Session 4 Lecture Notes Flashcards
Approximately what is the plasma constant level for glucose?
5mmol per L
What is the store of glucose called?
Glycogen
For hypoglycaemia what is the critical level - if our plasma level drops below this it can lead to death?
0.6mmol/L
What happens in glycation?
There is the addition of glucose to proteins such as the haemoglobin protein
Where is glycogen stored? (there are 2 places)
- In the muscle= to supply the muscles only with glucose
2. In the liver = to supply the rest of the body
What are 2 benefits of storing glycogen?
- Glucose can be released rapidly from multiple sites along the polymer
- There is reduced osmotic effect by storing it as one molecule rather than multiple glucose molecules
Which bonds join chains of glucose in glycogen?
a-1-4 glycosidic bonds
Which bonds form branch points every 8-10 residues in the glycogen polymer?
a-1-6 glycosidic bonds
What is the name of the dimer at the core of the glycogen polymer?
Glycogenin
Why can’t cellulose be broken down?
Because it contains b-1-4 glycosidic bonds (not a-1-4 like in glycogen) and we don’t have the enzymes for beta
What is glycogen synthesis called?
Glycogenesis
What is the first conversion step of glycogenesis?
Glucose 6-P (from glycolysis) is converted to Glucose 1-P by the enzyme Phosphoglucomutase
What is the 2nd conversion step in glycogenesis?
Glucose 1-P + UTP + H20 is converted to UDP-glucose + 2Pi by the enzyme G1P uridyltransferase
What is the final step in glycogenesis?
Glycogen (with its residues) reacts with UDP-glucose to form [Glycogen + 1 residue of glucose] + UDP
This reaction is catalysed by the two enzymes that create glycosidic bonds (a-1-4 and a-1-6) = glycogen synthase and branching enzyme
What enzymes synthesise a-1-4 and a-1-6 bonds in glycogenesis?
- glycogen synthase (a-1-4)
2. branching enzyme (a-1-6)
What is glycogen degradation called?
Glycogenolysis
What is the first step in glycogenolysis?
Glycogen + Pi = Glucose 1-P and [glycogen -1 residue of glucose]
What are the 2 enzymes called involved in breaking down glycosidic bonds in glycogen?
- Glycogen phosphorylase (a-1-4)
2. De-branching enzyme (a-1-6)
What is the 2nd step in glycogenolysis?
Glucose 1-P is converted to Glucose 6-P by phosphoglucomutase where it is transported to the muscles or liver
What happens to Glucose 6-P in the liver (after glycogenolysis)?
Glucose 6-P is converted
to glucose by the enzyme Glucose 6-Phosphatase and glucose then transported around the blood to tissues
What happens to Glucose 6-P in the muscles (after glycogenolysis)?
It is converted to lactate and then transported back to the liver for conversion to glucose
The muscles lack the enzyme glucose 6-phosphatase so can’t break glucose 6-P directly down into glucose
What are the rate limiting enzymes in glycogenesis and glycogenolysis?
- Glycogen synthase
2. Glycogen phosphorylase
What hormones increase rate of glycogenesis and which increase rate of glycogenolysis?
Insulin = increase rate of glycogenesis (glycogen synthesis)
Glucagon + adrenaline = increase rate of glycogenolysis (glycogen degradation)
Glucagon can only act at one place to to increase glycogenolysis- where?
At the liver
It has no effect at muscles
Instead AMP allosterically activates it at muscles
Give 2 examples of glycogen storage disease and what they do
Von Gierke’s disease - glucose 6 phosphatase deficiency (so it can’t be broken down to release glucose)
McArdle disease - muscle glycogen phosphorylase deficiency (so can’t carry out glycogenolysis and person is exhausted)
What is glucose synthesis called?
Gluconeogenesis
When does gluconeogenesis start to take place?
When liver stores of glycogen have run out = an alternative source of glucose is required
What are the 3 major precursors for gluconeogenesis?
- Lactate (from anaerobic glycolysis in muscles = Cori Cycle)
- Glycerol (from TAG in adipose tissue)
- AAs (glucogenic AAs such as alanine)
What are the key enzymes involved in gluconeogenesis? (there are 3)
- PEPCK (converts oxaloacetate to phosphoenolypyruvate)
- Fructose 1-6-bisphosphatase (converts Fructose 1-6-bisphosphate to Fructose 6-P)
- Glucose 6-Phosphatase (converts glucose 6-phosphatase to glucose)
Which 2 enzymes are regulated by hormones in gluconeogenesis?
- PEPCK
2. Fructose 1-6 bisphosphatase
Which hormones inhibit gluconeogenesis and which stimulate it?
Insulin = inhibits (hormone of plenty i.e. we already have enough glucose)
Glucagon and cortisol = stimulates
How long after eating a meal would gluconeogenesis take place?
8-10 hours after (after glycogen stores have been depleted in the liver first)
What are the carriers of TAG in the lacteals vs the blood? (during TAG metabolism)
In lacteals = chylomicrons
In blood = albumin
What 2 routes can TAG take when metabolised and in the blood?
- Can travel to adipose tissue for TAG storage
- Can travel to tissues for FA oxidation and energy release (note not in cells without mitochondria i.e. RBCs and not in brain as FAs can’t cross blood brain barrier)
What is fatty acid synthesis called?
Lipogenesis
Describe the process of lipogenesis and where it takes place
This mainly takes place in liver
Excess glucose is converted to pyruvate (glycolysis) in cytoplasm
Pyruvate enters mitochondria and forms Acetyl-CoA and oxaloacetate (from TCA cycle) which condense to form Citrate
Citrate goes back into cytoplasm and is cleaved back to Acetyl-CoA and OAA
Acetyl-CoA carboxylase forms Malonyl-CoA from Acetyl-CoA and the fatty acid synthase complex builds fatty acids by addition of 2 carbons provided by Malonyl-CoA
What is the key regulatory enzyme in lipogenesis?
Acetyl-CoA carboxylase
It converts 2 carbon Acetyl-CoA to 3 carbon Malonyl-CoA = using ATP in process
What is the breakdown of fat storage called?
Lipolysis
What happens in lipolysis?
TAG from adipose store is broken down by hormone sensitive lipase to glycerol and fatty acids
Glycerol is taken to liver for gluconeogenesis
Fatty acids travel on albumin in blood for beta oxidation
Above what cholesterol concentration are you at risk of cv diseases?
Above 5mmol/L
What is the structure of phospholipids?
A hydrophilic head (of choline and phosphate) attached by a glycerol backbone to 2 hydrophobic fatty acid tails
How are phospholipids classified?
According to their polar hydrophilic head
What is the difference between a liposome and a micelle?
Liposome = phospholipid bilayer that can transport a hydrophilic particle Micelle = single layer of phospholipids that can transport a hydrophobic particle
Where is most our cholesterol synthesised?
Give some examples of what it is a precursor for
In the liver
Precursor for:
steroid hormones eg cortisol, aldosterone, testosterone and oestrogen
bile acids
What is a cholesterol ester?
Cholesterol with a fatty acid tail (this is how most cholesterol is transported)
What is the cargo of lipoproteins?
TAG
cholesterol water
fat soluble vitamins (A, D, E and K)
Name the integral and peripheral apoplipoproteins
Integral = apoA and apoB Peripheral = apoC and apoE
Name the 5 classes of lipoproteins
- chylomicrons
- VLDL
- IDL
- LDL
- HDL
What lipoproteins are the main carriers of fat and of cholesterol?
Fat = chylomicrons and VLDL cholesterol = IDL, LDL and HDL
What are the most important apopolipoproteins and on which lipoproteins are they found?
apoB (on VLDL, IDL and LDL)
apoAI (on HDL)
What are the 2 roles of lipoproteins?
Structural = they package insoluble lipid Functional = co-factor for enzymes and ligand for cell surface receptor
What apolipoproteins are found on chylomicrons and when are they added?
apoB-48 = added in small intestines before entering lymph system
apoC and apoE added in left subclavian vein
Which apolipoprotein binds to lipoprotein lipase on adipocytes and muscle to release fatty acids?
apoC = the chylomicrons empty its fat contents until the chylomicron is at 20% capacity
It then detaches and becomes a chylomicron remnant
Which apolipoprotein binds to lipoprotein lipase receptor on hepatocytes in order for receptor mediated endocytosis of the chylomicron to take place?
apoE binds to LDL receptor (as lipoprotein lipase bound during fatty acid release at cells)
What apoliproteins are added to VLDL (used to transport TAG as well as chylomicrons)?
apoB100 added in small intestines and apoC and apoE added from HDL particles in the blood
(differs from chylomicrons which have apoB48 and then receive the other apolipoproteins in the L subclavian vein)
How are IDL and LDL formed that carry cholesterol esters?
VLDL become IDL and then LDL as the contents are depleted further and further
30% = IDL
10% = LDL
What happens to an IDL particle at 10% fat depletion?
It loses apoC and apoE and becomes an LDL with a high cholesterol content
Why do liver cells not take up LDL particles?
LDL particles don’t contain apoC or apoE and the liver LDL receptor has a high affinity for apoE
What is LDL at risk of in the blood?
It has a longer half life so is more susceptible to oxidative damage
Oxidised LDL taken up by macrophages can transform to foam cells and contribute to formation of athlerosclerotic plaques
How are HDL lipoproteins synthesised?
Synthesised by liver and intestine
They can also bud off from chylomicrons and VLDL as they are digested by LDL
What apoplipoprotein is on HDL liporproteins?
apoAI
How can apoAI form HDL lipoproteins?
ApoAI can acquire cholesterol and phospholipids from other lipoproteins and cell membranes to form nascent HDL
How do HDL particles mature?
They accumulate cholesterol and phospholipids from cells lining blood vessels to
The ABCAI protein facilitates the movement of cholesterol to HDL
How can HDL particles help reduce atherosclerotic plaque formation?
They can remove cholesterol from cholesterol laden cells and return it to the liver
This reduces likelihood of foam cells and atherosclerotic plaques forming
What is hyperlipoproteinaemia?
Raised plasma level of one or more lipoproteins
What is type I hyperlipoproteinaemia?
Defective lipoprotein lipase (LDL) means the lipoproteins can’t be broken down and fat removed
What is type III hyperlipoproteinaemia?
Defective apoE so not recognised by liver
What is type IIa hyperlipoproteinaemia?
Defective LDL receptor
What is hypercholesterolaemia and what are the 3 signs?
High level of cholesterol in the blood
Three signs:
1. Xanthelasma - yellow patches on eyelids
2.. Tendon Xanthoma - nodules on tendon
3. Corneal arcus - white circle around eye
Where do foam cells accumulate following oxidised LDLs being engulfed by macrophages?
In the tunica intima layer of the blood vessel forming a fatty streak
Give some ways to treat hyperlipoproteinaemia
Diet:
reduce cholesterol and saturated lipids
increase fibre intake
Drugs:
Statins
Bile salt sequestrants
