Liver Physiology

Question 1

4 Phase 0 Transporters

Answer 1

• NTCP - takes in bile salts, Hep B/D w/ Na+
• OATP (organic anions)- bilirubin, conjugated bile salts, statins, dig, salicylates, methotrexate)
• OCT (organic cation transporter) - histamine, serotonin, NE, dopamine
• OSTalpha/beta (organic solute transporter) - actually BACKFLOW of bile acids

Question 2

Enterohepatic Recycling of Bile Acids

Answer 2

• ASBT on enterocyte apical membrane –> OST alpha/beta on basal enterocyte –> blood –> liver sinusoids

Question 3

Phase I Drug Metabolism

Answer 3

• inc reactivity thru CYPs and make drug inactive unless prodrug

(oxidation, reduction, hydrolysis, hydroxylation, deamination, hydration, decarboxylation, isomerization)

• CYP450s in smooth ER/ many polymorphisms
  Ex) - CYP3A - metabolizer of grapefruit juice, cyclosporine, statins, macrolides, erythromycin, etc
  Ex) - CYP2E1 - metabolizer of ethanol and some acetaminophen

Question 4

Phase II Drug Metabolism

Answer 4

• covalent modification; add large polar molecules to make more soluble for clearance usually in kidney; REQUIRE ENERGY

(glucouronidation, glutathione conjugation, sulfation, acetylation, methylation)

• Glutathione Conjugation - add glutathione (cysteine, glutamate, lysine) w/ GSTs
• Glucouronidation - add glucose w/ UGTs

Question 5

Phase III Transporters

Answer 5

• transport out of hepatocyte into bile canaliculi (all are ABC transports - ATP binding cassettes)
• MDR (multi-drug res transporters) - hydrophobic, cations/neutral
  - BSEP -bile salt export pump
• MRP (multi-drug res proteins) - hydrophobic, antions
  - MRP2 -bilirubin glucouronidases and sulfates eliminated
  - MRP3 - bile salt backflow

Question 6

Acetaminophen Metabolism

Answer 6

• Normally 95% undergoes phase II reaction w/ glucouronidation or sulfate addition and 5% undergoes CYP450 2E1 reaction –> NAPQI (toxic)
• If not enough glucose for glucouronidation then may get more in CYP450 2E1 path
• Tx - N-acetyl-cysteine - replenished glutathione which then conjugates NAPQI (used w/in 24 hrs)

Question 7

Glucose Metabolism

Answer 7

• Liver contains glucokinase which quickly converts glucose –> glucose-6-p to trap it in cell
  
  • High Km, low affinity so that most of the glucose flow thru to pancreas t o stimulate insulin secretion
  • But stimulated by insulin
• Gluconeogenesis via pyruvate from AA, lactate but not from FAs /acetyl CoA

Question 8

Protein Production

Answer 8

• Liver makes all proteins except immunoglobulins (takes in, break down, make new)
• Albumin - carries anything hydrophobic and maintains oncotic pressure
• Glycoprotein transport proteins - transcortin, pre-albumin, sex hormone, transferrin, lipoproteins (except apoB48)
• Acute phase proteins
• Clotting factors 5, 7, 8, 9, 10, 11, 13, prothrombin, anti-thrombin, protein C, protein S, fibrinogen

Question 9

Ammonia Handling

Answer 9

• Alanine (from skeletal muscle) taken up by liver then transfer amine group…
• Alanine + alpha-KG –> glutamate + pyruvate (via ALT)
• Glutamate + oxaloacetate –> aspartate + alpha-KG (via AST)
  
  • Both require Vit B6
• Aspartate then enters urea cycle…
  
  • Urea has 2 amine groups (1 from aspartate, 1 from free ammonia in blood)
  • Liver is only organ w/ arginase (final enzyme in urea cycle)
• Free ammonia = toxic to brain

Question 10

Fat Metabolism

Answer 10

• Regulates metabolism of acetyl CoA (make FAs, chol, bile salts/acids, enter TCA cycle, etc)
• Packages and secretes TGs and cholesterol
• Fat retention

Question 11

Primary v Secondary Bile Salts

Answer 11

• Primary bile salts made exclusively in liver from cholesterol
  - Cholic acid, chenodeoxycholic acid
• Secondary bile salts - formed when bacteria in gut work on primary bile salts
  - Deoxycholic acid, lithocholic acid

Question 12

Bilirubin

Answer 12

• Bilirubin = waste product of heme breakdown
• Heme (travels on albumin in blood) –> biliverdin (green) –> bilirubin (yellow)
• Bilirubin gets taken up by liver via OATP transporter then conjugated (glucouronide) and sent out by MRP2 transporter

Question 13

Immune Function of Liver + Cell Type

Answer 13

• TOLERANCE
• Kupffer cells (macrophages), NK cells, sinusoidal endothelial cells, B cells, T cells (CD8+> CD4+), dendritic cells in portal triad (mainly tolerant)

Question 14

Pos Acute Phase Reactants (6) v Negative Acute Phase Reactants (3)

Answer 14

• Pos Acute Phase Proteins (up-reg in inflam in response to IL-6)
  
  • CRP
  • Fibrinogen
  • Alpha-1 anti-trypsin
  • Ferritin
  • Ceruloplasmin
  • Alpha-2 macroglobulin
• Neg Acute Phase Proteins (down-reg in inflam in response to IL-6)
  
  • Albumin
  • Transferrin
  • Transthyretin/ pre-albumin

Question 15

What 6 vitamins and minerals are stored in the liver?

Answer 15

• Vit A - in stellate cells
• Vit D
• Vit B12
• Vit K in lipoprotein particles themselves
• Iron
• Copper - uses Wilson’s ATPase