S2: Metabolic functions of the Liver Flashcards
Explain how 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.
- 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.
Describe the removal of glucose from the blood after a meal with the role of the liver
- 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.
Describe the Importance of the Liver for Protein and Amino Acid Metabolism
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.
Describe liver in fat transport
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).
Describe the liver’s role in synthesis and 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.
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
Why is their a need to metabolise alcohol?
- Evolved as a consequence of our diet
- Gut synthesises ethanol by microorganisms present in gut
What are the two routes of metabolism of alcohol?
- Oxidation through the activity of alcohol dehydrogenase
2. Microsomal ethanol oxidising system (MEOS) using cytochrome P450
Describe oxidation of alcohols
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)
- 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:
- 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.
Symptoms of acetaldehyde
- Vasodilation
- Facial flush
- Tachycardia
- Nausea
What is acetate a substrate for?
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.
What is ‘asian flush’?
Having low levels of aldehyde dehydrogenase hence intolerance to the consumption of alcohol
Pathways inhibited by metabolism of alcohol
- 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.
Pathways stimulated by alcohol metabolism
- 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.
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Consequences of acetylaldehyde
- 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
What are the 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.
