Metabolic functions of liver

Question 1

The liver is …..

Answer 1

first major organ in line from gut therefore can handle large amounts of newly absorbed nutrients

Question 2

Where is liver located?

Answer 2

Between gut and heart therefore it protects major vessels from direct contact with dietary nutrients etc

Question 3

What does liver empty directly into?

Answer 3

it empties directly major vessels entering the heart so ensures rapid circulation of its products

Question 4

What are some roles of the liver?

Answer 4

• plays central role in regulating [glucose]
• mostly its role in times where there is excess of glucose, it can act as organ that will store excess glucose in form that is readily accessible + for long time storage for FAs
• important in generating glucose from non-carbohydrate sources so it’s heavily involved in gluconeogenesis
• liver contributes to lowering blood glucose levels

Question 5

What is importance of liver for protein + amino acid metabolism?

Answer 5

1. Liver is major site for synthesis of many serum proteins such as albumin + blood clotting factors
2. Liver degrades excess amino acids particularly during gluconeogenesis
3. Liver= major site for transamination + deamination of AAs + for detoxification of ammonia

Question 6

How does liver interact with muscle?

Answer 6

In actively contracting muscle. it will produce by-products -> one which is lactate under anaerobic conditions + other is from breakdown of proteins that produces alanine -> liver deals with these 2 products by synthesising glucose from these products

Question 7

Where is cholesterol made in the body?

Answer 7

50% of cholesterol made in body is made by liver rest made by intestine, adrenal cortex + reproductive tissue

Question 8

What is cholesterol made from? what is key enzyme involved in its formation?

Answer 8

made from acetyl CoA

key enzyme is HMG-CoA reductase

Question 9

What is cholesterol transported as from the liver?

Answer 9

transported from the liver as VLDL

Question 10

How is cholesterol excreted?

Answer 10

body doesnt degrade cholesterol

disposed of by biliary system either as cholesterol or following conversion to bile acids/salts

Question 11

What are 2 routes to metabolism of ethanol?

Answer 11

oxidation through activity of alcohol dehydrogenase (90%)

Microsomal oxidation using cytochrome P450 (10-20%)

Question 12

Metabolism of ethanol occurs by 2 reactions. What are these reactions?

Answer 12

1. Ethanol –> acetaldehyde
   involves enzyme alcohol dehydrogenase (cytosolic enzyme)
   also generates NADH
2. Acetaldehyde –> acetate
   - involves enzyme aldehyde dehydrogenase (mitochondrial enzyme)
   - also generates NADH

Question 13

Metabolism of ethanol is not regulated by….

Answer 13

negative feedback so enzymes involved are not product inhibited -> as result, large quantities of acetyl-CoA, NADH + ATP are formed

Question 14

What are pathways inhibited by metabolism of ethanol?

Answer 14

acetyl CoA, NADH + ATP formed inhibit glucose metabolism by inhibiting PFK + pyruvate dehydrogenase
NADH inhibits TCA cycle + acetyl-CoA increase further
Gluconeogenesis is inhibited
conversion of lactate of pyruvate is inhibited
Conversion of FA to acetylcoA is inhibited

Question 15

What is microsomal ethanol oxidising system (MESO)?

Answer 15

Second route of metabolism
involves oxidation of ethanol by members of cytochrome P450 family of enzymes
system uses NADPH which is required for synthesis of antioxidant glutathione which protects body from oxidative stress so excess alcohol will lead to situation where body is less able to protect itself from oxidative stress

Question 16

What is acetaldehyde?

Answer 16

highly reactive + can accumulate with excessive ethanol intake
can inhibit enzyme, their function
in liver, can lead to secretion of both serum protein + VLDL
can also enhance free-radical production leading to tissue damage such as inflammation + necrosis

Question 17

What are 3 stages of alcohol liver damage?

Answer 17

1. Fatty liver -> deposition of excess fat within liver tissue which has significant effect on functioning of liver
2. Alcohol hepatitis, groups of cells die resulting in inflammation
3. Cirrhosis which includes fibrosis, scaring + cell death

Question 18

What are xenobiotics?

Answer 18

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

Question 19

Metabolism of xenobiotics occurs in 3 common phases. What are they?

Answer 19

Phase 1: oxidation
Phase 2: Conjugation
Phase 3: Elimination

Question 20

What occurs in Phase 1 in Xenobiotics metabolism?

Answer 20

Oxidation= most common modification but also get hydroxylation + reduction

• Modification increases solubility of molecule
• introduces functional groups which enables participation in further reactions to aid its ultimate elimination
• reactions are promoted by family of enzymes called cytochrome P450

Question 21

What is cytochrome P450?

Answer 21

• found mainly in liver + cells of intestine. Found in ER
• Make up family of about 50 different enzymes -> they are haem proteins so they are iron containing molecules + are related to mitochondrial enzymes
• P450 enzymes are inducible by both by their own substrates but also related substrates

Question 22

What happens in Phase 2 of xenobiotic metabolism?

Answer 22

Phase 2= Conjugation
Xenobiotic are modified by addition of groups such as glutathione, glucuronic acid and sulphate
modification with these groups increase solubility + targets them for excretion

Question 23

Liver and drug metabolism. Why is it important?

Answer 23

Xenobiotics metabolism is part of bodies natural defences
Metabolism of drugs by liver can play significant role in their effectiveness
A drug taken orally will pass through liver first
Modifications made by liver can significantly reduce effectiveness of drug

Question 24

What do statins inhibit?

Answer 24

Statins inhibit HMG-CoA reductase so they involved in regulating cholesterol metabolism

Question 25

What are statins degraded by?

Answer 25

degraded by CYP3A4 (isoform of cytochrome P450) -> CYP3A4 activity is inhibited by grapefruit juice

Question 26

What is aflatoxin B1?

Answer 26

produced by fungus Aspergillus flavus

Aflatoxin activated by P450 isoenzymes leading to epoxide (toxic molecule) formation + hepatocarcinogenesis

Question 27

How is paracetamol metabolised?

Answer 27

In normal circumstances, it undergoes Phase 1 and Phase 2 changes that makes it more soluble
Small proportion of paracetamol will be acted on by CVP2E1 + it forms molecule called NAPQI (toxic)
Under normal circumstances, NAPQI will react with glutathione to give water soluble relatively harmless molecule that can be excreted by kidney as urine

Question 28

What happens when alcohol is consumed with paracetamol?

Answer 28

Alcohol has significant effect on metabolism -> has negative effect in pathway where NAPQI reacts with glutathione
P450 pathway itself will be stimulated so flow of metabolites through these pathways increase so NAPQI will increase which cant be metabolised in harmless route so it will be subsequently in harmful route

Question 29

What happens to modified compounds?

Answer 29

Small water soluble molecules can be removed by kidney
Actively transported in to bile + then into intestines
Large molecules will end up back in gut
Some of those metabolites wont be excreted, Fraction of them will be reabsorbed so they will continue to circulate .
Fate of these molecules are 3 fold: Digestion, excretion + reabsorption via enterohepatic circulation

Question 30

What are roles of liver?

Answer 30

Regulation of carbohydrate metabolism 
Regulation of fat metabolism
Regulation of protein metabolism
Cholesterol synthesis and excretion
Synthesis of specialized molecules
Central role in the metabolism of xenobiotics