Metabolic Functions of the Liver Flashcards
What is the first port of call for most things taken up in the gut? why is this important?
why is drugs important when thinking of liver?
where does the liver lie between? effect of this?
what happens to products of liver? what does it rapdily influence?
The liver is the first port of call for most things taken up in the gut (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.
The liver ensures rapid circulation of its products and the bile ducts empty directly into the gut. It can rapidly influence the digestive process.
As the liver lies between the gut and heart it ‘protects’ major vessels from direct contact with dietary nutrients.
How does the liver maintain constant blood glucose levels? (3)
role of excess glucose to FA?
why is glucose maintained?
role of liver and muscles with glucose and energy?
- By storing excess glucose in the form of glycogen
- By restoring blood glucose levels through glycogenesis //glycogenolysis.
- By regulating the fluxes through glycolysis, gluconeogenesis and pentose phosphate pathway.
Importance of the Liver for Protein and Amino Acid Metabolism
example of serum proteins are made at the liver?
what happens to proteins? 2 outcomes
what can the protein molecule be used for? what is toxic?
which ammino acids make sugars and what do the other amino acids make?
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 via gluconeogenesis, but the N is toxic and needs to be removed.
o Glucogenic amino acids -> sugars
o Ketogenic amino acids -> ketone bodies
The liver is the major site for transamination & deamination of amino acids and for the detoxification of ammonia through production of urea.
Liver in Fat Transport
what fat is synthesised in the gut and where do they go? what happens to the rest?
what happens to cholesterol?
where is cholesterol made? what is it made from and what is the enzyme used? how is it transported as?
The liver is involved in the cycle of fats. 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).
The liver plays a central role in the synthesis & removal of cholesterol. 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.
o It is made from Acetyl CoA; the key enzyme is HMG-CoA reductase. It is transported from the liver as VLDL.
Metabolism of Ethanol
why is ethanol present in the body even if we don’t drink alcohol?
what are the 2 routes of getting rid of ethanol?
which is the more predominant route?
what does preferential substrate mean and how does this relate to ethanol?
why is it an empty calorie source?
what is the first action? enzyme used? from where? what is the issue here?
what is the product of this and issue here? effects of this? how is this dealt with?
why do some asians have intolerance to consumption of alcohol?
why does excessive alcohol consumption have an significant effect on metabolism? what builds up and why is this an issue?
The need to metabolise ethanol has evolved as a consequence of our diet. Even if you do not consume alcohol, your gut synthesises ethanol by the microorganisms present in the gut.
So, for this reason we have evolved a way to get rid of it.
There are 2 routes to the metabolism of ethanol:
- Oxidation through the activity of alcohol dehydrogenase
- Microsomal ethanol oxidising system (MEOS) on using cytochrome P450
The predominant route is the first one, through the activity of alcohol dehydrogenase.
Ethanol is a preferential substrate for the body, the body will start to break it down in preference to other substrates.
But ethanol is considered to be an empty calorie, all it has is calorific value, it lies above pure carb and a little below fat as a source of energy.
The first step is by the action of alcohol dehydrogenase, which is predominantly found in the liver, it has a very high affinity for alcohol so has a low Km and is very readily saturated.
o It is saturated after the first drink. This means you quite quickly exceed the capacity of this enzyme to metabolise ethanol.
o The body metabolises approx. 10g of alcohol/hour
The product of alcohol dehydrogenase is acetaldehyde, this is very toxic (very reactive). If it builds up it has lots of effects: o Vasodilation o Facial flush o Tachycardia o Nausea.
Acetaldehyde is broken down by aldehyde dehydrogenase to form acetate.
Acetate is a substrate for enzymes that will produce Acetyl CoA.
o There are two different isoforms of the enzyme, ALDH-1 and ALDH-2.
o The latter is mitochondrial and with a low Km.
40% of Chinese, Japanese, Mongolians, Koreans, Vietnamese, Indonesians and Native Americans have relatively low levels of aldehyde dehydrogenase and hence they will have an intolerance to the consumption of alcohol.
As mentioned earlier, oxidation of alcohol takes precedence over other nutrients.
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: ONLY produced when ENERGY IS REQUIRED. But with this alcohol consumption a lot of this that is produced isn’t being negatively regulated.
Cause a build up -> mess of normal metabolism by inhibiting certain reactions e.g. glycolysis.
Hence excessive alcohol consumption = would have a significant effect on metabolism.
What does alcohol metabolism produce a lot of?
what are the consequences of this? 2
how is fatty liver formed?
how does ethanol lead to oxidative stress?
why does excess nadph reduce the ability to produce antioxidants and effect of this?
To summarise simply, alcohol metabolism will produce a lot of NADH, Acetyl CoA and ATP.
The consequences of this are various, including:
- Inhibiting 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
- One of the primary effects is that alcohol will stimulate fatty acid synthesis, as is its subsequent esterification to TAGs for export as VLDLs (Mobilisation of fats).
o But if the liver gets overwhelmed by the alcohol levels (esp. acetaldehyde), there will be deposition of fat in the liver -> fatty liver - Ethanol also undergoes microsomal oxidation by members of the cytochrome P450 family of enzymes, this leads to oxidative stress
This system uses NADPH which is required for the synthesis of the antioxidant glutathione therefore excess alcohol reduces the ability to produce antioxidants, which results in damage by Reactive oxygen species produced by acetaldehyde
- The generation of these free radicals can lead to tissue damage such as inflammation and necrosis.
Liver Damage
3 stages of alcohol liver damage?
what happens with cirrhotic liver?
how can you get lactic acidosis?
how can you suffer from ketoacidosis?
what effect will reduced oxaloacetate have?
There are three stages of alcohol liver damage:
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.
Cirrhosis arises in 25% of alcoholics and 75% all cirrhosis is due to alcohol.
There are effects on glycogenesis and glycogenolysis (depending on nutritional status).
The large consumption of alcohol will also lead to a build-up of lactate, BECAUSE lactate back to pyruvate is no longer preferred, pyruvate -> lactate is now preferred = lactic acidosis.
A large amount of acetyl CoA -> generation of fatty acids + production of ketones = suffer ketoacidosis.
Some of this excess Acetyl CoA can be used in TCA, but if it does build up (along with NADH) then TCA will be inhibited.
- Reduce oxaloacetate which will impair the livers ability to maintain blood glucose via gluconeogenesis.
Xenobiotics - what are these?
examples?
what is the role of the liver here? what does it usually convert it into and why?
what other organs are usually involved?
what are the three phases?
what is the first phase and aim of this phase? what is intorduced in this stage and why? what promotes thes reactions and where are they found/what are they? what enduces these enzymes?
what is the next phase and its aim? what three molecules can it react with?
why must we be careful with drug designs in relation to liver?
Xenobiotics covers everything the body cannot really use, has no nutritional value such as: o Plant metabolites o Synthetic compounds o Food additives o Agrochemicals o Cosmetics - By-products of cooking - Drugs
These are xenobiotics from the Greek for strange. The body however has evolved systems to deal with these things.
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 of, usually that is making it water-soluble.
o 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.
Also involved are the intestines and lungs.
The metabolism of Xenobiotics is broken down into three common phases:
o Phase I oxidation
o Phase II conjugation
o Phase III elimination
Oxidation (Phase I)
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 -> make the compound more reactive to allow it to react with another functional group. It is not a one-step thing it is a multistep process e.g. paracetamol.
These reactions are promoted by a family of enzymes called cytochrome P450 enzymes.
- Cytochrome P450 enzymes are mainly found in the liver and intestinal cell. They make up a family of about 50 enzymes and are haem proteins that are related to the ones found in mitochondria.
- These enzymes are also found in endoplasmic reticulum
P450 enzymes are also inducible by both their own substrates (5-10x) but also related substrates (2-5x).
- Early humans were not expected to metabolise these drugs, but we can because of this characteristic.
These enzymes are clinically very important
Conjugation (Phase II) 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.
Xenobiotic metabolism is part of the body’s natural defences, the body however cannot distinguish between harmful compounds and beneficial compounds such as drugs.
- Hence in terms of drug design we need to consider how the liver (and intestine and lung) will take these drugs and how they will metabolise them and what the consequence will be.
It could be a drug given for a particular purpose is very quickly broken down and then becomes ineffective.
Another possible consequence could be the drug we introduce gets metabolised in a way that it now becomes more toxic.
So how the body deals with these xenobiotics is important because it can affect how we give it, how often we give it (do we need to give it multiple times to maintain a therapeutic level of the drug?), whether we give it at all.
Depending on which route we choose will determine what happens to it, if we give it orally it will pass through the liver, this may end up having a positive or negative effect.
So as a summary, 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.
Statins
what is it used to treat? mode of action?
what degrades statins? what prevents this?
Statins are used to treat high cholesterol and work by inhibiting HMG-CoA, the key regulatory enzyme in cholesterol synthesis, 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, statin levels can rise by 15-fold. This is evidently a huge increase in dosage.
Aflatoxin B1
what is this produced by?
what happens if this is metabolised? consequence of this?
In some cases, 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 = extremely toxic and hepatocarcinogenesis (liver tumour).
What Happens to the Modified Compounds?
small soluble molecules?
larger molecules?
what could happen to these molecules?
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.
summary
- Regulates carbohydrate metabolism to maintain blood glucose
- Regulates fat metabolism (via synthesis and beta oxidation)
- Regulates protein metabolism (plasma protein synthesis and detoxification of ammonia -> urea formation)
- It is involved in cholesterol synthesis and excretion
- In the synthesis of specialised molecules e.g. bile acids, haemin
- It plays a central role in the metabolism of xenobiotics
