L3: Energy Storage Glycogen and Fat

Question 1

What is the normal plasma level of glucose?

Answer 1

5mM elevates after meal

Question 2

What tissues have an absolute requirement for glucose?

Answer 2

RBC (few mitochondrial ↑SA for heamoglobin and O2)
Neutrophils (mitochondrial burst> metabolism)
Lens of the eye (poor blood supply- no OP)
Innermost cells of the kidney medulla

Question 3

What is special about the brain and glucose?

Answer 3

Can use ketone bodies–> time to adapt + only 50% energy requirement
GLUT1 transport Km=0.6mM, plasma < doesn’t use glucose

Question 4

What happens to excess glucose?

Answer 4

Stored as glycogen

Question 5

Where does glycogen get stored?

Answer 5

Stored as granules in:
Skeletal muscle–> inter- between cells, intra- within cells
Liver–> hepatocytes

Question 6

What is the structure of glycogen?

Answer 6

Polymer
Branched every 8-10 residues–> originates from dimer glycogenin
alpha 1-4 glycosidic bonds in chain
alpha 1-6 glycosidic bond to branches

Question 7

Why is it stored as a branched molecule?

Answer 7

Branches–> more sites for synthesis or degradation
Easier to release glucose
Reduced osmotic effect –> less water

Question 8

Name the process of glycogen synthesis?

Answer 8

Glycogenesis

Question 9

Name the main enzymes involved in glycogenesis?

Answer 9

1. Hexokinase (glucokinase in liver)
2. Phosphoglucomutase
3. G1P uridyltransferase
4. Glycogen synthase or branching enzyme

Question 10

What is each step of glycogenesis?

Answer 10

Step 1. Glucose + ATP –> Glucose-6-phosphate and ADP (requires hexokinase)
Step 2. Glucose-6-phosphate < –>Glucose-1-phosphate (phosphoglucomutase)
Step 3. Glucose-1-phosphate + UTP + H20 –> UDP-glucose + PPi (G1P Uridyltransferase) UTP=ATP
Step 4. Glycogen(n) + UDP-glucose –> Glycogen (n+1) + UDP (glycogen synthase alpha1-4 glycosidic bond or branching enzyme alpha1-6 glycosidic bond)

Question 11

How many ATPs are required for glycogenesis?

Answer 11

2 ATP (1ATP and 1UTP)

Question 12

What is glycogen breakdown called?

Answer 12

Glycogenolysis

Question 13

What are the enzymes involved in glycogenolysis?

Answer 13

Glycogen phosphorylase or de-branching enzyme

Phosphoglutamutase

Question 14

What is the common process of glycogenolysis in muscle and liver?

Answer 14

Glycogen(n) + Pi–> Glucose-1-phosphate + Glycogen(n-1) (glycogen phosphorylase or de-branching enzyme)
Glucose-1-phosphate –> glucose-6-phosphate (phosphoglucomutase)

Question 15

What happens to glucose-6-phosphate in muscle? What happens to glucose-6-phosphate in liver?

Answer 15

Muslce –> lacks glucose-6-phosphatase–> GP6 enter glycolysis
Liver–> converted to glucose by glucose-6-phosphatase–> released into blood –> buffer of blood glucose

Question 16

How is glycogen metabolism regulated in liver?

Answer 16

Hormonal control
Rate limiting enzymes= glycogen synthase and glycogen phosphorylase
Insulin and glucagon/adrenaline

Question 17

How is glycogen metabolism regulated in the muscles? What is another allosteric activator?

Answer 17

Hormonal control
Rate limiting enzymes- glycogen synthase and glycogen phosphorylase
Insulin and adrenline –> no glucagon receptor
AMP allosteric activator of Glycogen phosphorylase

Question 18

How does insulin and glucagon/adrenaline affect the rate limiting enzymes?

Answer 18

↑ Insulin and ↓ glucagon/adrenaline = ↑ glycogen synthase

↓ Insulin and ↑ glucagon/adrenaline = ↓glycogen phosphorylase

Question 19

What are glycogen storage diseases?

Answer 19

Inherited
Dysfunctional or deficiency of enzymes of metabolism
12 distinct types
Severity–> varies–> depends on enzyme/tissue affected

Question 20

What are the results of glycogen storage disease?

Answer 20

Liver +/or muscle affected
Excess –> tissue damage
Diminished –> hypoglycemia + poor exercise tolerance

Question 21

Give two examples of disease caused by excess storage and name the dysfunctional enzyme involved?

Answer 21

Von Gierke’s disease –> glucose-6-phosphase deficiency

McArdles disease –> glycogen phosphorylase deficiency (muscle)

Question 22

What is the production of new glucose called?

Answer 22

Gluconeogenesis

Question 23

Why do we need gluconeogenesis?

Answer 23

> 8hrs fasting –> ↓ glycogen stores –> alternative source

Question 24

Where does gluconeogenesis occur?

Answer 24

Majority –> liver

Minor –> kidney cortext

Question 25

What are the precursors for gluconeogenesis?

Answer 25

Lactate--> anaerobic glycolysis (muscle and RBC)- Cori cycle Glycerol --> released from adipose tissue from TAG Amino acids --> mainly alanine

Question 26

What is the Cori cycle?

Answer 26

Muscle --> glucose converted to 2x lactate --> blood--> liver (gluconeogenesis) --> glucose --> muscle cyclic process

Question 27

Why can acetyl CoA not be used as a substrate for glucose synthesis?

Answer 27

``` Acetyl CoA (2C) --> not converted to pyruvate--> pyruvate dehydrogenase reaction irreversible No net synthesis of glucose from Acetyl CoA as 2 xCO2 lost ```

Question 28

What are the key enzymes involved in gluconeogenesis?

Answer 28

1. Phosphoenolpyruvate carboxykinase (PEPCK): pyruvate--> oxaloacetate --> phosphoenolpyruvate (PEPCK converts occeloacetate) 2. Fructose 1,6- bisphosphatase: fructose 1,6-bisphophate --> fructose 6-phosphate 3. Glucose 6-phosphatase: glucose 6-phosphate --> glucose *not simply the reversal of glycolysis as irreversible steps in glycolysis*

Question 29

How is gluconeogenesis regulated?

Answer 29

Hormonal control; Insulin and glucagon/cortisol | key enzymes: PEPCK (phosphoryenolpyruvate carboxykinase) + Fructose 1,6-bisphosphate

Question 30

What affect does insulin and glucagon/cortisol have on gluconeogenesis?

Answer 30

Insulin --> inhibits--> ↓ PEPCK + fructose 1,6-bisphosphate | Glucagon/cortisol--> stimulates--> ↑ PEPCK + fructose 1,6-bisphosphate

Question 31

How long after eating does glycogenolysis and gluconeogenesis occur?

Answer 31

Glucose- 2 hours Glycogenolysis >2 hours <8 hours Gluconeogenesis >8 hours

Question 32

How is excess energy stored?

Answer 32

Converted to triacylglycerol for storage

Question 33

Where are triacylglycerides stored and how?

Answer 33

Adipose tissue Hydrophobic --> stored anhydrous form Highly efficient energy store Energy content x2 of carbs/protein

Question 34

When are TAG utilised?

Answer 34

Prolonged exercise, stress, starvation and during pregnancy

Question 35

What controls the storage and utilisation of TAG?

Answer 35

Hormones

Question 36

What are the adipocytes? What are some of the characterisitcs?

Answer 36

``` Fat storage cells Large lipid droplet Organelle at edge 0.1mm diameter 30 billion--> 15kg ```

Question 37

How do adipocytes increase in number?

Answer 37

Expand --> Fourfold -->Divide

Question 38

How do fats get from your food into the adipocytes?

Answer 38

SI--> pancreatic lipase --> fatty acids and glycerol Intestinal epithelial cell--> TAG reformed -->chylomicrons Lymphatic system --> thoracic duct--> left subclavian vein --> blood Stroage --> Adipose tissue

Question 39

How do we mobilise TAG for use?

Answer 39

Hormone sensitive lipase --> mobilise TAG Regulated by insulin and glucagon/adrenaline Broken down into FA and glycerol Transported FA-albumin to tissue Tissue --> fatty acid oxidation Glycerol --> gluconeogenesis

Question 40

Which cells cannot use FA for energy?

Answer 40

Cells without mitochondria | Brain --> cannot pass BBB

Question 41

Where does fatty acid synthesis occur?

Answer 41

Liver

Question 42

What is lipogenesis?

Answer 42

Synthesis of fatty acids from acteyl CoA

Question 43

What is the process of lipogeneis?

Answer 43

Pyruvate (glycolysis of glucose)--> Acetyl CoA by pyruvate dehydrogenase (in mitochondria) Combines with oxaloacetate --> citrate (in mitochondria) In cytoplasm cleaved release Acetyl CoA and oxaloacetate Acetyl CoA --> malonyl CoA by acetyl CoA carboxylase Oxaloacetate --> malate --> pyruvate + NADPH (malic enzyme) Malonyl CoA and NADPH --> fatty acid synthesis complex--> FA

Question 44

Why does pyruvate get converted to Acetyl Co-A to citrate and then broken back down again?

Answer 44

Pyruvate conversion to Acetyl CoA can only occur in the mitochondria No transporters for Acetyl CoA--> converted to Citrate--> into cytoplasm--> broken down

Question 45

What are the key regulators of lipogenesis?

Answer 45

Acetyl CoA carboxylase (produces malonyl CoA from Acetyl CoA which is need for the fatty acid synthase complex) Hormonal control Insulin (dephosphorylates) and citrate (allosteric) --> ↑activity Glucagon/ adrenaline (phosphorylation) and AMP (allosteric) --> ↓activity

Question 46

How does the fatty acid synthase complex work?

Answer 46

Addition of 2C provided by malonyl-CoA (produce CO2) | NADPH is required

Question 47

What happens to fatty acids once they have been synthesised?

Answer 47

Esterification to TAG with glycerol 3-phosphate | Transported by VLDL to tissue

Question 48

Compare and contrast fatty acid synthesis and oxidation (beta oxidation)?

Answer 48

Synthesis followed by oxidation - -> add 2C from malonyl CoA / removes 2C as acetyl CoA - -> Consumes acetyl CoA/ produces acetyl CoA - -> cytoplasm / mitochondria - -> multienzyme complex / separate enzymes - -> reductive (NADPH required) / oxidative (NADH and FADH2 produced) - -> Require ATP / Small amount ATP required - -> intermediate linked to FA synthase by carrier protein / intermediates linked to CoA - -> Regulated directly --> acetyl CoA carboxylase / Indirectly via avaliability of FA - -> Glucagon and adrenaline inhibit/ Stimulate - -> insulin stimulates / Inhibits

Question 49

What is the benefit of synthesis and oxidation occurring by different pathways?

Answer 49

Greater flexibility --> substrates and intermediates different Better control --> independently or coordinately Themodynamically irreversible steps bypassed