Energy Storage

Question 1

Which tissues have an absolute requirement for glucose as an energy source?

Answer 1

Red blood cells - dot have mitochondria for TCA
Neutrophils - respiratory burst
Innermost cells of kidney medulla - deep in , cant get same oxygen supply
Lens of the eye - needs to be be clear so not many blood vessels

Question 2

Why does the brain need glucose?

Answer 2

Stable blood glucose level
absolutely essential for normal brain function.

Brain can adapt to use ketone bodies in starvation - requires time for enzymes to click in for brain to utilise ketone bodies - can only derive around half energy req from ketone bodies - glut1 responsible for getting lucid into RBCs

Question 3

What is glucose stored as and why?

Answer 3

To enable blood glucose to be kept at required levels, a store of glucose is required…GLYCOGEN
Need to keep plasma glucose in defined region
Need a store of glucose to cell on when plasma glucose conc - glycogen

Question 4

Describe plasma glucose conc after a meal and what is glycation?

Answer 4

Insulin crucial in allowing body to deal with metabolites from meal
Plasma glucose remains high after meal - chronic complications in patients - can start to react with proteins - glycation (different from glycosylation which is normal)
Glycation is a non enzymatic reaction.- high conc of glucose reacts with proteins - indicator = glycation haemoglobin to look at long term glucose concentration

Question 5

What are the consequences of hypoglycaemia?

Answer 5

2. 8mmol/L - confusion
3. 7mmol/L - weakness, nausea
4. 1mmol/L - muscle cramps
5. 6mmol/L - brain damage, death

Question 6

How is glycogen stored?

Answer 6

Granules
In muscle - intra and inter myofibrillar glycogen - 300mg in skeletal muscles

Granules in hepatocytes - 100mg n liver

Question 7

What is the purpose of the muscle and liver stores fo glycogen?

Answer 7

Stores serve different purposes
In muscle - local store of glucose for muscle contraction - muscle lacks key enzyme to convert g-6-p to glucose
Liver glycogen can be use as a store to replenish plasma glucose

Question 8

Describe the structure of glycogen

Answer 8

• Glycogen is a polymer consisting of chains of
glucose residues
• Chains are organized like the branches of a tree originating from a dimer of the protein glycogenin (acts as a primer at core of glycogen structure).
• Glucose residues linked by α-1-4 glycosidic bonds with α-1-6 glycosidic bonds forming branch points every 8-10 residues

Lots of end points torelease glucose from

Question 9

What are the key steps in glycogenesis

Answer 9

HEXOKINASE - Glucose + ATP -> Glucose 6-phosphate + ADP

PHOSPHOGLUCOMUTASE - Glucose 6-phosphate -> glucose 1-phosphate

G1P URIDYLYLTRANSFERASE - Glucose 1-phosphate + UTP = H2O -> UDP-glucose +PPi

GLYCOGEN SYNTHASE (1-4) / BRANCHING ENZYME (1-6) - Glycogen (n residues) + UDP-glucose -> glycogen(n+1 residues) + UDP

Question 10

What is glycogenolysis

Answer 10

Glycogen (n residues) + Pi -> Glucose 1-phosphate + Glycogen (n-1 residues)
Catalysed by GLYCOGEN PHOSPHORYLASE or DE-BRANCHING ENZYE
Then
Glucose 1-phosphate glucose 6-phosphate
Catalysed by PHOSPHOGLUCOMUTASE

This goes to muscle and liver
Muscle - for energy prodution
Liver - released by liver into blood for use by other tissues

Glycogenolysis is Not a simple reversal of glycogenesis. Different enzymes allow for simultaneous inhibition of one pathway and stimulation of another

Question 11

How do the glycogen stores differ in liver and muscle and why?

Answer 11

G6P converted to glucose and exported to blood. Liver glycogen is a buffer of blood glucose levels.

Muscle lacks the enzyme Glucose-6-phosphatase. G6P enters glycolysis for energy production

• Muscle glycogen stores differ in that Glucagon has no effect.
Also AMP is an allosteric activator of muscle glycogen phosphorylase but not of the liver form of enzyme

Question 12

Give an overview of glycogen metabolism

Answer 12

SEE LSIDE

Question 13

What are the rate limiting enzymes for glycogen synthesis and degradation

Answer 13

Synthesis - GLYCOGEN SYNTHASE

Degradation - GLYCOGEN PHOSPHORYLASE

Question 14

What is the action or glucagon/adrenaline and insulin on glycogen synthase and glycogen phosphorylase

Answer 14

Glucagon and adrenaline phosphorylate the enzymes - DECREASE glycogen synthase and INCREASE glycogen phosphorylase activity

Insulin dephosphorylates the enzymes - INCREASE glycogen synthase activity and DECREASE glycogen phosphorylase activity

Question 15

How do glycogen storage diseases arise?

Answer 15

• Inborn errors of metabolism (inherited diseases)
• Arise from deficiency or dysfunction of enzymes of glycogen metabolism
• 12 distinct types. Incidence varies ~1 in 20,000 – ~1 in 100,000. Severity depends on enzyme/tissue affected

Question 16

What organs/tissues are affected by glycogen storage disease

Answer 16

• Liver and /or muscle can be affected
• Excess glycogen storage can lead to tissue damage • Diminished glycogen stores can lead to hypoglycaemia & poor exercise tolerance
Severity of disease depends on which enzyme/tissue affected

Question 17

Name 2 examples of glycogen storage diseases

Answer 17

• von Gierke’s disease - glucose 6-phosphatase deficiency - liver cant export glucose as g-6-p cant be converted back to glucose - increase in size of liver
• McArdle disease - muscle glycogen phosphorylase deficiency - patients very intolerant to excercise - cannot mobilise glycogen stored in muscle

Question 18

What is gluconeogenesis

Answer 18

The production of new glucose
• Beyond ~ 8 hours of fasting, liver glycogen stores start to deplete and an alternative source of glucose is required: Gluconeogenesis
• Occurs in Liver and to lesser extent in Kidney cortex
• Three major precursors

Question 19

What er ethe 3 main precursors for gluconeogenesis?

Answer 19

Lactate From anaerobic glycolysis in exercising muscle and red blood cells (Cori cycle)
Glycerol Released from adipose tissue breakdown of triglycerides.
Amino acids Mainly alanine

Question 20

What is the Cori cycle?

Answer 20

In liver
2 lactate -> glucose

In muscle
Glucose -> 2 lactate

Question 21

Why is there no net synthesis of glucose from acetyl CoA

Answer 21

Acetyl-CoA cannot be converted into pyruvate (pyruvate dehydrogenase reaction is irreversible) so there is no net synthesis of glucose from acetyl-CoA

Question 22

What are the key enzymes in gluconeogenesis?

Answer 22

GLUCOSE-6-PHOSPHATASE - glucose 6-phosphate to glucose

FRUCTOSE 1,6-BISPHOSPHATASE - fructose 1,6-bisphosphate to fructose 6-phosphate

PHOSPHOENOLPYRUVAE CARBPOXYKINASE (PEPCK) - oxaloacetate to phosphoeolpyruvate using energy from GTP

These are not simple reversals of their glycolysis steps

Question 23

How is gluconeogenesis regulated?

Answer 23

2 key enzymes regulated by hormones in response to:
• Starvation/fasting
• Prolonged exercise
• Stress

Fructose 1,6-bisphpsphatase and PEPCK

Question 24

What are the effects of the hormones glucagon/cortisol and insulin on fructose 1,6-bisphosphatase and PEPCK?

Answer 24

Glucagon and cortisol - increase amount of PEPCK, increase amount and activity of f1,6-bp - STIMULATE GLUCONEOGENESIS

Insulin - decrease amount of PEPCK and decrease amount/activity of f-1,6-bp - INHIBIT GLUCONEOGENESIS

Question 25

Describe the time course of glucose utilisation

Answer 25

Glucose from food ~2h
Glycogenolysis 8-10h
Gluconeogenesis 8-10h onwards

Question 26

How are lipids stored?

Answer 26

• Energy intake in excess of requirements is converted to Triacylglycerol (TAG) for storage
• TAGs are hydrophobic and therefore stored in an anhydrous form in specialised tissue – adipose tissue
• Highly efficient energy store. Energy content per gram twice that of carbohydrate or protein
• Utilised in prolonged exercise, stress, starvation, during pregnancy
• The storage & mobilisation of TAGs is under hormonal control

Question 27

Describe adipocytes

Answer 27

Large lipid droplet (mainly TAG and cholesterol ester) pushes organelles and cytoplasm to edge
• Typical adipocyte ~0.1mm in diameter. Cells expand as more fat added
• Average adult ~30 billion fat cells weighing ~15 kg.
• Can increase in size about fourfold on weight gain before dividing and increasing total number of fat cells

Also release hormones that are important in appetite

Question 28

Give an overview of TAG metabolism

Answer 28

Pancreatic lipase converts TAG to fatty caids and glycerol
In intestinal epithelial cells TAG is packaged into lipoprotein
Clylomicrosne enter lacteals first before blood
Thoracic duct drains into left subclavian vein - duct drains into blood
When in blood tag can be stored in adipose or utilised for energy production
Store can be mobilised
SEE SLIDE

Question 29

Describe fatty acid synthesis (lipo genesis)

Answer 29

• Mainly in liver. Dietary glucose as major source of carbon.
• Glucose -> pyruvate in cytoplasm (glycolysis).
• Pyruvate enters mitochondria and forms acetyl-CoA & OAA which then condense to form citrate
• Citrate -> cytoplasm and cleaved back to Acetyl-CoA &
OAA.
• Acetyl-CoA carboxylase (key regulator) produces malonyl-CoA from Acetyl-CoA.
• Fatty acid synthase complex builds fatty acids by sequential addition of 2 carbon units provided by malonyl-CoA.

ATP AND NADPH REQUIRED

Question 30

Describe liver lipogenesis (SEE SLIDE)

Answer 30

Source of reducing power - comes from NADPH
Need NADPH to regenerate glutathione to protect against oxy stressneed reducing power for pathways eg synthesis of fa
Comes from ppp
Glucose to pyruvate some goes into ppp
Pyruvate enters mitochondria, acted on by pyruvate dehydrogenase - acted on by acety co a
Combines with oaa from tca
Citrate is a 6 - exported from mitochondia - in cytoplasm - broken down into oaa and acetyl co a
Enzymes to break down pyruvate to acetyl coa in mitochondria
Fa enzymes in cytoplasm
Indirect shuttle needed using citrate to get acetyl co a out
Advantages - oaa is converted to malate - malate back to pyruvate - more reducing power made in NADPH
2 c unites add to f tail, converted to malonyl co a first, added to fa tail, lose co2, 3c becomes 2c
Fa can be combined with glycerol to make Tri acyl glycerol
Very low density lipoprotein particle
Key enzyme = acetyl co a carboxylate
Insulin increases this enzymes activity

Question 31

What is Acetyl-CoA carboxylase?

Answer 31

Acetyl-CoA carboxylase = Key regulatory enzyme Insulin (covalent de-phosphorylation), & citrate (allosteric) increase activity Glucagon / adrenaline (covalent phosphorylation) & AMP (allosteric) decrease activity

Question 32

Compare fatty acid synthesis and beta oxidation

Answer 32

See slide

Question 33

What is hormone sensitive lipase?

Answer 33

Mobilise fat stores - lipolysis
Hormone sensitive lipase - glucagon and adrenaline phosphorylase and so promote it eg in starvation or fight or flight
Insulin dephosphorylates and so inhibits this