Liver Biochemistry

Question 1

Liver endothelial cells function

Answer 1

Allow for exchange of material between the liver and blood through fenestrations in the PM.

Question 2

Kupffer cells function

Answer 2

Macrophages that protect the liver.

High degree of lysosomes.

Question 3

Hepatic stellate cells function

Answer 3

Serve as a storage site for vitamin A and other lipids.

Question 4

Pit cells function

Answer 4

NK cells of the liver.

Question 5

Cholangiocytes function

Answer 5

Line bile duct. Control bile flow rate and bile pH.

Question 6

Describe the liver’s unique cicrculation

Answer 6

It gets blood from enteric circulataion (portal v.) and from periphery (hepatic a.).
Low portal BP.

Question 7

What allows the liver to have increased access to the blood?

Answer 7

No BM and no tight junctions between hepatocytes and endothelial cells.

Question 8

How many CoAs (2C) make 1 IPP (5C)?

Answer 8

3

Question 9

IPP can go on to make (3):

Answer 9

Steroids
Lipid-soluble vitamins
Prenyl groups (ubiquinone)

Question 10

How can we generate acetyl CoA? (3)

How is it transported into the cytoplasm?

Answer 10

Decarboxylation of pyruvate.
Beta oxidation of FAs.
Breakdown of AAs.

Citrate shuttle.

Question 11

___ units of IPP form a tetracyclic (4-ring) sterane ring

Answer 11

6 units

Question 12

What is the molecular weight of an allicyclic compound:
How many carbons?
Where is the -OH group?

Answer 12

386 g/mol
27 C
-OH at C3

Question 13

Where can cholesterol be found? (4)

Answer 13

PMs
Bile acids/salts
Vit D
Steroid Hs

Question 14

Recommended daily intake of cholesterol:
Daily production of cholesterol:
Daily excretion of cholesterol:

Answer 14

< 300 mg
0.75-1.0 g
5% excreted, 95% reabsorbed

Question 15

How is biosynthesis of cholesterol related to dietary intake?

Answer 15

Inversely proportional

Question 16

How many acetyl CoA, ATP, NADPH and O2 to create 1 cholesterol?

Answer 16

Acetyl CoA - 18
ATP - 18
NADPH - 16
O2 - 4

Question 17

Phase 1 of cholesterol synthesis:

Answer 17

Acetyl CoA —> (acetyl CoA acetyltransferase) acetoacetyl CoA —> (HMG synthase) HMG CoA —> (HMG CoA reductase) mevalonate —> IPP

Question 18

What is the RLS of cholesterol synthesis?

Answer 18

HMG CoA reductase

Question 19

Phase II of cholesterol synthesis (no enzymes)

Answer 19

6 IPP —> Squalene —> Lanosterol —> Cholesterol

Question 20

What is a concern for someone on long-term statin use?

Answer 20

Statin-mediated myopathy due to depletion of muscle levels of ubiquinone (CoQ 10).

Question 21

Where is the HMG CoA reductase enzyme located and what’s unique about it?

Answer 21

On the ER and has an 8-pass transmembrane component.

Question 22

What sort of inhibitor is a statin against HMG CoA reductase?

Answer 22

Competitive inhibitor

Question 23

What is the Ki for statins?

Answer 23

5-45 nM

Question 24

What is a direct inhibitor of cholesterol synthesis (HMG CoA reductase)?

Answer 24

FFAs
Bile acids
Oxysterols

Question 25

When is HMG CoA reductase active: Phospho or dephosphorylated?

Answer 25

Active in dephosphorylated form.

Question 26

Transcriptional Control of cholesterol synthesis

Answer 26

Binding of TFs to promoter on HMG CoA reductase gene increases mRNA levels.

Question 27

Mechanism of transcriptional control of cholesterol

Answer 27

SREBP-SCAP is usually bound to the ER membrane (to INSIG) when cholesterol is high. When cholesterol is low, it dissociates and goes to golgi where a part of SREBP is cleaved and enters the nucleus to act as a transcription factor to increase HMGR promoter.

Question 28

Antimycotics

Answer 28

Inhibit formation of ergosterol (required for PM of fungal cells). An anti fungal drug.

Question 29

Antiestrogens

Answer 29

Prevents conversion of desmosterol to cholesterol.

Question 30

Epileptogenic drugs

Answer 30

Inhibit conversion of squalene to lanosterol and impairs cholesterol trafficking.

Question 31

What can antipsychotic drugs induce?

Answer 31

Dyslipidemia

Question 32

How is cholesterol eliminated?

Answer 32

No enzyme can degrade the sterane ring of cholesterol. | Cholesterol can be converted to bile acids or secreted in feces.

Question 33

What does it mean when we say that bile acids/salts are strong detergents?

Answer 33

They help to form micelles which increase SA of lipids increasing their exposure to lipases.

Question 34

What enzyme is responsible for producing chenodeoxycholic acid and colic acid from cholesterol?

Answer 34

7a-hydroxycholesterol

Question 35

Conjugation of bile acids

Answer 35

Chalice ACOI —> cholyl CoA —> taurocholic acid (add taurine) or glycocholic acid (add glycine)

Question 36

At what pKa is best for the detergent effect (high or low)?

Answer 36

Low pKa

Question 37

4 primary conjugated bile acids

Answer 37

Glycocholic acid Taurocholic acid Glycochenodeoxycholic acid Taurochenodeoxycholic acid

Question 38

Secondary bile acids (2)

Answer 38

``` Deoxycholic (from colic acid) Lithocholic acid (from chenodeoxycholic acid) ```

Question 39

Cholestryamine

Answer 39

A resin that causes a large increase in excretion of bile acids.

Question 40

Effect of 7a-hydroxylase on bile acid synthesis

Answer 40

Increased by 7a-hydroxylase

Question 41

Overall, what is the effect of bile acid-binding resins on cholesterol?

Answer 41

It lowers plasma cholesterol levels and depletes liver cholesterol pool.

Question 42

What is in a gallstone?

Answer 42

Bile supersaturated w/ cholesterol.

Question 43

What can chronic disturbances in bile salt metabolism lead to?

Answer 43

Malabsorption (steatorrhea - fat in feces), deficiency of fat soluble vitamins.

Question 44

What is given to reduce cholesterol secretion into bile?

Answer 44

Ursodeoxycholic acid

Question 45

Phase I and phase II of detox in the liver

Answer 45

Phase I: increase polarity (reduction, oxidation, hydroxylation, hydrolysis) Phase II: conjugation of functional groups (conjugation, sulfation, methylation, glucuronidation)

Question 46

Inhibiting CYP 450 does what to drug concentrations in plasma?

Answer 46

Increases drug conc.