Metabolic Functions of the Liver Flashcards
What relevance is the positioning/functioning of the liver in the body? PART 1
- First major organ in line from the gut so handles large amounts of newly absorbed nutrients.
What relevance is the positioning/functioning of the liver in the body? PART 2
- Positioned between the gut and the heart - ‘protects’ major vessels from direct contact with dietary nutrients
What relevance is the positioning/functioning of the liver in the body? PART 3
Empties directly into major vessel entering the heart - ensure rapid circulation of products.
What relevance is the positioning/functioning of the liver in the body? PART 4
- Bile ducts empty directly into the gut - rapidly influence the digestive process.
How is the liver important in maintaining constant blood glucose levels?
- removal of glucose from the blood after a meal
- storing glucose in the form of glycogen
- restoring blood glucose levels through glycogenolysis and gluconeogenesis
What is the importance of the liver for protein and amino acid metabolism? PART 1
- Site for serum protein synthesis, such as albumin and blood clotting factors.
- Degrades excess amino acids, particularly during gluconeogenesis
What is the importance of the liver for protein and amino acid metabolism? PART 2
Major site for transamination and deamination of amino acids, and detoxification of ammonia.
How does the liver degrade excess amino acids during gluconeogenesis?
- Converts glucogenic amino acids to sugars
- Converts ketogenic amino acids to ketone bodies
Describe the synthesis of cholesterol in the body.
- 50% of cholesterol made in the body is made by the liver
- Remainder synthesised by the intestine and adrenal cortex
- Made from Acetyl CoA, and the key enzyme is HMG-CoA reductase
In what form is cholesterol transported?
As VLDL
Describe the excretion of cholesterol in the body.
- Body cannot directly degrade cholesterol
- 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 cytoplasm, ethanol is converted to acetaldehyde by alcohol dehydrogenase
- In the mitochondria, acetaldehyde is converted to acetate by aldehyde dehydrogenase
What is the rate-limiting enzyme within the conversion of ethanol to acetate?
Alcohol dehydrogenase
What can methanol be metabolised to form?
Formaldehyde
What are the effects of formaldehyde?
- Paralysis
- Loss of consciousness
Some people are more tolerant to alcohol than others. Suggest why.
Genetic variations in alcohol dehydrogenase which influence its rate, efficiency and structure
Describe the situation in which aldehyde dehydrogenase is rate limiting. PART 1
- Single amino acid substitutions (e.g glutamine to lysine)
- Produce dominant negative mutations
- In heterozygotes, the normal enzyme will function as if mutated
Describe the situation in which aldehyde dehydrogenase is rate limiting. PART 2
- Alcoholic treatment using aldehyde dehydrogenase inhibitor
What happens when NADH is used to treat alcoholics?
- Poor inhibitor of both dehydrogenases
- Will not affect either enzyme and will accumulate in cytosol
List some pathways inhibited by the metabolism of ethanol. PART 1
- Acetyl-CoA, NADH and ATP inhibit glucose metabolism by inhibiting PFK and pyruvate dehydrogenase.
List some pathways inhibited by the metabolism of ethanol. PART 2
- NADH inhibits the TCA cycle, causing accumulation of acetyl-CoA
How does ethanol metabolism trigger fatty acid synthesis and transport?
- Acetyl-CoA triggers ketone body formation and stimulates fatty acid synthesis in cytosol.
- Fatty acids are esterified to triglycerides for export as VLDL.
What is the microsomal ethanol-oxidising system (MESO) and what does it need?
- Oxidation by the members of the cytochrome P450 family of enzymes.
- Uses NADPH which is required for the synthesis of the antioxidant glutathione.
Describe acetaldehyde.
Highly reactive substance that accumulates with excessive ethanol intake.
What is the effect of acetaldehyde on the liver?
- Inhibit enzymes and their functions.
- Reduction in the secretion of serum protein and VLDL.
What process can acetaldehyde enhance?
Free-radical production
What is the effect of free-radical production?
Inflammation and necrosis
What is the first step of liver damage induced by alcohol abuse?
Fatty liver
What is the second step of liver damage induced by alcohol abuse?
- Alcoholic hepatitis
- Cell death resulting in inflammation
What is the third step of liver damage induced by alcohol abuse?
Cirrhosis - induces fibrosis, scarring and cell death
What are the effects of cirrhotic liver?
- Accumulation of ammonia
- Neurotoxicity, coma and death follow
What are xenobiotics?
Compounds with no nutritional value
Give examples of xenobiotics.
plant metabolites
synthetic compounds
cosmetics
drugs
What does the liver have to do with xenobiotic metabolism?
- Make xenobiotics harmless and more readily disposed of by the kidney in the urine or the gut in the faeces.
What are the three stages of the metabolism of xenobiotics?
PHASE 1: Oxidation
PHASE 2: Conjugation
PHASE 3: Elimination
Describe the first stage (oxidation) of xenobiotic metabolism.
- Introduces functional groups, which enables participation in further reactions and increases solubility.
- Promoted by a family of enzymes called cytochrome P450.
Describe cytochrome P450.
- Found mainly in ER of liver and intestine cells
- Haem proteins - also related to mitochondrial enzymes.
- Inducible by both their substrates (5-10 fold), but also by related substrates (2-4 fold).
Describe the second stage (conjugation) of xenobiotic metabolism.
Xenobiotics are sequentially modified by the addition of groups such as:
- glutathione
- glucuronic acid
- sulphate
Outline the purpose of conjugation.
Increases their solubility and targets them for excretion.
Describe aflatoxin B1.
- Produced by the fungus Aspergillus flavus.
- Activated by P450 isoenzymes, which leads to epoxide formation and hepatocarcinogenesis.
What happens to the modified compounds?
- Can be removed by the kidney.
- Actively transported in the bile and then into the intestines.
What are the three physiological processes that can happen to modified compounds?
digestion
excretion
reabsorption (via the enterohepatic circulation)
Describe the glucose alanine cycle. PART 1
→In the muscle, branched amino acids are taken and broken down.
→Carbon skeleton is used for energy production.
→NH4 can be used to convert pyruvate to Alanine. Alanine is then exported into the blood and travels to the liver.
Describe the glucose alanine cycle. PART 2
→ Alanine is then converted to glutamate via transamination (reacting with α-ketoglutarate) also producing pyruvate.
→The pyruvate can enter the gluconeogenic pathway to form glucose, and the glucose can be transported in the blood back to the muscle where it can be used for energy.
Describe the glucose alanine cycle. PART 3
→The glutamate will then be used along with the CO2 generated to produce urea in the liver.
What are the symptoms for ethanol intolerance?
→ Vasodilation
→ tachycardia
→ Nausea
What is the consequence of alcohol metabolism not being regulated by negative feedback?
→ Large quantities of Acetyl CoA, NADH and ATP are formed
RECAP TO FPP: Why is drug metabolism important and when can it be harmful?
→ Body cannot distinguish between harmful and beneficial compounds such as therapeutic drugs
→A drug taken orally will pass through the liver first
→ Modifications made by the liver can significantly reduce the effectiveness of a drug
→ Advantageous because the liver can activate the drug
What do statins inhibit and what are they degraded by?
→ HMG- CoA reductase
→ Degraded by CYP3A4
