L25 - Liver Function

• What are the main functions of the liver?

  - Drug metabolism- cholesterol synthesis- host defense
• Why is cholesterol important?

  - component of bile- gives rigidity to csm (fluid-mosaic)- affects molecule signalling within csm- precursor for several molecules eg vit. D, cortisol, aldosterone, bile salts

  
• How is cholesterol synthesised?- where?- where are components from?- what synthesised from?- via what mechanism?

  - de novo- in liver- obtained from diet- synthesised from Acetyl Co-A- via -ve feedback mechanism: Eg low cholesterol levels induce its production

  
• Cholesterol Synthesis: Step 1

  Acetoacetyl CoA + Acetyl CoA = HMG-CoAHMG-CoA reacts with HMG-CoA Reductase to form Mevalonate

  
• How do statins work?

  Statins inhibit HMG-CoA reductase, so Mevalonate can't formHence they prevent synthesis of cholesterol at early stages (step 1)
• Cholesterol Synthesis: Step 2

  Mevalonate is phosphorylated, and CO2 is lost to form 3-isopentenylpyrophosphate

  
• Cholesterol Synthesis: Step 3

  - Squalene is synthesised from isopentenyl pyrophosphate- cyclization of squalene forms Lanosterol- Lanosterol eventually forms cholesterol

  
• How is cholesterol transported in the body?

  Cholesterol = lipophilic, so needs a carrier to ensure it's not deposited= Lipoproteins
• Lipoproteins- what are the 2 types?- what are they made of?

  - HDL and LDL- lipid core (cholesterol esters and triglycerides)- hydrophilic outer surface (phospholipids and apolipoproteins)

  
• What's the difference between HDL and LDL?

  High/Low Density LipoproteinsDensity in terms of protein composition - high density have more protein

  
• What is atherosclerosis?- what does it cause?- what causes it?- treatment?

  progressive thickening/hardening of the arteries.Cause of cardiovascular diseases/strokes- Caused by high LDL levels- Treatment = drugs to lower cholesterol

  
• How is cholesterol lowered?

  - Inhibitors HMG-CoA Reductase (eg statins - prevent cholesterol production)- Inhibitors of absorption (eg ezetimibe)- Inhibitors of bile reuptake (eg cholestyramine)
• Bile production- where?- how?- what does hepatic bile contain?

  - in liver, by hepatocytes- hepatocytes secrete bile into bile canaliculi- epithelial cells lining bile ducts secrete HCO3- to increase bile volume- called ductal bile as it flows down biliary ducts- contains bile salts/pigments, cholesterol, lecithin, HCO3-

  
• What are primary bile acids?- what are the synthesised from?

  synthesised from cholesterolreleased into intestine upon hormone stimulationEg cholic acid
• What are secondary bile acids?

  Bile acids modified by bacterial flora in small intestineEg deoxycholic
• What's Bile Acid Conjugation?

  Primary/Secondary bile acids are conjugated to amino acids to generate water-soluble bile saltsEg cholic acid + glycine = glycocholate (salt)
• What are bile salts?- how are they formed?- structure/function?- importance?

  bile salt = bile acid + amino acid to form a salt- hydrophobic and hydrophilic regions that aggregate to form micelles at CMC- important for emulsification of fats

  
• Where does conjugation of bile acids occur?

  Liver

  
• Where does deconjugation of bile salts occur?

  Small intestine, by microbiota

  
• What's enterohepatic circulation?

  Recycling of bile salts from GI tract to liver (from small intestine via portal vein)
• What's the Sphincter of Oddi?- what does it control?- what's it controlled by?

  smooth muscle ring where common bile duct meets small intestine. Controls movement of bileControlled by CKK (cholecystokinin)

  
• What is Cholecystokinin? (CKK)What stimulates its release?

  Peptide hormone produced by small intestine that control sphincter of OddiRelease stimulated by food - amino acids/fatty acids in small intestine

  
• How is bile secretion regulated?

  - Fatty acids are consumed- increase in CCK production in small intestine- plasma [CCK] increases- gallbladder contracts and spinchter of oddi relaxes- increase in bile flow into small intestine

  
• What happens to bile if the sphincter of oddi is closed?

  Bile diverted to gall bladder for storage- bile concentrated by removal of salts/water
• What are bile pigments?What are they responsible for?What's the major pigment?

  = breakdown products of haem from erythrocytes broken down in liver and spleen- responsible for yellow/green colourmajor = bilirubin
• What proteins does the liver secrete?

  AlbuminGlobulinClotting Factors eg fibrinogen and prothrombin
• Insulin-like growth factors- what is it?- where synthesised?- what are two types?

  IGF = mediator of growth hormone action synthesised in liver- IGF1 and IGF2
• When do IGF1 levels peak and decline?When is IGF2 important?

  IGF1 levels low in infancy, peak in puberty and decline in adultsIGF2 important in foetal/neonatal growth
• What happens in phase 1 metabolism?- what processes occur?- what enzyme is involved?

  - oxidation, hydroxylation, reduction, hydrolysis etc- cytochrome P450

  
• What factors affect cytochrome P450 enzymes?

  - population variation between individuals, so some drugs won't work as well in some individuals due to metabolism step 1- environment: eg grapefruit juice can inhibit!
• What is clopidogrel?

  anti-thrombotic pro-drug that inhibits platelet activationprevents blood clots forming!

  
• How does clopidogrel work?

  - Binds selectively and irreversible to P2Y12 receptor on platelet membranes- Deactivates G proteins on membrane-activates 2nd messenger adenylate cyclase (ATP -> cAMP)- causes decrease in activation of fibrinogen binding protein, so less clotting

  
• Clopidogrel metabolismwhat needs to happen?what's an issue?

  clopidogrel = pro-drug, so needs to be metabolised by the liver to generate active drug- uses hepatic cytochrome P450 to generate active metabolite which reacts w/plateletsIssue = genetic variation in P450 enzymes may mean reduced response to clopidogrel treatment. Some ppl may not have the enzymes to metabolise it- 2 step metabolism leads to delayed onset, so doesn't act quickly

  
• What happens in phase 2 metabolism?

  Conjugation - attachment of an ionic group to a drug/metabolite to increase polarity- inactivates a drug and makes it less lipid soluble
• Describe the liver's role in immunity

  - Kupffer cells act as tissue macrophages in sinusoid lumens.- tries to eliminate toxins before they reach central vein, thus circulation- remove pathogens via endocytosis- Kupffer cells also remove activated host cells (eg platelets, neutrophils)