18. Metabolic profiles and interactions between major organs

Question 1

What are the 7 important metabolic pathways for organ specialisation?

Answer 1

1. Glycolysis
2. Gluconeogenesis
3. Glycogenesis / glycogenolysis
4. TCA
5. Oxidative phosphorylation
6. Fatty acid synthesis / degradation
   7. Amino acid synthesis / degradation

Question 2

What are the metabolic fuels that can be obtained from the diet / stored?

Answer 2

1. Glucose / Glycogen
2. Protein / amino acid
3. Fatty acid / TAG
4. Ketone bodies

Question 3

What are the 6 important organs / tissues in metabolism?

Answer 3

1. Brain
2. Liver
3. Kidney
4. Heart
5. Adipose
6. Muscle

Question 4

The flux of nutrients between different organs depend on…?

Answer 4

Nutritional state of the body

Question 5

Organ : muscle

In the muscle, is glycogen or fatty acids more preferred for ATP production and why? [2]

Answer 5

Glycogen is preferred.
1. There are localised glycogen stores within skeletal muscles, making it more efficient to utilise them for energy production, whereas FA would need to diffuse from bloodstream into muscle before it can be utilised.
2. Glycogen is broken down into glucose, and glucose can be metabolised anaerobically

Point 2 : anaerobic resp = not oxygen dependent ;; disadvanatges of anaerobic resp in lect 20)

Question 6

Organ : muscle

Rate of ___ metabolism is the primary regulator of the balance between glucose and fatty acid oxidation in muscle.

Answer 6

Glucose
Rate of glucose metabolism affects [DHAP], thus [G3P] for esterification of FA into TAG. It also affects release of insulin / glucagon, which affects rate of both glucose metabolism and FA synthesis / oxidation

DHAP produced through glycolysis

Question 7

Organ : muscle

During exercise, how does the ATP source change? [4]

Answer 7

1. Immediate ATP stores in muscle
2. ATP from phosphocreatine (phosphocreatine + ADP ⇌ creatine + ATP)
3. Glycolysis
4. Oxidative phosphorylation

Question 8

Organ : muscle

Why can’t anaerobic respiration (glycolysis) be sustained as an ATP source throughout long periods of exercise? [2]

Answer 8

1. Glycolysis will produce NADH, which needs to get oxidised to regenerate NAD⁺
2. Glycogen stores are limited, thus it will be depleted over time and cannot continually be used to support energy needs.

Question 9

Inter-Organ Cycles

The cori cycle occurs during ____ respiration of muscle cells. What occurs during the cori cycle? (What are the 2 metabolic fates of glucose that is transported from liver into muscle)?

Answer 9

Anaerobic.

What happens in cori cycle
- Lactate from anaerobic resp is transported from the muscle to liver.
- Lactate converted into glucose in liver through gluconeogenesis
- Glucose from liver enters muscle cells again, for :
1. Release of energy via glycolysis
2. Storage as glycogen

Question 10

Inter-Organ Cycles

When does the glucose-alanine cycle occur? What occurs in the glucose-alanine cycle?

Answer 10

Occurs during starvation, where muscle proteins are broken down into AA for energy (then ammonia grp in AA needs to be removed so C skeleton can be used to generate glucose via gluconeogenesis in liver;; then glucose re-supplied to muscle for energy metabolism)
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What occurs during the alanine cycle
1) Transamination, where
- AA (from protein breakdown) → alpha keto acid
- Pyruvate (frm glycolysis) → alanine

2) Alanine from muscle is transported into liver, deaminated into pyruvate and converted into glucose via gluconeogenesis

3) Glucose transported from liver into muscle, which :
- undergoes glycolysis for ATP production
- stored as glycogen

Question 11

Inter-Organ Cycles

In the glucose-alanine cycle involving breakdown of muscle protein, alanine is converted into glucose in the liver. The glucose formed in the liver is only transported back and thus can only be used by muscle. True or False?

Answer 11

False, the glucose can be transported to other tissues too. Thus. muscle supplies glucose to other tissues via muscle protein breakdown.

Question 14

Organ : heart

The cardiac muscle is in continuous use to pump blood from the heart to the body. The cardiac muscle is rich in _____ (organelle)

Answer 14

Mitochondria (requires alot of ATP to pump blood, and a lot of ATP is generated in mitochondria via oxidative phosphorylation)

Question 15

Organ : heart

In the resting state, the heart prefers to use ____ as the fuel source. (Why?) During heavy work, ____ is used as the fuel source.

Answer 15

Fatty acids (if use glucose, and if anaerobic resp occurs -> generate lactate and fatigue, but cardiac muscle cant be fatigued!!)

glucose (from limited glycogen stores)

Question 16

Organ : Adipose

How is the storage and release of FA in adipose tissue controlled? [3]

Answer 16

1) Hormonal control : insulin and glycogen

2) Covalent modification (phosphorylation) based on energy state of the cell
- Low energy state : AMPK (AMP-activated protein kinase) phosphorylates Acetyl-CoA Carboxylase (ACC), decreasing ACC activity, inhibiting FA synthesis + promoting beta oxidation in liver
- AMPK also decreases hormone-sensitive lipase activity to prevent excessive mobilisation of fat stores and promoting oxidation of existing and circulating glucose / fatty acid

3) Rate of glucose uptake (also controlled by insulin) : the higher the glucose uptake, more precursors to make glycerol backbone, thus promoting synthesis and storage of FA

Question 17

The rate of fatty acid mobilisation depends on ??

Hint : related to another fuel

Answer 17

The rate of glucose uptake.
- Higher glucose uptake = more glycolysis, more DHAP = more G3P for glycerol backbone = more TAG storage and less FA mobilisation
- Lower glucose uptake = less glycolysis = less DHAP, G3P to make glycerol backbone = more mobilisation of FA

Question 18

Organ : liver

Other than energy metabolism, what are 3 other main functions of the liver?

Answer 18

1. Maintaining blood glucose levels (homeostasis) via gluconeogenesis
2. Fructose metabolism
   3. Conversion of ammonia into a less toxic form, urea, for excretion (detoxification)

Question 19

Organ : liver

What is the K_m for hexokinase and glucokinase? Explain.

Answer 19

Hexokinase (expressed in peripheral cells) : 50µM
- Low K_m, high affinity to glucose.
- Even at low [glucose], hexokinase activity is high and reaches V_max very fast, allowing cells to quickly uptake glucose for energy metabolism / storage
- Esp impt for organs such as the brain which only utilised glucose as a sole energy source

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Glucokinase (isoform expressed in liver / pancreas): 5mM
- higher K_m, lower affinity to glucose.
- At low [glucose], glucokinase activity is very low, ensuring that liver does not compete with other organ for glucose.
- However, when [glucose] increases at higher conc, and when hexokinase in other cells are already operating at maximal capacity, it indicates there is too much glucose. Thus, heokinase acitivity increases rapidly, buffering blood glucose. High K_M ensures that rate of glucose uptake varies directly with glucose concentration, ensuring bffering effect and maintaining homeostasis.

Question 20

Organ : liver

How is hexokinase and glucokinase regulated?

Answer 20

Hexokinase: product inhibition by G6P

Glucokinase
- no inhibition by G6P (so even when blood glucose is high, can continue to uptake)
- Allosteric regulation (competitive inhibitor = F6P ;; activator = F1P)

F6P = intermediate in glycolysis, so if F6P (product) is high, it means glycolysis is not proceeding fast enough as cell in high energy state -> inhibit Glucokinase

F1P = only obtained through fructose intake from diet. Food intake activates metabolism to breakdown food for energy

Question 21

Organ : liver

Glucokinase in liver phosphorylates glucose into G6P. What are the 4 fates of G6P in the liver?

Answer 21

1) Low [glucose] : G6P converted into glucose
2) Low demand for glucose : conversion into glycogen
3) Glycolysis : converted in acetyl-CoA via glycolysis & pyruvate dehydrogenase for other purposes (e.g. FA synthesis when glycogen storage capacity is reached)
4) Produce NADPH through the PPP

Question 22

Organ : liver

What is fructose converted into when we ingest it? What enzyme catalyses this conversion?

Answer 22

Fructose → F1P ;; catalysed by fructokinase

Question 23

Organ : liver

Why is fructose consumption associated with obesity?

F1P

Answer 23

Metabolism of F1P produces DHAP (→ G3P), which can be used the synthesise backbone of TAG and glycerophospholipids.

More TAG storage = fat = obesity

Question 24

Organ : liver

When there is a high demand for fuels (low energy state due to physical activity, stress, starvation), how are the fuels utilised?

Fuels : FA, acetyl-CoA, oxaloacetate, ketone bodies

Answer 24

1. FA undergoes degradation / β-oxidation to yield acetyl-CoA
2. Acetyl CoA + oxaloacetate undergoes TCA & oxi phos to yield ATP
3. Oxaloacetate converted into pyruvate, and into glucose through gluconeogenesis
4. Excess acetyl CoA and oxaloacetate runs out → ketone bodies generated

**Note : oxaloacetate in muscle cells will NOT run out as muscle cells do not undergo TCA!! **

Question 25

# **Organ : liver** When there is a lower demand for fuels (high energy state e.g. fed state), how are the FA utilised (by adipocytes and liver)?

Answer 25

1. Adipocytes : FA are incoporated into TAG 2. Liver : excess FA packaged into VLDL, VLDL secreted into bloodstream for FA uptake by adipose tissue

Question 26

# **Organ : liver** During a fast, muscle protein degrades into the amino acids, ___ and ___. Glucose is then produced from the carbon backbone of these AA.

Answer 26

Alanine, **glutamine**

Question 27

# **Organ : liver** What are the main functions of kidney?[2]

Answer 27

1. Dispose of metabolic waste : excess ketone bodies, urea & NH₄⁺ 2. Excretes excess H⁺, thus managing pH and lowering acidity in cells - NH₃ + H⁺ → NH₄⁺

Question 28

# **Organ : liver** What metabolic process can the kidney do? (hint : under starvation)

Answer 28

Gluconeogensis - supplies up to 50% glucose from AA catabolism products

Question 29

# **Organ : brain** Why does the brain require massive amount of ATP?

Answer 29

Needed for nerve membrane potential to send nerve impulses. - Pump sodium out of cell and pump potassium into cell so that nerve impulses can be sent to control body

Question 30

# **Organ : brain** What are the fuels sources for the brain?

Answer 30

1. Glucose (main) 2. Ketone bodies (starvation, when oxaloacetate in liver runs out and cannot produce enough glucose)

Question 31

# **Organ : brain** Why can't brain utilise FA for energy?

Answer 31

FA are too huge and cannot cross the blood-brain barrier

Question 32

As time passes and food is not intaken, what is the order of fuels that are utilised by the body?

Answer 32

1. Glucose 2. Amino acids 3. Fat 4. Ketone bodies