Session 5 Flashcards
Where do lipids found in the blood come from and where are they going?
- Come from diet or synthesised in the body
- Transported to tissues for storage and/or utilisation
What classes of lipids are found in the blood?
- Triaclyglycerols
- Fatty acids
- Cholesterol
- Cholesterol esters
- Phospholipids
How are lipids carried in the blood?
- Are insoluble in water so must be carried in the plasma associated with proteins
- Most (98%) is carried as lipoprotein particles (highly specialised non-covalent assemblies)
- Remaining (2%) (mostly fatty acids) are carried bound non-covalently to albumin
Where are the albumin bound fatty acids from and what are they used for?
- From fatty acids released from adipose tissue during lipolysis
- Used as a fuel by tissues eg muscle
What is the blood fatty acid level and why?
- ~3 mmol/L
- Albumin has a limited capacity to transport fatty acids
Why are plasma lipoproteins significant in medicine?
- Disorders in lipoprotein metabolism is associated with important diseases eg atherosclerosis and coronary artery disease
What are plasma lipoprotein particles?
- Multi-molecular complexes
- Contain variable amount of different lipids (phospholipids; triacylglycerols; cholesterol esters) in non-covalent (mostly hydrophobic) association with specific proteins
What is the primary function of lipoproteins?
- Transport water-insoluble lipid molecules in the bloodstream
How do classes of lipoproteins differ? (Simple)
- Lipid being transported
- Origin of the lipid
- Destination
What are the protein components of lipoproteins?
- Specific proteins (apoproteins) that have functional and structural roles
What are the structural roles of apoproteins and why are they effective?
- Packaging non-water soluble lipid molecules into soluble form as multi-molecular particles
- Are effective as they contain hydrophobic regions that interact with the lipid molecules and hydrophilic regions that interact with water
What are the functional roles of apoproteins?
- Involved in the activation of enzymes or recognition of cell surface receptors
- Function depends on the particular apoprotein’s composition
What is the structure of a mature lipoprotein in normal human plasma?
- Spherical
- Consists of a surface coat (shell) and hydrophobic core
- Surface coat contains phospholipids, cholesterol and apoproteins
- Hydrophobic core contains triacyglycerols and cholesterol esters
When are lipoprotein particles stable?
- If they maintain their spherical shape
- Depends on ratio of core to surface lipids
- Therefore as lipid from the hydrophobic core is removed and taken up by tissues, the surface coat must also be reduced
How are core and surface coat components be removed from the lipoprotein particles?
- Surface coat: free to transfer to different particles and to cell membranes
- Core: only be removed by special proteins eg lipases and transfer proteins
How can classes of lipoproteins be identified?
How does this allows them to be separated?
- Differ in:
~ relative amount of different types of lipids either contain
~ apoprotein composition - This gives particles different physical properties such as:
~ net electrical charge
~ size
~ molecular weight
~ density - Allows classes to be separated by electrophoresis or ultracentrifugation
What are the classes of mature lipoproteins?
- Chylomicrons
- Very Low Density Lipoproteins (VLDL)
- Low Density Lipoproteins (LDL)
- High Density Lipoproteins (HDL)
What are the classes of remnant lipoproteins?
- Chylomicron remnants
- VLDL remnants (Intermediate Density Lipoproteins)
How are remnant lipoproteins formed?
- Removal of lipids from (mostly triacylglycerols) from chylomicrons and VLDL
What is the transport function of the different classes of lipoproteins determined by?
- Largely by apoprotein composition
What is the transport function of chylomicrons?
- Transport dietary triacyglycerols from the intestine to tissues eg adipose tissue
What is the transport function of VLDL?
- Transport of triacylglycerols synthesised in the liver to the adipose tissue for storage
What is the transport function of LDL?
- Transport of cholesterol synthesised in the liver to tissues
What is the transport function of HDL?
- Transport of excess cholesterol to the liver for disposal as bile salts
How do dietary triacyglycerols become associated with chylomicrons?
- Cannot be absorbed directly
- Hydrolysed in the small intestine by pancreatic lipase which releases fatty acids and glycerol
- Fatty acids enter epithelial cells of small intestine
- Fatty acids are re-esterified back to triacyglycerols (using glycerol phosphate produced from glucose metabolism in epithelial cells)
- These triacyglycerols are packaged with other dietary lipids (eg cholesterol, fat soluble vitamins) into chylomicrons
What happens to chylomicrons once they have triacyglycerols?
- Released from epithelial cells into the blood stream via the lymphatic system
- Carried in the blood stream to tissues eg adipose
- Tissues have extracellular enzyme lipoprotein lipase
- Enzyme hydrolyses the triacylglycerols to release fatty acids which enter the cell
- Fatty acids are converted back to triacylglyerols for storage
What are dyslipoproteinaemias?
- Any defect in the metabolism of plasma lipoproteins
- Primary: familial inborn error of lipoprotein metabolism
- Secondary: acquired as a result of diet, drugs or underlying disease eg diabetes
What is found in hyperlipoproteinaemias?
- Raised levels of one or more of the plasma lipoproteins
Why is it important to be able to recognise different types of hyperlipoproteinaemias?
- Each have a different risk of coronary artery disease
- Have different causes
- Respond to different treatments
How are different types of hyperlipoproteinaemias identified and classified?
- Fredrickson (WHO) system
- Based on measurement of fasting plasma glucose concentrations, total cholesterol and triacyglycerols and examination of plasma lipoprotein separations by electrophoresis
How many different types of hyperlipoproteinaemias are there?
- 6
What is type I hyperlipoproteinaemia?
- Chylomicrons in fasting plasma
- No link with coronary artery disease
- Caused by defective lipoprotein lipase
What is type IIa hyperlipoproteinaemia?
- Raised LDL
- Associated with coronary artery disease that may be severe
- Casued by a defective LDL receptor
What is type IIb hyperlipoproteinaemia?
- Raised LDL and VLDL
- Associated with coronary heart disease
- Defect unknown
What is type III hyperlipoproteinaemia?
- Raised LDL and chylomicron remnants
- Associated with coronary heart disease
- Caused by defective apoprotein (Apo. E)
What is type IV hyperlipoproteinaemia?
- Raised VLDL
- Associated with coronary heart disease
- Defect unknown
What is type V hyperlipoproteinaemia?
- Raised chylomicrons and VLDL in fasting plasma
- Associated with coronary heart disease
- Cause unknown
How is hyperlipoproteinaemia treated?
- First with diet and lifestyle modifications eg increased exercise
- Drug therapy (statins) if the above doesn’t work
How do diet and lifestyle modifications treat hyperlipoproteinaemia?
- Aim to reduce/eliminate cholesterol from the diet
- Reduce intake of triacyglycerols especially those containing saturated fatty acids
- If these do not achieve desired results drug therapy must be used
How does drug therapy work?
- Statins (eg simvastatin) are a group of drugs that lower plasma cholesterol levels
- Do this by reducing cholesterol synthesis in the liver by inhibiting the enzyme HMG-CoA reductase
How is cholesterol removed from the body?
- Liver converts cholesterol to bile salts that are secreted in the bile
- Small amount of cholesterol is secreted from the bile
- Bile salt sequestrants (eg cholestyramine) lowers plasma cholesterol by increasing its disposal from the body; bind to bile salts in GI tract preventing them being reabsorbed into the hepatic portal circulation and promoting their loss in faeces
How is the enzyme lipoprotein lipase involved in lipoprotein metabolism?
- Responsible for removing core triacyglycerols from lipoprotein particles eg chylomicrons and VLDL
- Found attached to inner surface of capillaries in tissues eg adipose, muscle
- Insulin increases enzyme synthesis by tissues
- Enzyme hydrolyses triacyglycerols in lipoprotein particles releasing fatty acids (taken up by tissues) and glycerol (transported to liver)
- Secondary effect of statins is to increase lipoprotein lipase
How is the enzyme lecithin:cholesterol acyltransferase (LCAT) involved in lipoprotein metabolism?
- Increases stability of lipoproteins when core lipids are removed increasing the ration of surface to core lipids by converting some surface lipid to core lipid
- Important in formation and structure maintenance of lipoprotein particles
- Converts cholesterol to cholesterol ester using fatty acid derived from lecithin (phophatidylcholine)
- Deficiency results in unstable lipoproteins of abnormal structure and a general failure of lipid transport processes causing lipid deposits in many tissues and atherosclerosis
Which lipoprotein particles remain outside the cell?
- Chylomicrons and VLDL
- Supply tissues with triacyglycerols using extracellular lipoprotein lipase enzyme
How do tissues obtain cholesterol?
- From LDLs by the process of receptor-mediated endocytosis
- LDL particles are taken up by the cell and the cholesterol released inside the cell
Which cell is unable to synthesise cholesterol from acetyl CoA?
- Erythrocytes
Why do cells prefer to take up preformed cholesterol from plasma lipoproteins instead of synthesising it instead?
- Close control of whole body cholesterol content
How do cells take up LDLs?
- Cells requiring cholesterol synthesis specific LDL receptors that are exposed on the cell surface
- LDL receptors recognise and bind to specific apoproteins (Apo B100) on the surface of the LDL particles
- LDL receptor and bound LDL particle is taken up into the cell by endocytosis and is subjected to lysosomal digestion
- Cholesterol esters are converted to cholesterol that is released into the cell
- This cholesterol can be stored (as cholesterol esters) or used by the cell
- Accumulation of too much cholesterol in the cell is prevented by ip the inhibition of cholesterol synthesis and the synthesis and exposure of LDL receptors
What is familial hyperlipoproteinaemia? (Type IIa)
- Absence (homozygous) or deficiency (heterozygous) of functional LDL receptors
- Characterised by elevated levels of LDL and cholesterol in the plasma
- Homozygotes develop extensive atherosclerosis early in life
- Heterozygotes develop atherosclerosis later in life
What does oxygen normally do in cells?
- Oxidise compounds to produce energy
What happens in the electron transport chain in mitochondria if electrons do not reach the final electron acceptor (oxygen) to produce water?
- Electron prematurely reduces oxygen
- Forms superoxide radicals O2-
- Are highly reactive as they have an unpaired electron
- Are known as free radicals or reactive oxygen species (ROS)
- Continual leak out of mitochondria
What defence mechanism do human cells have against superoxide radicals?
- Isoforms of superoxide dismutase (SOD) enzyme
- Catalyses reaction of superoxide radicals together to form oxygen and hydrogen peroxide
- Hydrogen peroxide (itself a powerful oxidising agent) is rapidly broken down to oxygen and water by catalase enzyme
- However superoxide dismutase cannot cope with all superoxide molecules
How do superoxide molecules cause damage?
- Oxidise lipids, proteins and DNA
- Lipids: lipid peroxidation reaction; can damage lipid membranes; early process in atherosclerosis; produces hydroxyl radicals
- Hydroxyl radicals (*OH) are highly reactive agent and cause damage to cells especially to membranes; cannot be eliminated by enzymatic reaction
How else are radicals produced?
- Ionising radiation - contributes to pathology and ageing
- Toxins eg herbicide paraquat: cause production of superoxide radicals which are toxic to cells
- Superoxide radicals can react with other free radicals eg nitric oxide (NO* a signalling molecule produced by some cells) to form peroxynitite (ONOO-) which is a highly reactive molecule capable of oxidising variety of molecules
- Drugs eg antimalarials act as oxidising agents
What else defends against reactive oxygen species (ROS)?
- NADPH: reducing agent produced in pentose phosphate pathway
- Glutathione (GSH): tripeptide is abundant in cells and is the most important antioxidant
- Thiol (-SH) group in cysteine: acts as a reducing agent when donating a H atom
What is the oxidised form of glutathione (GSH)?
- Glutathione disulphide (GSSG)
- Is reduced back to glutathione by NADPH
How do glutathione and NADPH work together to remove reactive oxygen species (ROS)?
- ROS reacts with water to form hydrogen peroxide (H2O2)
- GSH reduces H2O2 to H2O and is oxidised itself to GSSG (catalysed by glutathione perosidases)
- NADPH reduces GSSG back to GSH and is oxidised itself to NADP+
- More NADPH is then formed through the pentose phosphate pathway
What other molecules are important?
- Vitamin C
- Vitamin E
- Trace elements eg selenium
What is the purpose of the ‘5 a day’ campaign?
- So people get enough antioxidant vitamins from fruit and vegetables
What is oxidative stress?
- Low levels of antioxidants to cope with ROS
- Underlies pathology of atherosclerosis, Parkinson’s disease and Alzheimer’s disease
- Also involved in inflammation reactions
In what circumstances are ROS a problem?
- Cells normally have enough antioxidant power to cope with ROS production
- A problem when:
~ ROS production is excessive
~ antioxidant levels are low
What is an example of an inflammation reaction?
- Enzyme inducible nitric oxide synthase producing large amount of nitric oxide which is converted to peroxnitrite radicals
Why do some immune cells eg neutrophils and monocytes produce ROS?
- Rapidly produce ROS in an oxidative burst when stimulated
- Destroys cells and also surrounding bacteria and fungal cells
- Important part of body’s immune response to infection
How is the oxidative burst produced?
- Membrane-bound enzyme NADPH oxidase
- Present in cell membrane and in membrane of phagosomes
- Transfers electrons from NADPH across the membrane to couple to molecular oxygen to generate superoxide radicals
- Enzyme is important in the development of atherosclerosis
Why are ROS important in certain disease States?
- Have a role as signalling molecules
