GIS16 Functions Of The Liver

Question 1

Carbohydrate metabolism in liver

Answer 1

1. Fructokinase [liver]
   Fructose —> F-1-P —> DAP —> feed into glycolysis —> generate ATP anaerobically / aerobically (NADH)
2. Galactokinase [liver]
   Galactose —> Gal-1-P —> G-1-P —> feed into glycolysis —> generate ATP anaerobically / aerobically (NADH)

Storage: polymer of Glucose rather than fructose / galactose —> Glycogen

Question 2

Amino acid metabolism

Answer 2

Fed state: Amino acids —>

1. Proteins (e.g. albumins, cell proteins, muscle protein etc.)
2. Nitrogen-containing compounds
   - glutathione
   - Creatine —> Creatine phosphate
   - monoamine neurotransmitter e.g. dopamine, noradrenaline, adrenaline, serotonin
3. Glucose (Carbon skeleton of a.a.) —> glycogen / blood
4. CO2

Fasting:
Muscle protein —> amino acids —> TCA cycle —>
1. **Glutamine —> **Gut / Kidney —> Alanine to liver / Deamination in kidney —> Serine / Alanine —> glucose / ketones bodes / urea
2. ***Alanine —> Liver —> glucose / ketones bodes / urea
3. Other a.a. —> Liver —> glucose / ketones bodes / urea

• **Functions of liver:
  1. Produce Urea —> urine
  2. Produce Glucose
  3. Produce Ketone bodies

Ketone bodies: energy for muscle / kidney
Glucose: energy for brain / RBC

Question 3

Fate of amino group

Answer 3

**Liver cells mitochondria:
Transamination coupled to Oxidative Deamination
—> release NH2 (amino group) as **ammonia
—> **Hyperammonemia: failure of liver to dispose excess ammonia from catabolism of N-containing compound
—> Ammonia into body cells + α-ketoglutarate —> Glutamate
—> α-ketoglutarate **depleted
—> TCA cycle stopped (dangerous for tissue dependent on oxidative phosphorylation)

1. Transamination:
   - **Alanine / Other a.a. —(減去NH2)—> **Pyruvate —> Glucose
   —> **α-ketoglutarate (獲得NH2) —> **Glutamate
2. Subsequent Transamination:
   - Glutamate —(減去NH2)—> α-ketoglutarate
   —> **Oxaloacetate —(獲得NH2)—> **Aspartate
   —> **Aspartate
   —> **Urea cycle
   —> 第一個 amino group in urea

(Glutamate-oxaloacetate transaminase (GOT) / Aspartate aminotransferase (AAT))

2. Oxidative Deamination:
   - **Glutamate dehydrogenase (GDH)
   —> Glutamate (減翻NH2) —> α-ketoglutarate (同一時間NAD —> NADH)
   —> NH4+ released as ammonia
   —> Urea cycle
   —> **Carbamoyl phosphate
   —> 第二個 amino group in urea

記住:

• Glutamate配α-ketoglutarate
• Aspartate配Oxaloacetate

Question 4

Sources of NH4

Answer 4

1. Glutamine —> Glutamate
   * **2. Glutamate —> α-ketoglutarate (Oxidative deamination)
2. Asparagine —> Aspartate
3. Aspartate —> Fumarate (Purine nucleotide cycle)
4. Urea
5. Serine —> Pyruvate
6. Threonine —> α-ketobutyrate
7. Histidine —> Urocanate

Question 5

***Urea cycle

Answer 5

Urea: have 2 amino groups
First one: from **Carbamoyl phosphate
Second one: from **Aspartate

Mitochondrion:
1. CO2 + NH4 —(**Carbamoyl phosphate synthetase 1, use ATP)—> **Carbamoyl phosphate (第一個NH2)

2. captured by Ornithine (an amino acid):
   * **Ornithine —(Ornithine transcarbamoylase)—> Citrulline

Outside mitochondrion:
3. **Citrulline + **Aspartate (第二個NH2) —(Argininosuccinate synthetase, use ATP)—> Argininosuccinate

4. Argininosuccinate —(Argininosuccinase)—> ***Arginine + Fumarate
5. **Arginine + H2O —(Arginase: hydrolysis)—> **Urea + Ornithine
6. Ornithine continue into cycle capturing NH2 group from Carbamoyl phosphate

Question 6

Feed-forward regulation of Carbamoyl phosphate formation

Answer 6

Arginine (from food) promote:
- Glutamate + Acetyl CoA —> N-Acetyl-glutamate

N-Acetyl-glutamate promote:
- Conversion of CO2 + NH4 —> Carbamoyl phosphate

Overall: Eat more protein rich food —> contain more Arginine —> force more ***Carbamoyl phosphate formation —> ↑ Urea cycle —> ↑ NH4 excretion

Question 7

Fatty acid metabolism

Answer 7

1. ↑ Lipolysis (fasting, high fat/low carb diet, diabetes)
2. ↑ Glucagon / insulin ratio
3. ↑ Ketogenesis (in liver mitochondria: synthesis of ***Acetoacetate)
   - 2 x Acetyl CoA
   —> Acetoacetyl CoA —> (+ 1 Acetyl CoA by HMG CoA synthetase)
   —> HMG CoA —> (- 1 Acetyl CoA by HMG CoA lysase)
   —> Acetoacetate (Ketone bodies)
   —(spontaneous)—> Acetone

Other ketone bodies:

• D-β-hydroxybutyrate
• Acetone —> (reaching lung) —> acetone breath (in Ketosis: too many ketone bodies formed)

Question 8

Use / Oxidation of ketone bodies

Answer 8

Liver synthesise Acetoacetate
—> not yet converted to Acetoacetyl CoA
—> since Acetoacetate CoA transferase / ***Thiotransferase activity is low in liver mitochondria

Instead
—> transport to Muscle, Kidney, Brain mitochondria (where ***Thiotransferase activity is higher)
—> Acetoacetyl CoA (by Thiotransferase, CoA group from Succinyl CoA)
—> Acetyl-CoA
—> enters TCA cycle to generate energy

Question 9

Haem degradation

Answer 9

Haemoglobin
—> ***Heme (+ Globin) (Heme oxygenase)
—> ***Biliverdin
—> ***Bilirubin (+ Fe + CO) (in reticuloendothelial system of spleen)
—> Bilirubin-albumin

Bilirubin (放翻走albumin)
—> + UDP-Glucuronate (by UDP-glucuronosyl transferase in hepatocytes ER)
—> **Bilirubin diglucuronide (more water soluble)
—> Bile
—> **Urobilinogen in urine / ***Stercobilin in faeces