteinaemias Defective LDL receptor Hypercholesterolaemia High LDL in blood Lipoprotein lipase High Chylomicrons and deficiency VLDL Deficiency of C-II High chylomicrons and VLDL Deficiency of High chylomicron and apoproteins involved in VLDL remnant remnant uptake  Risk factors for Secondary hyperlipoproteinaemias Obesity Diabetes mellitus type 2 dietary cholesterol ? dietary fatty acid SFA V PUFA – n-6 PUFA lower cholesterol – n-3 lower TAG alcoholism  Lipoprotein (a) Lp(a) in plasma in high conc associated with increased risk of CHD LDL plus apoprotein a Levels genetic but can be increased by trans fats and decreased by oestrogen Related to plasminogen (target fibrin) Slows breakdown of blood clots by competing with plasminogen? High concentrations of blood cholesterol are associated with mortality from coronary heart disease High TAG are much less of a risk total serum cholesterol HDL cholesterol  Atherosclerosis Plaque complex structure involving inflammation and proliferation of smooth muscle in artery wall contains connective tissue and pool of cholesterol rich lipid starts as fatty streak from accumulation of foam cells foam cells are macrophages filled with lipid, mainly cholesterol Normal LDL metabolism Modified (oxidised) LDL is not recognised by the normal receptor but is taken up by scavenger receptors in foam cells. These receptors are not down regulated and the result is accumulation of cholesterol