Metabolic functions of the liver Flashcards
What is the liver extremely important in maintaining?
extremely important for maintaining constant blood glucose levels
How does the liver maintain constant blood glucose level?
- By 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 pentose phosphate cycle
What is the liver involved in the metabolism of?
involved in the metabolism of other sugars, such as fructose and galactose
What is the liver the major site of synthesis of?
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, and particularly when?
liver degrades excess amino acids, particularly during gluconeogenesis
What is the liver the major site involving amino acids for?
The liver is the major site for transamination and deamination of amino acids, and for detoxification of ammonia.
What interaction is there between muscles and liver?
Gluconeogenesis in the liver allows the synthesis of glucose which can be transported to muscles when the muscle requires it
How much cholesterol is made by the liver?
- 50% of cholesterol made in the body is made by the liver
Where is the rest of cholesterol made by?
rest made by intestine, adrenal cortex and reproductive tissue
How is cholesterol synthesized in the liver and what enzymes are involved?
- Made from acetyl CoA and the key enzyme is HMG-CoA reductase
What is cholesterol transported as in the liver?
- Transported from the liver as VLDL
How is cholesterol excreted from the body?
- disposed of by the biliary system either as cholesterol or following conversion to bile acids/salts
How does cholesterol enter the livers cholesterol pool?
- Cholesterol enters the livers cholesterol pool from a number of sources
o dietary
o de novo by extra-hepatic tissue
o makes its own
What flux is not tightly regulated in humans?
- In humans the flux of cholesterol is not tightly regulated. With time there is an accumulation of cholesterol in the tissues particularly in the endothelial cells
What are the 2 routes of the metabolism of ethanol?
– Oxidation through the activity of alcohol dehydrogenase
– Microsomal oxidation using cytochrome P450
How much ethanol does the body approximately metabolize per hour?
- The body metabolises approximately 10g of alcohol/hour
What is methanol metabolised into?
- Methanol is metabolised to formaldehyde
Side effect of formaldehyde and why?
associated with paralysis, loss of consciousness and blindness because its toxic
What drugs can alcoholics be treated with?
- Alcoholics can be treated with drugs that inhibit ALDH thereby inducing the symptoms experienced
What is not a good negative inhibitor and therefore what will accumulate?
- NADH is not a good negative inhibitor of either ADH or ALDH therefore NADH generated in the cytosol will accumulate
What are 3 problems with the metabolism of ethanol?
- Oxidation of alcohol takes precedence over other nutrients
- The metabolism of alcohol is not regulated by negative feedback
- As a result, large quantities of acetyl-CoA, NADH, and ATP are formed
What pathways are inhibited by the metabolism of ethanol?
- acetyl-CoA, NADH and ATP are formed and they 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 TG for export as VLDL
The steps and consequences due to high levels of NADH
- High levels of NADH inhibits fatty acid oxidation therefore FA accumulate in the liver.
- Increase G-3-P production together with the above leading to increased TG formation
- TG are incorporated into VLDL and released into the blood causing hyperlipidaemia.
- The high NADH/NAD ration shifts the OAA in the TCA cycle to malate and the acetyl-CoA formed from ethanol is diverted to ketone body formation leading to alcohol induced ketoacidosis
- The high NADH/NAD ration pushes the activity of lactate dehydrogenase towards lactate resulting in lactic acidosis
- The high NADH/NAD ration inhibits gluconeogenesis in a fasting individual this would lead to hypoglycaemia
What is the second route of metabolism of ethanol?
Microsomal Ethanol-Oxidising System (MESO)
What does MESO involve?
• Involves the oxidation by members of the cytochrome P450 family of enzymes
What does MESO use and what is it required for?
• This system uses NADPH which is required for the synthesis of the antioxidant glutathione
What is the reactivity of acetaldehyde like and with what can it accumulate with?
• Is highly reactive and can accumulate with excessive ethanol intake
What can acetaldehyde inhibit?
can inhibit enzyme function
What can acetaldehyde lead to i the liver?
ead to a reduction in the secretion of both serum protein and VLDL in the liver
What can acetaldehyde enhance and what can this lead to?
Can also enhance free-radical production – leading to tissue damage such as inflammation and necrosis
What are the 3 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
What are xenobiotics?
compounds with no nutritional value
What compounds are excreted more easily in the urine?
Water soluble compounds can be excreted easily in the urine, lipophilic compounds are more difficult
What type of metabolism does the liver play a major role in?
Liver plays a major role in xenobiotic metabolism
What is the aim in xenobiotic metabolism?
- The aim is to make the xenobiotic harmless and more readily disposed of by the kidney in urine or the gut in faeces
What are the 3 common phases in xenobiotic metabolsim?
Phase I • Oxidation Phase II • Conjugation Phase III • Elimination
What is the most common modification in phase 1?
- Oxidation is the most common modification but also get hydroxylation and reduction
What does modification in phase 1 increase?
- Modification increases solubility
What does phase 1(oxidation) introduce?
- Introduces functional groups which enables participation in further reactions
What promotes the reactions in phase 1?
- These reactions are promoted by a family of enzymes called cytochrome P450
Where is Cytochrome P450 mainly found?
• Found mainly in liver and cells of the intestine
Where in the cells is cytochrome P450 found?
• They are found in the endoplasmic reticulum
What are P450 induced by?
• P450 enzymes are inducible by both by their own substrates (5-10 fold) but also related substrates (2-4 fold)
What happens to xenobiotics in phase 2(Conjugation)?
- Xenobiotic are modified by addition of groups such as
- Glutathione
- Glucuronic acid
- Sulphate
- Modification with these groups increase solubility and targets them for excretion
In phase 2, how are the compounds modified?
• Compounds are often sequentially modified
What do statins regulate?
- Regulate cholesterol metabolism
What do statins inhibit?
- Statins inhibit HMG-CoA reductase
What are statins degraded by?
- They are degraded by CYP3A4
What can inhibit CYP3A4 activity?
o CYP3A4 activity is inhibited by grapefruit juice
What is aflatoxin beta 1 produced by?
• Produced by the fungus Aspergillus flavus and found in peanuts
What is aflatoxin activated by and what does it lead to the formation of what?
• Aflatoxin is activated by P450 isoenzymes and leads to epoxide formation and hepatocarcinogenesis
What happens to modified small water soluble compounds?
• Small water soluble molecules <60,000kDa can be removed by the kidney
Where are modified compounds actively transported to?
• Actively transported in to bile and then into the intestines
What is the fate of these modified compounds?
– Digestion
– Excretion
– Re-absorption via the enterohepatic circulation
What is the Central Role of the Liver in the regulation of metabolism?
- Regulation of carbohydrate metabolism
- Regulation of fat metabolism
- Regulation of protein metabolism
- Cholesterol synthesis and excretion
- Synthesis of specialized molecules
- Central role in the metabolism of xenobiotics
