Session 5 Flashcards
Explain how tissues obtain the lipids they require from lipoproteins
Chylomicrons:
From intestine to adipose tissue
Dietary TAGs can’t be directly absorbed so are hydrolysed in small intestine by pancreatic lipase –> fatty acid + glycerol then re-esterified using glycerol phosphate
Travel via lymphatic system to adipose which have lipoprotein lipase
Lacteal –> lymphatic system –> thoracic duct –> left subclavian vein (bypass liver, lacteal wall leaky)
Normally only present in blood 4-6h after meal (serum should be pale straw)
vLDL:
Transport TAGs from liver to adipose tissue for storage
LDL:
Transport cholesterol from liver to tissues (ApoB100 important)
HDL:
Transport cholesterol from tissue to liver for disposal as bile salts
Describe how lipids are transported in the blood
Insoluble in water so carried in blood associated with protein
98% - lipoprotein particles
2% bound non-covalently to albumin (<3mmol/L)
Lipoproteins are a spherical shape consisting of a surface coat (shell) and hydrophobic core
Surface coat - phospholipids, cholesterol, apoproteins
Hydrophobic core - TAGs, cholesterol esters
Explain the transfer of TAGs and cholesterol in more detail
Transfer of TAGs:
Endothelial cells of capillaries and muscle have lipase on outside membrane
TAG –> glycerol (back to liver to be reused)
–> fatty acids (enter tissues for B-oxidation)
vLDL remnants removed by liver or converted
Transfer of cholesterol:
Cells have LDL receptor to recognise ApoB100
Complex proteins bind LDL
Receptor/LDL complex taken into cell by endocytosis
Lysosomal digestion
LDL receptor expression controlled by cholesterol concentration in cell
Loading HDL:
Some synthesised in liver (nascent HDL)
Some from vLDL remnants
Both sequester cholesterol from capillaries
Mature into HDL
Carry cholesterol to liver –> bile salts –> lost in bile
Explain how disturbances to the transport of lipids can lead to clinical problems
Atherosclerosis
Oxidised LDL –> macrophages engulf faulty LDLs –> foam cells –> accumulate in intima of blood vessel walls causing swelling –> fatty streak –> atheroma (swelling of wall of vessel)
Plaque ruptures –> thrombus –> CHD
Analyse simple problems that involve disturbances to lipid transport
Clinical problems of hyperlipoproteinaemia may be due to: Defective enzyme (lipase), receptors (LDL receptor), apoproteins (ApoE)
Clinical signs include xanthelasma, tendon xanthoma and corneal arcus.
Explain how hyperlipoproteinaemias may be treated
Diet - reduce/eliminate cholesterol, reduce intake of TAGs (especially saturated fat)
Lifestyle - increased exercise, stop smoking
Drugs - statins e.g. Simvastatin reduce cholesterol synthesis in liver by inhibiting HMG-CoA reductase, convert cholesterol to bile salts and secrete cholesterol directly in bile which increases disposal from body, cholesterol is prevented from reabsorption into hepatic portal vein, promoted loss in faeces
Describe the production of superoxide radicals
When electrons don’t reach the end of the electron transport chain they prematurely reduce oxygen to the superoxide, O2- which constantly leaks out of mitochondria.
O2- has a free electron so is very reactive.
Discuss other reactive oxygen species produced in cells
Hydroxyl radicals (.OH), nitric oxide (NO.), peroxynitrite (ONOO-), hydrogen peroxide (H2O2)
Hydroxyl radicals - produced from H2O2, O2- or ionising radiation (UV light, x-rays, y-rays) cause damage to membranes, oxidise proteins, lipid and DNA
Nitric oxide:
Arginine –> NO. (iNOS -inducinle nitric oxide synthase)
NO. + O2 –> ONOO- damages cells
Outline cellular defences against reactive oxygen species
Superoxide radicals (SOD), catalase, NADPH, glutathione, cysteine, antioxidants (vit.A,C,E, polyphenols, B-carotene, selenium, zinc)
Superoxide radicals –> H2O2 –> H20 + O2 (SOD, catalase)
Glutathione (GSH, tripeptide, antioxidant, abundant in cells, primary defense)
NADPH (reducing agent)
Cysteine (reducing agent)
Explain the role of oxidative stress in disease states
Oxidative stress is when antioxidant levels are low e.g. Atherosclerosis, Parkinson’s, Alzheimer’s, cancer, emphysema, pancreatitis, Crohn’s, inflammatory reactions
Oxidative burst is when neutrophils and monocytes rapidly produce a release of ROS - cell is destroyed as well as surrounding bacteria/fungus, part of immune response to infection, produced by NADPH oxidase (membrane bound enzyme complex)
Oxidising agents (e.g. primaquine, paraquat, paracetamol) can cause oxidative stress
Explain the role of LCAT enzyme
Lecithin:Cholesterol Acetyltransferase
Removal of core lipids from lipoprotein protein makes them unstable as ratio increases
Stability is restored as surface lipid –> core lipid (LCAT)
Important in formation of lipoprotein particles and maintaining their structure
Converts cholesterold –> cholesterol ester using fatty acid derived from lecithin
Deficiency of lecithin –> unstable lipoproteins of abnormal structure and failure in lipid transport process
Explain the action of statins in more detail
Acetyl CoA –> HMG-CoA –> cholesterol or ketone bodies
HMG-CoA reductase catalysed HMG-CoA –> cholesterol so statins inhibit this enzyme
However statins also reduce production of Coenzyme Q10 (supplements may be taken but they are not NICE recommended)
Statins may have side effects such as muscle pain and memory loss but they may also extend life
