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Metabolism > Session 5 > Flashcards

Session 5 Flashcards

0
Q

Where do lipids found in the blood come from and where are they going?

A
  • Come from diet or synthesised in the body

- Transported to tissues for storage and/or utilisation

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1
Q

What classes of lipids are found in the blood?

A
  • Triaclyglycerols
  • Fatty acids
  • Cholesterol
  • Cholesterol esters
  • Phospholipids
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2
Q

How are lipids carried in the blood?

A
  • 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
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3
Q

Where are the albumin bound fatty acids from and what are they used for?

A
  • From fatty acids released from adipose tissue during lipolysis
  • Used as a fuel by tissues eg muscle
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4
Q

What is the blood fatty acid level and why?

A
  • ~3 mmol/L

- Albumin has a limited capacity to transport fatty acids

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5
Q

Why are plasma lipoproteins significant in medicine?

A
  • Disorders in lipoprotein metabolism is associated with important diseases eg atherosclerosis and coronary artery disease
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6
Q

What are plasma lipoprotein particles?

A
  • Multi-molecular complexes
  • Contain variable amount of different lipids (phospholipids; triacylglycerols; cholesterol esters) in non-covalent (mostly hydrophobic) association with specific proteins
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7
Q

What is the primary function of lipoproteins?

A
  • Transport water-insoluble lipid molecules in the bloodstream
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8
Q

How do classes of lipoproteins differ? (Simple)

A
  • Lipid being transported
  • Origin of the lipid
  • Destination
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9
Q

What are the protein components of lipoproteins?

A
  • Specific proteins (apoproteins) that have functional and structural roles
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10
Q

What are the structural roles of apoproteins and why are they effective?

A
  • 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
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11
Q

What are the functional roles of apoproteins?

A
  • Involved in the activation of enzymes or recognition of cell surface receptors
  • Function depends on the particular apoprotein’s composition
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12
Q

What is the structure of a mature lipoprotein in normal human plasma?

A
  • Spherical
  • Consists of a surface coat (shell) and hydrophobic core
  • Surface coat contains phospholipids, cholesterol and apoproteins
  • Hydrophobic core contains triacyglycerols and cholesterol esters
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13
Q

When are lipoprotein particles stable?

A
  • 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
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14
Q

How are core and surface coat components be removed from the lipoprotein particles?

A
  • Surface coat: free to transfer to different particles and to cell membranes
  • Core: only be removed by special proteins eg lipases and transfer proteins
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15
Q

How can classes of lipoproteins be identified?

How does this allows them to be separated?

A
  • 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
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16
Q

What are the classes of mature lipoproteins?

A
  • Chylomicrons
  • Very Low Density Lipoproteins (VLDL)
  • Low Density Lipoproteins (LDL)
  • High Density Lipoproteins (HDL)
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17
Q

What are the classes of remnant lipoproteins?

A
  • Chylomicron remnants

- VLDL remnants (Intermediate Density Lipoproteins)

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18
Q

How are remnant lipoproteins formed?

A
  • Removal of lipids from (mostly triacylglycerols) from chylomicrons and VLDL
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19
Q

What is the transport function of the different classes of lipoproteins determined by?

A
  • Largely by apoprotein composition
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20
Q

What is the transport function of chylomicrons?

A
  • Transport dietary triacyglycerols from the intestine to tissues eg adipose tissue
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21
Q

What is the transport function of VLDL?

A
  • Transport of triacylglycerols synthesised in the liver to the adipose tissue for storage
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22
Q

What is the transport function of LDL?

A
  • Transport of cholesterol synthesised in the liver to tissues
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23
Q

What is the transport function of HDL?

A
  • Transport of excess cholesterol to the liver for disposal as bile salts
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24
Q

How do dietary triacyglycerols become associated with chylomicrons?

A
  • 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
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25
Q

What happens to chylomicrons once they have triacyglycerols?

A
  • 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
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26
Q

What are dyslipoproteinaemias?

A
  • 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
27
Q

What is found in hyperlipoproteinaemias?

A
  • Raised levels of one or more of the plasma lipoproteins
28
Q

Why is it important to be able to recognise different types of hyperlipoproteinaemias?

A
  • Each have a different risk of coronary artery disease
  • Have different causes
  • Respond to different treatments
29
Q

How are different types of hyperlipoproteinaemias identified and classified?

A
  • Fredrickson (WHO) system
  • Based on measurement of fasting plasma glucose concentrations, total cholesterol and triacyglycerols and examination of plasma lipoprotein separations by electrophoresis
30
Q

How many different types of hyperlipoproteinaemias are there?

A
  • 6
31
Q

What is type I hyperlipoproteinaemia?

A
  • Chylomicrons in fasting plasma
  • No link with coronary artery disease
  • Caused by defective lipoprotein lipase
32
Q

What is type IIa hyperlipoproteinaemia?

A
  • Raised LDL
  • Associated with coronary artery disease that may be severe
  • Casued by a defective LDL receptor
33
Q

What is type IIb hyperlipoproteinaemia?

A
  • Raised LDL and VLDL
  • Associated with coronary heart disease
  • Defect unknown
34
Q

What is type III hyperlipoproteinaemia?

A
  • Raised LDL and chylomicron remnants
  • Associated with coronary heart disease
  • Caused by defective apoprotein (Apo. E)
35
Q

What is type IV hyperlipoproteinaemia?

A
  • Raised VLDL
  • Associated with coronary heart disease
  • Defect unknown
36
Q

What is type V hyperlipoproteinaemia?

A
  • Raised chylomicrons and VLDL in fasting plasma
  • Associated with coronary heart disease
  • Cause unknown
37
Q

How is hyperlipoproteinaemia treated?

A
  • First with diet and lifestyle modifications eg increased exercise
  • Drug therapy (statins) if the above doesn’t work
38
Q

How do diet and lifestyle modifications treat hyperlipoproteinaemia?

A
  • 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
39
Q

How does drug therapy work?

A
  • 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
40
Q

How is cholesterol removed from the body?

A
  • 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
41
Q

How is the enzyme lipoprotein lipase involved in lipoprotein metabolism?

A
  • 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
42
Q

How is the enzyme lecithin:cholesterol acyltransferase (LCAT) involved in lipoprotein metabolism?

A
  • 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
43
Q

Which lipoprotein particles remain outside the cell?

A
  • Chylomicrons and VLDL

- Supply tissues with triacyglycerols using extracellular lipoprotein lipase enzyme

44
Q

How do tissues obtain cholesterol?

A
  • From LDLs by the process of receptor-mediated endocytosis

- LDL particles are taken up by the cell and the cholesterol released inside the cell

45
Q

Which cell is unable to synthesise cholesterol from acetyl CoA?

A
  • Erythrocytes
46
Q

Why do cells prefer to take up preformed cholesterol from plasma lipoproteins instead of synthesising it instead?

A
  • Close control of whole body cholesterol content
47
Q

How do cells take up LDLs?

A
  • 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
48
Q

What is familial hyperlipoproteinaemia? (Type IIa)

A
  • 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
49
Q

What does oxygen normally do in cells?

A
  • Oxidise compounds to produce energy
50
Q

What happens in the electron transport chain in mitochondria if electrons do not reach the final electron acceptor (oxygen) to produce water?

A
  • 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
51
Q

What defence mechanism do human cells have against superoxide radicals?

A
  • 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
52
Q

How do superoxide molecules cause damage?

A
  • 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
53
Q

How else are radicals produced?

A
  • 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
54
Q

What else defends against reactive oxygen species (ROS)?

A
  • 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
55
Q

What is the oxidised form of glutathione (GSH)?

A
  • Glutathione disulphide (GSSG)

- Is reduced back to glutathione by NADPH

56
Q

How do glutathione and NADPH work together to remove reactive oxygen species (ROS)?

A
  • 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
57
Q

What other molecules are important?

A
  • Vitamin C
  • Vitamin E
  • Trace elements eg selenium
58
Q

What is the purpose of the ‘5 a day’ campaign?

A
  • So people get enough antioxidant vitamins from fruit and vegetables
59
Q

What is oxidative stress?

A
  • Low levels of antioxidants to cope with ROS
  • Underlies pathology of atherosclerosis, Parkinson’s disease and Alzheimer’s disease
  • Also involved in inflammation reactions
60
Q

In what circumstances are ROS a problem?

A
  • Cells normally have enough antioxidant power to cope with ROS production
  • A problem when:
    ~ ROS production is excessive
    ~ antioxidant levels are low
61
Q

What is an example of an inflammation reaction?

A
  • Enzyme inducible nitric oxide synthase producing large amount of nitric oxide which is converted to peroxnitrite radicals
62
Q

Why do some immune cells eg neutrophils and monocytes produce ROS?

A
  • 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
63
Q

How is the oxidative burst produced?

A
  • 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
64
Q

Why are ROS important in certain disease States?

A
  • Have a role as signalling molecules

Metabolism (11 decks)

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