Liver Biochemistry

Question 1

What is the structure of the liver?

Answer 1

4 lobes: right, left, caudate, quadrate

Question 2

What is the blood supply to the liver?

Answer 2

The hepatic portal vein - brings nutrient-rich venous blood from GI tract (75%)
hepatic arteries (25%)

Question 3

What are the cells of the liver? (6)

Answer 3

hepatocytes
endothelial cells
hepatic stellate cells
cholangiocytes
pit cells
kupffer cells

Question 4

What is the function of hepatocytes?

Answer 4

They’re the main cell type in the liver (80%), carry out metabolic liver functions.

CAN REGENERATE

Question 5

What is the function of liver endothelial cells?

Answer 5

Allow exchange b/w liver and blood via pores & fenestrations in their plasma membrane

Question 6

What is the function of hepatic stellate cells?

Answer 6

Are storage site for Vitamin A and other lipids

Question 7

What is the function of cholangiocytes?

Answer 7

They line the bile duct, control bile flow rate and bile pH

Question 8

What is the function of pit cells?

Answer 8

These are NK cells that protect liver from viruses and tumors (lymphocytes)

Question 9

What is the function of Kupffer cells? (4)

Answer 9

• Protect liver from gut-derived microbes
• Remove dead cells
• orchestrate immune response
• secrete cytokines
  Line the sinusoids. Are specialized macrophages w/good endocytic & phagocytic function and lots of lysosomes

Question 10

What are the general functions of the liver? (8

Answer 10

• Carbohydrate metabolism
• Lipid metabolism
• Nucleotide biosynthesis
• Protein and amino acid metabolism
• Removal of nitrogen generated by protein & aa metabolism
• Bilirubin metabolism
• Synthesis of blood proteins
• Deactivates/detoxes/biotransforms metabolites and xenobiotics

Question 11

What specifically does the liver do in carbohydrate metabolism? (6)

Answer 11

Glucostasis (keep blood gluc stable)
Glycogen synthesis
Glycogenolysis
Gluconeogenesis
Makes ketones when starving
Has Glucose-6-phosphatase to release free gluc to blood

Question 12

What does the liver do in lipid metabolism? (3)

Answer 12

Biosynthesizes fats
Degrades fats
Regulates FFA Metabolism (making and breaking)

Question 13

What proteins does the liver synthesize? (7)

Answer 13

Acute phase proteins
 - CRP
 - protease inhibitors
 - alpha-1 antitrypsin
 - alpha-1 antichymotrypsin
albumin
IgG
apoproteins
fibrinogen
prothrombin
clotting factors V, VII, IX, X

Question 14

What ways has the liver adapted to facilitate its function? (3)

Answer 14

circulation
structural
cellular

Question 15

What circulatory adaptations does the liver have to facilitate its function?

Answer 15

It gets blood from enteric circulation and the periphery so it can have first pass for ingested substances

Question 16

What structural adaptations does the liver have to facilitate its function?

Answer 16

• No basement membrane
• No tight junctions b/w hepatocytes and endothelial cells
• gaps b/w endothelial cells
• pores in endothelial membrane
  Basically all this to allow more contact between the liver and blood

Question 17

What cellular adaptations does the liver have to facilitate its function?

Answer 17

Well-developed plasma membrane and ER, lots of lysosomes and metabolic enzymes

Question 18

What are the steps of emulsification? (4)

Answer 18

1. cholic acid (bile acid) ionizes to give bile salt
2. hydrophobic surface of bile salt associates w/TAG, several complexes aggregate to form micelle
3. hydrophobic surface of bile salt faces out, allows micelle to interact w/ pancreatic lipase
4. hydrophobic action of lipase frees FA’s to break into smaller micelle that’s absorbed through intestinal mucosa

Question 19

What are the primary bile acids?

Answer 19

• chenodeoxycholic acid

- cholic acid

Question 20

What are the secondary bile acids?

Answer 20

• deoxycholic acid

- lithocholic acid

Question 21

What is the difference between primary and secondary bile acids?

Answer 21

Primary - synthesized in liver

Secondary - result from bacterial action in colon. Also have no -OH on carbon 7. They inhibit 7 alpha-hydroxylase!

Question 22

What are gallstones?

Answer 22

Supersaturated gallbladder bile with cholesterol crystals

Question 23

What can cause gallstones? (3)

Answer 23

• inefficient bile salt secretion
• inefficient phospholipid secretion
• excess cholesterol secretion

Question 24

What is the treatment for gallstones? (2)

Answer 24

If too big, cholecystectomy
If small enough, can treat with oral ursodeoxycholic acid, a secondary bile acid that reduces cholesterol secretion, increases biliary cholesterol solubility

Question 25

How do cholesterol-lowering drugs work? (4 steps)

Answer 25

1. bind to bile, causing more of it to be excreted 2. bile acid synthesis rate increases by induction of 7alpha-hydroxylase 3. liver cholesterol pool depleted, increased uptake of LDL into liver 4. lowered plasma cholesterol levels!

Question 26

What is one cholesterol-lowering drug?

Answer 26

cholestyramine

Question 27

What are metabolites?

Answer 27

By products of metabolism that your body makes

Question 28

What are xenobiotics?

Answer 28

medicines/substances taken from 'outside'

Question 29

What are the steps of phase 1 reactions of detoxification of xenobiotics?

Answer 29

- Reduction - Oxidation - Hydroxylation - Hydrolysis

Question 30

What is the purpose of the phase one reaction?

Answer 30

To make a more polar primary metabolite

Question 31

What catalyzes the phase 1 reaction?

Answer 31

P450 Enzyme (CYP)

Question 32

What are the steps of the phase 2 reaction?

Answer 32

- Conjugation - Sulfation - Methylation - Glucuronidation

Question 33

What is the purpose of the phase 2 reaction?

Answer 33

The functional groups are conjugated for safe excretion

Question 34

What are cytochrome P450 enzymes?

Answer 34

A superfamily of enzymes that play a key role in the metabolism of multiple hydrophobic compounds

Question 35

What enzyme do CYP enzymes co-localize with?

Answer 35

cytochrome p450 reductase (CYPR)

Question 36

Why is CYPR important?

Answer 36

It is the rate-limiting enzyme

Question 37

Which 3 CYP enzymes are the most important?

Answer 37

CYP1, CYP2, CYP3

Question 38

What are other electron transport systems? (correlation box)

Answer 38

Are in the ER, act as mono-oxidases by utilizing pairs of e- from NADPH to incorporate molecular oxygen into the substrate while reducing a second O2 to water

Question 39

How do Cytochrome P450 and drugs interact? (correlation box)

Answer 39

Certain drugs increase the rate of reactions, some form a complex with CYP that inhibit them: drugs that inhibit CYP = increase drug levels of plasma drugs that stimulate CYP = decrease drug levels in plasma

Question 40

What is an example of a substance that inhibits CYP?

Answer 40

Citrus juices (esp grapefruit juice)

Question 41

What is an example of a substance that stimulates CYP?

Answer 41

St. John's Wort

Question 42

What sort of changes to the liver do you see in cases of liver disease?

Answer 42

- Normally-leaky basement membrane replaced by dense membrane w/lots of fibrillar collagen - fenestrations in plasma membrane & space b/w endothelial junctions lost - Hepatic vascular channels get stiffer, increasing resistance and intra-sinusoidal fluid pressure (portal HTN) Basically all the normal junk is donked (free exchange of material impaired)

Question 43

What are liver function tests? (9)

Answer 43

- Albumin - Transaminases (ALT/AST) - Alkaline phosphatase - prothrombin time - bilirubin (conj/unconj) - urea - glucose - TAG - cholesterol

Question 44

Which tests are the best indicators of liver damage?

Answer 44

ALT/AST (ALT more sensitive), they increase in liver disease

Question 45

Where are ALT/AST found?

Answer 45

Both found in mitochondria, but ALT also found in cytosol

Question 46

What are the steps of bile acid synthesis?

Answer 46

1. conversion of cholesterol to 7 alpha-hydroxycholesterol by 7 alpha-hydroxylase (committed step) 2. reduction, hydroxylation, conversion of hydroxyls to alpha becomes 3 alpha, 7alpha-diol 3. diverge now - an oxidation of a side chain leads to 3 alpha, 7 alpha, 12, alpha-triol to CHOLIC ACID or conversion of 3 alpha, 7 alpha-diol to CHENODEOXYCHOLIC ACID 4. cholic acid converted to cholyl coA, which is converted to taurocholic acid 5. cholyl coA becomes glycocholic acid

Question 47

Which bile acid is most effective?

Answer 47

Taurocholic acid, because the pKa is lower meaning it is more ionizing (better detergent)