Metabolic Liver Functions

Question 1

How does the liver play a role in carbohydrate and fat metabolism?

Answer 1

Regulation of carbohydrate metabolism: To maintain blood glucose

Regulation of fat metabolism: synthesis, β-oxidation
Produces lipoproteins so is important in fat transport around the body

Question 2

What are the 2 routes to ethanol metabolism?

Answer 2

There are 2 routes to the metabolism of ethanol:
Oxidation through the activity of alcohol dehydrogenase (90%)
Microsomal oxidation using cytochrome P450 (10-20%)

Question 3

What is the first step in ethanol metabolism?

Answer 3

Question 4

what is the second step in ethanol metabolism?

Answer 4

Question 5

Describe the Microsomal ethanol-oxidising system (MESO)

Answer 5

MESO is the second route of ethanol metabolism
Involves ethanol oxidation by the cytochrome P450 enzymes.
The pathway generates acetaldehyde and needs NADPH

This system consumes NADPH needed for the synthesis of the antioxidant glutathione. This results in more accumulation of ROS and therefore increased oxidative stress which damages proteins

Question 6

What is acetaldehyde?

Answer 6

Highly reactive and can accumulate with excessive ethanol intake
Can inhibit enzyme function.
In the liver this can lead to a reduced secretion of serum protein and VLDL. Inhibition of VLDL secretion will result in the accumulation of fats within the liver – fatty liver
Can also enhance free-radical production – leading to tissue damage such as inflammation and necrosis

Question 7

What are the 3 stages of alcohol liver damage?

Answer 7

Stage 1: Fatty liver (caused by the metabolism of ethanol through the microsomal route, produces acetaldehyde)

Stage 2: alcoholic hepatitis, groups of cells die resulting in inflammation

Stage 3: Cirrhosis which includes fibrosis, scaring and cell death

Question 8

Explain stage 3 of alcohol liver damage

Answer 8

As the cirrhotic liver cannot function properly, ammonia will accumulate resulting in neurotoxicity, coma and death
Cirrhosis arises in 25% of alcoholics

Question 9

Oxidation of alcohol is prioritised, what does this mean?

Answer 9

Oxidation of alcohol takes precedence over other nutrients
Metabolism of alcohol is not regulated by negative feedback
As a result, large quantities of acetyl-CoA, NADH and ATP are formed

Question 10

what is the consequence of high NADH produced from ethanol metabolism?

Answer 10

High NADH inhibits gluconeogenesis and stimulates the conversion of pyruvate to lactate leading to hypoglycaemia and lactic acidosis

High NADH inhibits fatty acid/beta oxidation and stimulates fatty acid synthesis and TG formation

NADH inhibits the TCA cycle and acetyl-CoA further increases inhibition

Question 11

what is the consequence of high acetyl-CoA produced from ethanol metabolism?

Answer 11

Acetyl-CoA, NADH and ATP formed inhibit glucose metabolism by inhibiting PFK and pyruvate dehydrogenase

NADH inhibits the TCA cycle and acetyl-CoA further increases inhibition
Acetyl-CoA results in ketone body formation and the stimulation of fatty acid synthesis

Question 12

What are xenobiotics?

Answer 12

They are compounds with no nutritional value such as:
plant metabolites
synthetic compounds
food additives
cosmetics
drugs
The liver’s aim is to make xenobiotic harmless and more readily disposed of by the kidney in urine or the gut in faeces in 3 phases

Question 13

Describe phase I of xenobiotic liver metabolism

Answer 13

Oxidation:
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 cytochrome P450

Question 14

What is cytochrome p50?

Answer 14

Found mainly in liver and cells of the intestine
Make ~50 different enzymes, they are haem proteins and are related to the mitochondrial enzymes
Found in the endoplasmic reticulum
P450 enzymes are inducible both by their own substrates (5-10 fold) but also related substrates (2-4 fold), which is clinically important

Question 15

Describe phase II of xenobiotic liver metabolism

Answer 15

Phase II: Conjugation
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 eg addition of glutathione followed by sulphate
Phase 3 is elimination

Question 16

Why is liver and drug metabolism important?

Answer 16

A drug taken orally will pass through liver first

Modifications made by the liver can significantly reduce the effectiveness of a drug but could also be advantageous

Question 17

Why shouldn’t you have paracetamol w alcohol?

Answer 17

~10% of the hepatic paracetamol metabolism produces NAPQI. NAPQI is cleared with glutathione (GSH). If its not cleared then NAPQI-protein adducts form, resulting in oxidative stress, mitochondrial dysfunction, and necrotic cell death.

This problem arises w insufficient GSH levels. NADPH is required for GSH synthesis.
So ethanol metabolism reduces NADPH and therefore GSH required to clear NAPQI. NADQI builds up causing liver damage.