Metabolic Functions of the Liver Flashcards
What relevance is the positioning/functioning of the liver in the body?
The liver is the first major organ in line from the gut. Therefore, it can handle large amounts of newly absorbed nutrients.
It is positioned between the gut and the heart; therefore, it ‘protects’ major vessels from direct contact with dietary nutrients, etc.
It empties directly into the major vessel entering the heart, ensuring the rapid circulation of its products.
The bile ducts empty directly into the gut, meaning that they can rapidly influence the digestive process.
How is the liver important in maintaining constant blood glucose levels?
- by the removal of glucose from the blood after a meal
- by storing glucose in the form of glycogen
- by restoring blood glucose levels through glycogenolysis and gluconeogenesis
- by regulating the fluxes through glycolysis, gluconeogenesis and the pentose phosphate cycle
What is 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 the blood clotting factors.
- The liver degrades excess amino acids, particularly during gluconeogenesis (it converts glucogenic amino acids to sugars, and ketogenic amino acids to ketone bodies).
- The liver is the major site for transamination and deamination of amino acids, and for the detoxification of ammonia.
Describe the synthesis and excretion of cholesterol in the body.
SYNTHESIS:
- 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’s made from Acetyl CoA, and the key enzyme is HMG-CoA reductase
- it’s transported from the liver as VLDL
EXCRETION:
- the body cannot degrade cholesterol
- it is disposed of by the biliary system, either as cholesterol or by following the conversion to bile acids/salts
What are the two routes to the metabolism of alcohol?
- oxidation through the activity of alcohol dehydrogenase (90%)
- microsomal oxidation using cytochrome P450 (10-20%)
Describe the first step of the metabolism of alcohol (ie. ethanol to acetate).
In the cytoplasma, ethanol is converted to acetaldehyde by alcohol dehydrogenase (NAD+ to NADH, H+).
Then, in the mitochondria, acetaldehyde is converted to acetate by aldehyde dehydrogenase (NAD+, H2O to NADH, 2H+).
Methanol is metabolised to formaldehyde - this is very toxic and is associated with paralysis, loss of consciousness and blindness.
Alcohol dehydrogenase is the rate limiting step, but it also needs NAD+. Genetic variations in alcohol dehydrogenase can lead to differences in the tolerance of alcohol.
Alcoholics are prone to vitamin and mineral deficiencies as they can survive on the calories alone.
Describe the situation in which aldehyde dehydrogenase is rate limiting.
Normally, aldehyde dehydrogenase (ALDH) is not rate limiting, but some single amino acid substitutions (Glu to Lys) produce what is known as a dominant negative mutation. Heterozygotes who produce some normal enzyme behave as if they only produce the mutant enzyme.
Oriental flush causes vasodilatation, facial flush and tachycardia. 40% of Chines, Japanese, Mongolians, Koreans, Vietnamese, Indonesians and Native Americans have the mutant gene.
Alcoholics can be treated with drugs that inhibit ALDH, thereby inducing the symptoms experienced. NADH is not a good negative inhibitor of either ADH or ALDH, therefore, NADH generated in the cytosol will accumulate.
List some pathways inhibited by the metabolism of ethanol.
- Acetyl-CoA, NADH and ATP are formed to inhibit glucose metabolism by inhibiting PFK and pyruvate dehydrogenase.
- NADH inhibits the TCA cycle and Acetyl-CoA increases further.
- Acetyl-CoA results in ketone body formation and the stimulation of fatty acid synthesis.
- Fatty acids are esterified to TGs for export as VLDL.
What is the microsomal ethanol-oxidising system (MESO)?
This is the second route of metabolism. It involves oxidation by the members of the cytochrome P450 family of enzymes.
This system uses NADPH which is required for the synthesis of the antioxidant glutathione.
Describe acetaldehyde.
It is highly reactive and can accumulate with excessive ethanol intake.
Because it is highly reactive, it can inhibit enzymes and their functions. In the liver, this can lead to a reduction in the secretion of both serum protein and VLDL.
It can also enhance free-radical production - leading to tissure damage such as inflammation and necrosis.
What are the 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, scarring 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% of all cirrhosis is due to alcohol.
What are xenobiotics?
They are compounds with no nutritional value such as:
- plant metabolites
- synthetic compounds
- food additives
- agrochemicals
- cosmetics
- by-products of cooking, etc.
- drugs
What does the liver have to do with xenobiotic metabolism?
The liver plays a major role in xenobiotic metabolism.
The aim is to make xenobiotics harmless and more readily disposed of by the kidney in the urine or the gut in the faeces.
The intestine and the lungs are also involved.
What are the three stages of the metabolism of xenobiotics?
There are three common phases:
- PHASE 1: Oxidation
- PHASE 2: Conjugation
- PHASE 3: Elimination
Describe the first stage (oxidation) of xenobiotic metabolism.
Oxidation is the most common modification, but we also get hydroxylation and reduction. The modification increases solubility.
It introduces functional groups, which enables the participation in further reactions. These reactions are promoted by a family of enzymes called cytochromoe P450.
