Session 5 (1) - Lipid transport Flashcards
Why are lipids carried in association with proteins?
Because they’re insoluble in plasma
What are the two ways in which lipids are carried in blood, and in what proportions does this occur
~98% carried as highly specialised non-covalent assemblies called lipoprotein particles
~2% mostly fatty acids are carried bound non-covalently to albumin.
What is the significance of albumin bound fatty acids?
fatty acids released from adipose tissue during lipolysis and are used as a fuel by tissues
Why can only a limited amount of fatty acids be carried on albumin?
Albumin has limited capacity for fatty acids, therefore blood fatty acid levels do not normally exceed ~3mM.
What two diseases do disorders of lipoprotein metabolsim have significance in?
atherosclerosis and coronary artery disease.
Give five types of lipid
Cholesterol (transports fatty acids) Cholesterol Ester Phospholipids Triacylglycerol Fatty Acids
Give four functions of cholesterol
Major component of membranes
Precursor of steroid hormones
Precursor of bile acids
Can be esterified with a fatty acid, which elminates the only polar part.
Where does cholesterol come from? What is it synthesised from? What enzyme is used?
Some from diet, but mostly synthesied in liver
Hydroxymethylglutaric acid, a product of acetyl CoA catabolism via “synthase” enzyme. Reductase enzyme helps convert hmga to cholesterol.
Give three features of phospholipids
Diacylglycerl with phosphate group
Major component of membranes
Phosphate is polar
How do lipoproteins differ?
in the lipid being transported, the origins of the lipid and its destination
What are the protein components of a lipoprotein known as?
apoproteins
What is the structural role of apoproteins in lipoproteins? What two features allow them to fulfill this role?
apoproteins are involved in packaging non-water soluble lipids into soluble form. This is possible as they contain hydrophobic regions that interact with lipid molecules and hydrophilic regions that interact with water.
What is the functional role of apoproteins?
activation of enzymes or the recognition of cell surface receptors.
What does apoprotein composition determine?
Function of a lipoprotein particle
What is the macrostructure of a lipoprotein?
Spherical particles that consist of a surface coat (shell) and a hydrophobic core.
What does the surface coat of a lipoprotein contain?
phospholipids, cholesterol and apoproteins
What does the hydrophobic core of a lipoprotein contain?
Triacylglycerol and cholesterol esters
What must occur when core lipids are removed, and why?
the surface coat must be reduced, as lipoproteins are only stable if they maintain their spherical shape
What is the difference between core and surface components in terms of transferability?
Many components of the surface coat are free to transfer. The core components can only be removed by special proteins e.g. lipases and transfer proteins.
Give the transport function of chylomicrons. How long are they present after a meal?
Transport dietary triacylglycerols from the intestine to tissues such as adipose tissue. Normally only present in blood 4-6 hours after meal (see below)
Give the transport function of VLDL’s
Transport of triacylglycerols synthesised in the liver to adipose tissue for storage. Combine TAGs synthesised in liver with specific apoproteins.
Give the transport function of LDLs
Transport of cholesterol synthesised in the liver to tissues. Combine synthesised cholesterol in liver with specific apoproeins.
Give the transport function of HDL
Transport of excess tissue cholesterol to the liver for disposal as bile salts.
What does higher levels of LDLs signify?
Higher risk of atherosclerosis
What does a low HDL/LDL ratio lead to?
Cardiovascular disease
Why are TAGs transported in Chylomicrons?
Because they cannot be absorbed directly
Give the digestive path of TAGs and their consituents
TAGs hydrolysed in SI by pancreatic lipase, which releases fatty acids and glycerol
Fatty acids enter epithelial cells of SI where they’re re-esterified to TAGs using glycerol phosphate from glucose metabolism.
The TAGs are then packaged with other dietary lipids into chylomicrons.
How are chylomicrons released from epithelial tissues into blood stream?
The lymphatic system
What tissues are chylomicrons transported to?
Tissues such as adipose tissue which express extracellular enzyme lipoprotein lipase.
What does extracellular lipoprotein lipase do, and where is it located?
Attached to inner surface capillaries of tissues such as adipose and muscle. Hydrolyses TAGs in lipoproteins, releasing fatty acids and glycerol. Then takes up fatty acids and glycerols go to liver.
What does LCAT do?
Restores stability of lipoproteins by coverting surface lipid to core lipid. Converts of cholesterol to cholesterol ester using fatty acid lethicin.
What does deficiency of LCAT do?
Results in unstable lipoproteins of abnormal structure, so failure of lipid transport. Lipid deposits occur in many tissues, causing atherosclerosis.
What three things are produced from VLDL metabolism?
- Glycerol – remains in circulation
- Fatty acids – enter tissues for metabolsim
- VLDL remnants - Usually removed by liver or converted to other types of lipoprotein particles
What process is used in LDL metabolism?
receptor-medicated endocytosis. LDL particles are taken up by the cell and the cholesterol released inside the cell.
What two ways can cells receive cholesterol?
able to synthesise cholesterol from acetyl~CoA
uptake of pre-formed cholesterol circulating in plasma lipoproteins.
How do cells uptake preformed cholesterol?
Cells requiring cholesterol synthesise LDL receptors that are exposed on the cell surface.
These receptors recognise and bind to specific apoproteins (Apo B100) on the surface of the LDL.
The LDL receptor with its bound LDL is then endocytosed by the cell and subjected to lysosomal digestion.
Cholesterol esters are converted to free cholesterol that is released within the cell.
What happens to cholesterol once inside a cell?
The cholesterol can be stored (as cholesterol esters) or used by the cell
What is hyperlipoproteinaemias?
Raised levels of one or more lipoprotein classes
What three things can Hyperlipoproteinaemias be caused by?
defective
Enzymes
Receptors
Apoproteins
Describe type 1
Presentation
Disease links
Cause
Chylomicrons in fasting plasma
No link to coronary artery disease
Caused by defective lipoprotein lipase
Describe type IIa (familial hypercholesterolamia)
Presentation
Disease links
Cause
Raised LDL
Associated with coronary artery disease that may be severe
Caused by defective LDL receptor
Describe type IIb
Presentation
Disease links
Cause
Raised LDL and VLDL
Associated with coronary artery disease
Defect unknown
Describe type III
Presentation
Disease links
Cause
Raised IDL and chylomicrons remnants
Associated with coronary artery disease
Caused by defective apoprotein (Apo. E)
Type IV
Presentation
Disease links
Cause
Type V
Presentation
Disease links
Cause
Raised VLDL
Associated with coronary artery disease
Defect unknown
Raised chylomicrons and VLDL in fasting plasma
Associated with coronary artery disease
Defect unknown
Give six steps of atheroma formation
Oxidised LDL –> Macrophages –> Foam cells –> accumulate in intima of blood vessel walls –> Fatty streak → Atheroma
What is familial hypercholesterolaemia? What is caused by? What is it characterised by?
What happens to homozygotes and heterozygotes?
Type IIa hyperlipoproteinaemia)
A condition in which there may be an 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 and heterozygotes develop the condition later in life.
What are three symptoms of hyperchoesterolaemia?
Xanthelasma – Cholesterol deposits in eyelids
Tendon Xanthoma – Cholesterol deposits in tendons
Corneal arcus – Cholesterold deposits in cornea
How can you treat hyperlipoproteinaemias?
Diet and lifestyle modifications - Aim to reduce cholesterol and TAG in diet.
Drug therapy - Statins, Bile sequesterants
Druge therapy - Statins lower plasma cholesterol by reducing synthesis of cholesterol in tissue. Also increase expression of LDL receptors in hepatocytes.
What is the biological mechanism of statins? Why are there side effects?
Statins inhibit production of other intermediates in the HMG-CoA reductase metabolic pathway, which may account for side effects. Addition of Co-enzyme Q-10 to diet my alleviate some side effects however.
How does liver dispose of cholesterol?
by converting it into bile salts and secreting a small amount directly in the bile.
How do bile salt sequestarants lower plasma cholesterol?
by binding to bile salts in the GI tract preventing them from being reabsorbed into the hepatic-portal circulation and promoting their loss in the faeces.
