Metabolic functions of the liver Flashcards
Where the liver located and what therefore does it protect?
Between the gut and the heart.
Therefore it “protects” major vessels from direct contact with dietary nutrients etc.
Describe the venous drainage of the liver
What does this allow?
Empties directly into major vessel entering the heart.
Ensures the rapid circulation of its products.
How is the liver involved with digestion?
Bile ducts empty directly into gut.
Can rapidly influence the digestive process
What does the liver regulate which is found in the blood?
Contributes to lowering blood glucose levels
Where does the liver transport glucose to remove glucose from the blood?
- The liver transports glucose to the intestine
- The live transports glucose to the brain, adipose tissue and muscle
- Triglycerides are transported as VLDL to the adipose tissue
What does the liver synthesise?
- The liver is the major site for the synthesis of many serum proteins, such as albumin and the blood clotting factors.
What does the liver degrade?
By what process?
- The liver degrades excess amino acids, particularly during gluconeogenesis.
• glucogenic amino acids -> sugars
• ketogenic amino acids -> ketone bodies
What does the liver to do AA and ammonia?
- The liver is the major site for transamination and deamination of amino acids, and for detoxification of ammonia.
Describe the interaction between the liver and muscle
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How does the liver play a central role in the synthesis, transport and metabolism of lipids and fats?
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Where is cholesterol synthesised?
What is it made from?
What is it transported as?
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
How is cholesterol excreted?
Excretion
- body can not degrade cholesterol
- disposed of by the biliary system either as cholesterol or following conversion to bile acids/salts
Describe cholesterol movement and metabolism
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What 2 methods are used to metabolise ethanol?
There are two routes to the metabolism of ethanol:
- Oxidation through the activity of alcohol dehydrogenase = 90%
- Microsomal oxidation using cytochrome P450 = 10-20%
How is ethanol first metabolised?
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What is the second step in ethanol metabolism?
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What four pathways are inhibited by the metabolism of ethanol?
- 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
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What occurs in the Microsomal ethanol-oxidising system MESO?
What enzyme does it involve and what else does it require to synthesize?
- 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
What are the side effects of the accumulation of Acetaldehyde?
- 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
What are the 3 stages of alcoholic liver damage?
- 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
What are xenobiotics and give some examples
Are compounds with no nutritional value such as: • plant metabolites • synthetic compounds • food additives • agrochemicals • cosmetics • by-products of cooking etc • drugs
How is the liver involved in xenobiotic metabolism?
- 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
What are the 3 stages of xenobiotics metabolism
Three common phases
- Phase I oxidation
- Phase II conjugation
- Phase III elimination
What happens in phase 1 of xenobiotics metabolism?
What other processes occur?
Does solubility increase?
What enzymes?
- 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
What is cytochrome P450 involved in?
Where are they found?
What are they induced by?
- 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
Describe the second stage in xenobiotic metabolism
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
Why is the metabolism of xenobiotics important?
- 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
What do statins inhibit, what are they degraded by?
- Statins inhibit HMG-CoA reductase
* Are degraded by CYP3A4
What is Aflatoxin B1?
What is it produced by?
What is it activated by and what does this lead to?
- Produced by the fungus Aspergillus flavus
* Aflatoxin activated by P450 isoenzymes leading to epoxide formation and hepatocarcinogenesis
Describe the metabolism of paracetamol?
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What happens to the modified compounds?
Small molecules?
What are the 3 fates of the molecules?
What is T1/2?
• 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
Describe the central role of the liver in the regulation of metabolism
• 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
