Metabolic functions of the liver

Question 1

Where the liver located and what therefore does it protect?

Answer 1

Between the gut and the heart.

Therefore it “protects” major vessels from direct contact with dietary nutrients etc.

Question 2

Describe the venous drainage of the liver

What does this allow?

Answer 2

Empties directly into major vessel entering the heart.

Ensures the rapid circulation of its products.

Question 3

How is the liver involved with digestion?

Answer 3

Bile ducts empty directly into gut.

Can rapidly influence the digestive process

Question 4

What does the liver regulate which is found in the blood?

Answer 4

Contributes to lowering blood glucose levels

Question 5

Where does the liver transport glucose to remove glucose from the blood?

Answer 5

1. The liver transports glucose to the intestine
2. The live transports glucose to the brain, adipose tissue and muscle
3. Triglycerides are transported as VLDL to the adipose tissue

Question 6

What does the liver synthesise?

Answer 6

1. The liver is the major site for the synthesis of many serum proteins, such as albumin and the blood clotting factors.

Question 7

What does the liver degrade?

By what process?

Answer 7

2. The liver degrades excess amino acids, particularly during gluconeogenesis.
   • glucogenic amino acids -> sugars
   • ketogenic amino acids -> ketone bodies

Question 8

What does the liver to do AA and ammonia?

Answer 8

3. The liver is the major site for transamination and deamination of amino acids, and for detoxification of ammonia.

Question 9

Describe the interaction between the liver and muscle

Answer 9

On image

Question 10

How does the liver play a central role in the synthesis, transport and metabolism of lipids and fats?

Answer 10

On image

Question 11

Where is cholesterol synthesised?

What is it made from?

What is it transported as?

Answer 11

Synthesis

• 50% of cholesterol made in the body is made by the liver rest made by intestine, adrenal cortex and reproductive tissue
• Made from acetyl CoA and the key enzyme is HMG-CoA reductase
• Transported from the liver as VLDL

Question 12

How is cholesterol excreted?

Answer 12

Excretion

• body can not degrade cholesterol
• disposed of by the biliary system either as cholesterol or following conversion to bile acids/salts

Question 13

Describe cholesterol movement and metabolism

Answer 13

On image

Question 14

What 2 methods are used to metabolise ethanol?

Answer 14

There are two routes to the metabolism of ethanol:

• Oxidation through the activity of alcohol dehydrogenase = 90%
• Microsomal oxidation using cytochrome P450 = 10-20%

Question 15

How is ethanol first metabolised?

Answer 15

On image

Question 16

What is the second step in ethanol metabolism?

Answer 16

On image

Question 17

What four pathways are inhibited by the metabolism of ethanol?

Answer 17

• acetyl-CoA, NADH and ATP formed inhibit glucose metabolism by inhibiting PFK and pyruvate dehydrogenase
• NADH inhibits the TCA cycle and acetyl-CoA increases the inhibition further
• acetyl-CoA results in ketone body formation and the stimulation of fatty acid synthesis
• Fatty acids are esterified to TG for export as VLDL

on image

Question 18

What occurs in the Microsomal ethanol-oxidising system MESO?

What enzyme does it involve and what else does it require to synthesize?

Answer 18

• This is the second route of metabolism
• Involves the oxidation of ethanol by members of the cytochrome P450 family of enzymes.
• This system uses NADPH which is required for the synthesis of the antioxidant glutathione

Question 19

What are the side effects of the accumulation of Acetaldehyde?

Answer 19

• Is highly reactive and can accumulate with excessive ethanol intake
• Acetaldehyde is very reactive and can inhibit enzyme function.
• In the liver this can lead to a reduction in the secretion of both serum protein and VLDL
• Can also enhance free-radical production – leading to tissue damage such as inflammation and necrosis

Question 20

What are the 3 stages of alcoholic liver damage?

Answer 20

• Three stages of alcohol liver damage
• Stage 1: Fatty liver
• Stage 2: alcoholic hepatitis, groups of cells die resulting in inflammation
• Stage 3: Cirrhosis which includes fibrosis, scaring and cell death
• As the cirrhotic liver cannot function properly ammonia will accumulate resulting in neurotoxicity, coma and death
• Cirrhosis arises in 25% of alcoholics and 75% all cirrhosis is due to alcohol

Question 21

What are xenobiotics and give some examples

Answer 21

Are compounds with no nutritional value such as:
•	plant metabolites
•	synthetic compounds 
•	food additives 
•	agrochemicals
•	cosmetics
•	by-products of cooking etc
•	drugs

Question 22

How is the liver involved in xenobiotic metabolism?

Answer 22

• The aim to make xenobiotic harmless and more readily disposed of by the kidney in urine or the gut in faeces
• Also involved are the intestines and the lungs

Question 23

What are the 3 stages of xenobiotics metabolism

Answer 23

Three common phases

1. Phase I oxidation
2. Phase II conjugation
3. Phase III elimination

Question 24

What happens in phase 1 of xenobiotics metabolism?

What other processes occur?

Does solubility increase?

What enzymes?

Answer 24

• Oxidation is the most common modification but also get hydroxylation and reduction
• Modification increases solubility
• Introduces functional groups which enables participation in further reactions
• These reactions are promoted by a family of enzymes called cytochrome P450

Question 25

What is cytochrome P450 involved in?

Where are they found?

What are they induced by?

Answer 25

• Found mainly in liver and cells of the intestine
• Make up a family of about 50 different enzymes, they are haem proteins and are related to the mitochondrial enzymes
• They are found in the endoplasmic reticulum
• An example of their action would be the hydroxylation of ibuprofen
• P450 enzymes are inducible both by their own substrates (5-10 fold) but also related substrates (2-4 fold)
• This is clinically important

Question 26

Describe the second stage in xenobiotic metabolism

Answer 26

Conjugation (Phase II)

Xenobiotic are modified by addition of groups such as
• Glutathione
• Glucuronic acid
• Sulphate

Modification with these groups increase solubility and targets them for excretion

Compounds are often sequentially modified

Question 27

Why is the metabolism of xenobiotics important?

Answer 27

• Xenobiotics metabolism is part of the bodies natural defences
• However the body does not distinguish between harmful compounds and beneficial compounds such as therapeutic drugs
• Metabolism of drugs by the liver can play a significant role in their effectiveness
• A drug taken orally will pass through liver first
• Modifications made by the liver can significantly reduce the effectiveness of a drug
• Although this could also be advantageous

Question 28

What do statins inhibit, what are they degraded by?

Answer 28

• Statins inhibit HMG-CoA reductase

* Are degraded by CYP3A4

Question 29

What is Aflatoxin B1?

What is it produced by?

What is it activated by and what does this lead to?

Answer 29

• Produced by the fungus Aspergillus flavus

* Aflatoxin activated by P450 isoenzymes leading to epoxide formation and hepatocarcinogenesis

Question 30

Describe the metabolism of paracetamol?

Answer 30

On image

Question 31

What happens to the modified compounds?

Small molecules?

What are the 3 fates of the molecules?

What is T1/2?

Answer 31

• Small water soluble molecules <60,000kDa can be removed by the kidney
• Actively transported in to bile and then into the intestines
• The fate of these molecules are 3 fold
Digestion
Excretion
Re-absorption via the enterohepatic circulation
t½ is the time required for 50% of a substance to be lost

Question 32

Describe the central role of the liver in the regulation of metabolism

Answer 32

•	Regulation of carbohydrate metabolism 
o	To maintain blood glucose
•	Regulation of fat metabolism 
o	synthesis
o	β-oxidation
•	Regulation of protein metabolism 
o	Plasma protein synthesis
o	Detoxification of ammonia - Urea formation
•	Cholesterol synthesis and excretion
•	Synthesis of specialized molecules
o	bile acids
o	haemin 
•	Central role in the metabolism of xenobiotics