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Flashcards in S2: Metabolic functions of the Liver Deck (25)
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1
Q

Explain how the liver is the first port of call for most things taken up in the gut

A
  • The liver receives blood directly from the gut
  • This is important from a nutritional sense in terms of carbohydrates but also drugs
  • As ingested drugs will be delivered to the liver first and we must consider the affect the liver may have on this drug.
  • It handles large amounts of newly absorbed nutrients and ‘protects’ major vessels from direct contact with dietary nutrients.
  • The liver ensures rapid circulation of its products and the bile ducts empty directly into the gut. It can rapidly influence the digestive process.
2
Q

Describe the removal of glucose from the blood after a meal with the role of the liver

A
  • The liver is important for maintaining constant blood glucose after an meal for brain and RBCs
  • It stores excess glucose in the form of glycogen , by restoring blood glucose levels through glycogenesis and glycogenolysis
  • Also by regulating the fluxes through glycolysis, gluconeogenesis and pentose phosphate pathway.
  • The liver also has a major role in converting excess glucose into fatty acids which can later be converted back into glucose if need be
  • The liver produces fatty acids which are largely sent off to the adipocytes for storage via VLDLs.

Importantly there is also interaction between liver and muscle, this is seen in anaerobic respiration with the production of lactate and also in proteolysis:
- Excess lactate has to be converted back to glucose.
- Degradation of proteins will largely form alanine, this will also be transported in the blood to the liver where it can be converted back to glucose and used for further muscle activity or for brain.

3
Q

Describe the Importance of the Liver for Protein and Amino Acid Metabolism

A

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

Importantly the body doesn’t store protein, it utilises it for building tissue and if there is any excess then that will be broken down.

The carbon skeleton can be used for energy (gluconeogenesis) but the N is toxic and needs to be removed.

Glucogenic amino acids –> sugars

Ketogenic amino acids –> ketone bodies

The liver is the major site for transamination and deamination of amino acids and for the detoxification of ammonia through production of urea.

4
Q

Describe liver in fat transport

A

Chylomicrons are synthesised in gut and transport the TAG to peripheral tissues. The chylomicron remnants go to the liver where there will be repackaging of lipids into lipoproteins (VLDLs).

5
Q

Describe the liver’s role in synthesis and removal of cholesterol

A

Cholesterol cannot be used for energy. Hence the body cannot degrade cholesterol so it is disposed of by the biliary system either as cholesterol or following conversion to bile acids.

50% of cholesterol made in the body is made by the liver, the rest is made by the intestine, adrenal cortex and reproductive tissue.
It is made from Acetyl CoA, the key enzyme is HMG-CoA reductase. It is transported from the liver as VLDL.

To liver cholesterol pool:

  • Dietary cholesterol as chylomicron remnants
  • De novo synthesis in liver
  • HDL from extrahepatic tissue forms cholesterol

From liver cholesterol pool:

  • Secretion as VLDL
  • Free cholesterol in bile
  • Converted to bile acids
6
Q

Why is their a need to metabolise alcohol?

A
  • Evolved as a consequence of our diet

- Gut synthesises ethanol by microorganisms present in gut

7
Q

What are the two routes of metabolism of alcohol?

A
  1. Oxidation through the activity of alcohol dehydrogenase

2. Microsomal ethanol oxidising system (MEOS) using cytochrome P450

8
Q

Describe oxidation of alcohols

A

In the cytosol:

Ethanol is a preferential substrate for the body, the body will start to break it down in preference to other substrates (above carb, below fat)

  1. Action of alcohol dehydrogenase (mostly found in liver). This has very high affinity for alcohol (low Km) so is readily saturated. This means you quite quickly exceed the capacity of this enzyme to metabolise ethanol.
    NAD+ is converted to NADH.

In mitochondria:

  1. The product of alcohol dehydrogenase is acetaldehyde, this is very toxic (very reactive). Acetaldehyde is broken down by aldehyde dehydrogenase to form acetate.

Metabolism of alcohol is not regulated by negative feedback, it will continue to be metabolised so long as there is substrate available.
As a result of this, large quantities of acetyl-CoA, NADH and ATP are formed. NADH is formed by the reactions produced by the alcohol and aldehyde dehydrogenase. Cells use NADH to produce ATP.

Under normal circumstances this occurs when energy is required but with alcohol consumption a lot of this is produced which messes with normal metabolism by inhibiting certain reactions e.g. glycolysis.

9
Q

Symptoms of acetaldehyde

A
  • Vasodilation
  • Facial flush
  • Tachycardia
  • Nausea
10
Q

What is acetate a substrate for?

A

Acetate is a substrate for enzymes that will produce Acetyl CoA.
There are two different isoforms of the enzyme, ALDH-1 and ALDH-2.
The latter is mitochondrial and with a low Km.

11
Q

What is ‘asian flush’?

A

Having low levels of aldehyde dehydrogenase hence intolerance to the consumption of alcohol

12
Q

Pathways inhibited by metabolism of alcohol

A
  • Glucose metabolism by inhibiting PFK and pyruvate dehydrogenase
  • High levels of ATP and NADH (and depletion of NAD+) will result in TCA cycle being inhibited. This will continue until the metabolism of NADH and ATP have re-established themselves This will reduce the amount of oxaloacetate which will impair the livers ability to maintain blood glucose via gluconeogenesis.
  • The large consumption of alcohol will also lead to a build up of lactate, because the conversion of lactate back to pyruvate is no longer preferential, the reverse (pyruvate to lactate) is preferential. So individuals consuming alcohol will suffer lactic acidosis.
13
Q

Pathways stimulated by alcohol metabolism

A
  • Alcohol will stimulate fatty acid synthesis as its subsequent esterification to TAGs for export as VLDLs (it is mobilising fats). But if the liver gets overwhelmed by the alcohol levels (esp. acetaldehyde), there will be deposition of fat in the liver (-> leading to fatty liver)
  • A large amount of acetyl CoA will lead to generation of fatty acids but there is also production of ketones, so the person will also suffer ketoacidosis.

-

14
Q

Consequences of acetylaldehyde

A
  • Is highly reactive and can accumulate with excessive ethanol intake
  • Acetaldehyde is very reactive and can inhibit enzyme their 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
15
Q

What are the three stages of alcohol liver damage?

A

Stage 1: Fatty liver
Stage 2: Alcoholic hepatitis, where groups of cells die and inflammation results
Stage 3: Cirrhosis which includes fibrosis, scarring and cell death

A cirrhotic liver cannot function properly, ammonia will accumulate resulting in neurotoxicity, coma and death.

16
Q

What are xenobiotics?

A

Xenobiotics covers everything the body cannot really use and has no nutritional value

17
Q

List some xenobiotics

A
  • Plant metabolites
  • Synthetic compounds
  • Food additives
  • Agrochemicals
  • Cosmetics
  • By-products of cooking
  • Drugs
18
Q

What is the role of the liver in the metabolism of xenobiotics?

A

So the liver plays a significant role in dealing with these compounds.
The function of the liver here is to take these compounds and make them into something that the body can get rid off, usually that is making it water-soluble. This is because water-soluble compounds can be excreted easier in the urine than lipophilic compounds.
The liver tries to make it less toxic as well (but sometimes doesn’t work).

19
Q

What are the 3 phases of metabolism of xenobiotics?

A

Phase I oxidation
Phase II conjugation
Phase III elimination

20
Q

Describe phase I: oxidation in the metabolism of xenobiotics

A

Oxidation is the most common modification but it could instead/also get hydroxylation and reduction.
The aim is to increase the solubility, to aid removal of it.

  • This stage introduces functional groups which may make the compound more reactive to allow it to react with another functional group.
  • Reactions are promoted by enzymes cytochrome P450 family found in endoplasmic reticulum
21
Q

Describe phase II: conjugation in the metabolism of xenobiotics

A

This is where we are reacting the molecule we want to get rid of with some other compound that will aid in its removal, the molecules that it will be conjugated with are things such as:
- Glutathione
- Glucuronic acid
- Sulphate

The purpose of modifying with these groups is to make them more reactive for further reactions and or increase solubility which targets them for excretion.
These are sequential events.

22
Q

Why is liver and drug metabolism important (drug design)?

A

Xenobiotic metabolism is part of the bodies natural defences, the body however cannot distinguish between harmful compounds and beneficial compounds such as drugs.

In drug design:

  • Consider how liver, intestines and lungs will metabolise the drugs and the consequences
  • If drug is too quickly broken down it may be ineffective
  • Drug could be metabolised into more toxic substrate

A drug taken orally will pass through the liver first, modification made by the liver can significantly reduce the effectiveness of a drug, although this could be advantageous.

23
Q

What are statins?

How does grapefruit juice affect them?

A

Statins are used to treat high cholesterol and work by inhibiting HMG-CoA (the key regulatory enzyme in cholesterol synthesis) and statins are degraded by CYP3A4 (not too important to remember name)

CYP3A4 activity is inhibited by grapefruit juice, so if you consume grapefruit while taking statins, stain levels can rise by 15 fold. This is evidently a huge increase in dosage.

24
Q

What is Aflatoxin B1

and how does liver metabolism affect it?

A

In some cases however, metabolism by the liver may produce a substance that is worse than the original. Aflatoxin is produced by the fungus aspergillus flavus. If Aflatoxin is activated/metabolised by the P450 isoenzymes it will lead to epoxide formation (which is extremely toxic!) and hepatocarcinogenesis (liver tumour). This wasn’t originally foreseen.

25
Q

What happens to small soluble molecules and large molecules (drugs once modified)?

A

Small water-soluble molecules can be removed by the kidney.
Larger molecules may have to be removed in another way, one of these ways is via actively transporting it into bile. The bile will then be emptied into the gut and excreted.
However some of these drugs may end up getting re-absorbed by the kidneys or in the intestine.