Lecture 4.2 - Lipid transport.pdf

Lipids: ◦Structurally diverse group of compounds ◦Hydrophobic molecules insoluble in water = problem for transport in blood ◦Solution - transported in blood bound to carriers ◦~2% of lipids (mostly fatty acids) carried bound to albumin but this has a limited capacity (~3...

Lipids: ◦Structurally diverse group of compounds ◦Hydrophobic molecules insoluble in water = problem for transport in blood ◦Solution - transported in blood bound to carriers ◦~2% of lipids (mostly fatty acids) carried bound to albumin but this has a limited capacity (~3 mmol/L) ◦~98% of lipids are carried as lipoprotein particles consisting of phospholipid, cholesterol, cholesterol esters, proteins and TAG ◦Approximately 38% of the calories (kilocalories) come from fat ◦According to current recommendations, fat should provide no more than 30% of the total calories of a healthy diet. Typical plasma lipid concentrations: Lipoproteins - structure: Triacylglycerol: ◦Triacylglycerols are the major fat in the human diet ◦Triacylglycerols contain a glycerol backbone to which three fatty acids are esterified ◦Digestion - hydrolysis to fatty acids and 2-monoacylglycerol in the lumen of the intestine Phospholipids: Cholesterol: ◦Some cholesterol obtained from diet, but most synthesised in liver  ◦Essential component of membranes (modulates fluidity) ◦Precursor of steroid hormones ‣ Cortisol ‣ Aldosterone ‣ Testosterone ‣ Oestrogen ◦Precursor of bile acids ◦Transported around body as cholesterol ester Apolipoproteins: ◦Class of lipoprotein particle has a particular complement of associated proteins (apolipoprotein) ◦Six major classes (A,B,C,D,E and H) ‣ ApoB (VLDL, IDL and LDL) and apoAI (HDL) and apoE are important ◦Apolipoproteins can be: ‣ Integral passing through phospholipid bilayer ‣ Peripheral "resting" on top ◦Roles: ‣ Structural - packaging water insoluble lipid ‣ Functional - co-factor for enzymes, ligands for cell surface receptors ◦Polymorphisms, particularly for apoE result in early onset CVD Lipoproteins: ◦Five distinct classes named according to density ‣ Chylomicrons ‣ VLDL (very low density lipoproteins) ‣ IDL (intermediate density lipoproteins) ‣ LDL (low density lipoproteins) ‣ HDL (high density lipoproteins) ◦Levels of lipoproteins in blood are of significance - clinical importance ◦Each contains variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester ◦Density obtained by ultracentrifugation ◦Particle diameter inversely proportional to density (more dense means it has more protein) ◦Surface charge varies Classes of lipoprotein particle:  Chylomicrons: ◦Formed by enterocytes lining the small intestine ◦Combine triacylglycerols from food with specific apoproteins ◦Carry lipids from diet to tissue, especially adipose tissue ◦Normally only present in blood 4-6 hour after a meal and then cleared ‣ Persistence after 6 hour is a clinical problem ◦Milky look in serum means patient has had high intake of fats Packaging of chylomicrons: Chylomicron metabolism: ◦Chylomicrons loaded in small intestine, apoB-48 added, enter lymphatic system ‣ Travel to thoracic duct, empty into left subclavian vein and acquire apoproteins (apoC and apoE) in the blood ◦ApoC binds lipoprotein lipase (LPL) on adipocytes and muscle ‣ Released fatty acids enter cells depleting chylomicron of its fat content ◦Triglyceride reduced to ~20%, apoC dissociates and chylomicron becomes a chylomicron remnant ◦Chylomicron remnants return to liver. LDLrec on hepatocytes bind apoE and chylomicron remnant, taken up by receptor mediated endocytosis. ‣ Lysosomes release remaining contents for use in metabolism VLDL metabolism: ◦VLDL is formed in liver for transporting TAGs to other tissues ◦ApoB100 is added during VLDL formation ◦Released directly to blood as nascent VLDL ◦ApoCII and apoE are added to VLDL from HDL in blood ◦VLDL binds LPL on muscle and adipose releasing FAs and glycerol (VLDL remnant) ◦Some TGs are transferred to HDL and some cholesterol esters are transferred to VLDL ◦VLDL returns apoCII to HDL IDL and LDL metabolism: ◦Formation: ‣ VLDL -> IDL -> LDL ‣ As the Tg content of VLDL particles drops, VLDL particles dissociates from the LPL enzyme complex and return to liver ‣ If VLDL content depletes to ~30%, the particle becomes a short-lived LDL particle  IDL particles can be taken up by liver or rebind to LPL enzyme to further deplete in TAG content ‣ Upon depletion to ~10%, IDL loses apoC and apoE and becomes an LDL particle (high cholesterol content) ◦Function: ‣ LDL provides cholesterol from liver to peripheral tissues ‣ Peripheral cells express LDL receptor and take up LDL via receptor mediated endocytosis ‣ Importantly, LDL do not have apoC or apoE so are not efficiently cleared by liver (liver LDL - receptor has a high affinity for apoE) ◦Clinical relevance: ‣ Half life of LDL in blood is much longer than VLDL or IDL making LDL more susceptible to oxidative/damage (LDL is considered as the 'bad' cholesterol since its prone to oxidative stress) ‣ Oxidised LDL taken up by macrophages, that can transform to foam cells and contribute to formation of atherosclerotic plaques. VLDL, IDL and LDL metabolism: LDL enters cells by receptor-mediated endocytosis: ◦Cells requiring cholesterol express LDLrec on membrane ◦ApoB-100 on LDL acts as ligand for LDLrec ◦Receptor/LDL complex taken into cell by endocytosis into endosomes ◦Fuse with lysosomes to release cholesterol and fatty acids ◦LDLr expression controlled by cholesterol concentration in cdll ◦Clinically defects in LDLrec results in elevated blood cholesterol and CVD HDL metabolism: ◦Synthesis: ‣ New HDL synthesised by liver and intestine (low Triacylglycerol levels) - nascent ‣ HDL particles can also "bud off" from chylomicrons and VLDLs as they are digested by LPL (remnants of VLDL) ‣ Free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL ◦Maturation: ‣ Nascent HDL accumulate phospholipids and cholesterol from cells lining blood vessels ‣ Hollow core progressively fills and particle takes on more globular shape ‣ Transfer of lipids to HDL does not require enzyme activity  ‣ Excess cholesterol is secreted in the bile Cholesterol blood test: ◦Total cholesterol (TC) - ideally 5 mmol/L or less ◦Non HDL-cholesterol (total cholesterol minus HDL-cholesterol) - ideally 4 mmol/L or less ◦LDL-cholesterol (LDL-C) 'bad' - ideally 3 mmol/L or less ◦HDL-cholesterol (HDL-C) 'good' - ideally over 1 mmol/L (men) and over 1.2 mmol/L (women) ◦Total cholesterol:HDL-C ratio - ratio above 6 considered high risk - the lower the ratio the better ◦Triglyceride (TG) - ideally < 2mmol/L in fasted sample Hyperlipoproteinaemias: Clinical signs of hypercholesterolaemia: ◦High level of cholesterol in blood ◦Cholesterol depositions in various areas of the body ‣ Xanthelasma - yellow patches on eyelids ‣ Tendon xanthoma - nodules on tendon ‣ Corneal arcus - obvious white circle around eye. Common in older people but if present in young could be a sign of hypercholesterolaemia ◦What can affect cholesterol levels: ‣ Alcohol consumption ‣ Hypothyroidism ‣ Liver disease ‣ Nephrotic syndrome LDL and clinical relevance: ◦Half life of LDL in blood is much longer than VLDL or IDL ◦LDL is more susceptible to oxidative damage ◦Oxidised LDL is taken up my macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques Raised serum LDL is associated with atherosclerosis:  Plaque formation in large blood vessels: Treatment of hyperlipoproteinemias: ◦First approach: ‣ Diet: Reduce cholesterol and saturated lipids in diet Increases fibre intake ‣ Lifestyle: Increase exercise Stop smoking to reduce cardiovascular risk ◦If no response...drugs ‣ Statins: Reduce cholesterol synthesis by inhibiting HMG-CoA reductase e.g. Atorvastatin, Simvastatin Bile salt sequestrants bind bile salts in GI tract. Forces liver to produce more bile acids using more cholesterol e.g. Colestipol Statins mechanism of action: