Liver Biochemistry

Question 1

• Structure of the liver

Answer 1

• Largest solid organ in the body
• 1500 g
• 2 lobes divided into multiple lobes and sinusoids
• Blood supply: 75% from portal vein, 25% from hepatic artery
• Biliary components of bile duct and gallbladder

Question 2

• Liver cell types and their functions

Answer 2

• Hepatocytes:
  
  • ​Metabolic functions of liver
  • Capable of regeneration
  • Ribosomes, ER, enzymes
• Endothelial Cells:
  
  • ​Exchange of material from liver to blood and vice versa
  • Fenestrations in plasma membrane allows for exchange
• Kupffer cells
  
  • ​Macrophages of liver
  • Protect from microbes, remove damaged RBCs, secrete cytokines
  • Lots of lysosomes
• Hepatic stellate cells
  
  • ​Storage site for Vitamin A and other lipids
• Pit Cells
  
  • ​NK cells
  • Protect livert against viruses and tumor cells
• Cholangiocytes
  
  • ​Line bile duct
  • Control bile flow rate and pH

Question 3

• Functions of the liver in lipid and carbohydrate metabolism

Answer 3

• Carbohydrate metabolism
  
  • Glycolysis
  • Glycogenolysis and Glycogenesis
  • Gluconeogenesis (exclusive to liver)
• Lipid metabolism
  
  • Biosynthesis of TAGs, phospholipids, steroids (Steroids, cholesterol, bile acids and bile salts), lipoproteins
  • Degradation of TAG and plasma lipoproteins
  • Regulation of FFA metabolism
  • Breakdown of FFA via beta oxidation

Question 4

• Waste management functions of liver

Answer 4

• Inactivation
• Detoxification
• BIotransformation of metabolites and xenobiotics

Question 5

• Structural adaptations of the liver

Answer 5

• Unique circulation:
  
  • Receives blood from enteric circulation and from periphery
  • Low portal blood pressure (3-5 mm Hg)
• Structural features:
  
  • Fenestrations in endothelial membrane allow for greater access and increased contact between liver and blood
  • Lack of basement membrane and absence of tight junctions between hepatocytes and endothelial cells

Question 6

• Three acetyl coA molecules combine to generate one _ (5 carbon compound)
• This molecule serves as a building block for synthesis of isoprenoids
• Isoprenoids include:
  
  • ​Steroids
  • Lipid Soluble Vitamins (A,D,E,K)
  • Prenyl groups that attach to plasma membrane

Answer 6

• Isopentenyl phosphate (IPP)

Question 7

• Sources of acetyl coA

Answer 7

• Generated in mitochondria from:
  
  • Oxidative decarboxylation of pyruvate
  • Beta oxidation of fatty acids
  • Breakdown of amino acids
• Transported into cytoplasm via citrate shuttle

Question 8

• Six units of IPP combine to form _ which serves as the backbone for most steroids

Answer 8

Tetracyclic stearene ring

Question 9

• Structural features of cholesterol

Answer 9

• Allicyclic compound-made of stearene ring
• Has OH on C3
• Cyclic part consists of stearene ring
• Alliphilic part consists of hydrocarbon chain

Question 10

• Functions of cholesterol
• How much is made per day
• What is unique about the biosynthesis of cholesterol

Answer 10

• Component of plasma membranes
• Precursor for:
  
  • Bile acids and bile salts
  • Vitamin D
  • Steroid hormones
• Daily production: 0.7-1.0 g (most in liver)
• Biosynthesis is inversely proportional to dietary intake

Question 11

• What is phase I of cholesterol synthesis?
• What is phase II of cholesterol synthesis ?
• What is the rate limiting step in cholesterol synthesis and which phase does it occur in?

Answer 11

• Converting Acetyl CoA into IPP
• Making IPP into cholesterol
• Conversion of HMG CoA to Mevalonate via HMG CoA reductase

Question 12

• Antifungal drugs/Azoles target which part of cholesterol synthesis?

Answer 12

• Last step of cholesterol synthesis converting lanosterol to cholesterol

Question 13

• Key features of HMG CoA reductase

Answer 13

• 8 pass TM ER protein with catalytic domain
• Target of statin drugs that inhibit cholesterol synthesis

Question 14

• Statins

Answer 14

• Competitive inhibitors of HMG CoA reductase
• Ki is ten times stronger than Km for HMG CoA Reductase
• Also increases SREBP maturation and transcription of LDL receptor and enhanced clearance of cholesterol via LDL receptor mediated endocytosis
• Mytotoxic side effects-statin-mediated myopathy caused by depletion of muscle levels of ubiquinone (coQ10) and resultant impairment of mitochondrial function

Question 15

• Fate of cholesterol

Answer 15

• Packaged into VLDL and transported into the blood
• Goes to various areas:
• In liver:
  
  • Used to synthesize bile acids

Question 16

• Regulation of cholesterol synthesis

Answer 16

• via regulation of HMG CoA Reductase
  
  • Direct inhibition
    
    • Free fatty acids, bile acids and oxysterols and statins
  • Covalent modification
    
    • ​Inactive in phosphorylated form acitve in dephosphorylated form
  • Transcriptional control
    
    • ​Binding of transcriptional factors to promotor on HMG CoA reductase gene increases its mRNA levels
  • Translational control
    
    • ​Protein synthesis level
    • Reduced by gamma-tocrotrienol (Vitamin E family) and oxylanosterols
  • Post-Translational Control
    
    • ​Protein turnover/degradation
    • Enhanced by sterols, oxysterols and gamma tocotrienol

Question 17

• Mechanism of transcriptional control

Answer 17

• Inactive form of SREBP interacts with SREBP Cleavage protein (SCAP)
• In presence of cholesterol, SREBP-SCAP complex is retained in the ER d/t binding of INSIG
• Transcription of HMG CoA reductase is low in this case

Low sterol:

• Promotes release of SREBP-SCAP from ER to Golgi
• SREBP undergoes proteolysis to release mature form that dimerizes and translocates to the nucleus
• Mature SREBP binds SRE and promotes transcription of HMG CoA reductase and other enzymes in the cholesterol synthesis pathway

Question 18

• Late stage inhibitors of cholesterol synthesis

Answer 18

• Antimycotics-inhibit formation of ergosterol (needed to maintin the plasma membrane of fungal cells)

At high concentrations, inhibit enzyme that converts lanosterol to cholesterol