Liver Biochem

Question 1

Liver Circulation

Answer 1

Flow in: 75% by portal v. and 25% by hepatic a.

Flow out: 100% by IVC

Question 2

Hepatocytes

Answer 2

Metabolic functions of liver (can regenerate)

Question 3

Endothelial cells

Answer 3

Exchange of material from liver to blood (vice versa) via pores and fenestrations in plasma membrane

Question 4

Kupffer cells

Answer 4

• Present in lining of sinusoids

- Macrophages that protect liver from microbes, remove dead RBCs, orchestrate immune response

Question 5

Hepatic stellate cells

Answer 5

Storage of lipids (Vitamin A)

Question 6

Pit cells

Answer 6

NK cells (lymphocytes)

Question 7

Cholangiocytes

Answer 7

Line bile ducts, control bile flow rate and bile pH

Question 8

Isoprenoids

Answer 8

3 Acetyl CoA used to generate one IPP (building blocks of steroids and fat-soluble vitamins)

Question 9

Sterane ring structure

Answer 9

6 units of IPP form tetracyclic sterane ring (steroid backbone)

Question 10

Structure of cholesterol (OH group?)

Answer 10

• Allicyclic compound of 4 fused rings

* Hydroxyl group at C3

Question 11

Cholesterol

Answer 11

• Precursor to bile acids/salts

- Biosynthesis inversely proportional to dietary intake (95% reabsorbed)

Question 12

Cholesterol synthesis (Phase 1)

Answer 12

• Acetyl CoA – IPP
  1. Acetyl CoA – Acetoacetyl CoA
  2. Acetoacetyl CoA – HMG CoA (HMG CoA synthase)
  3. HMG CoA – Mevalonate (HMG CoA reductase) (*rate-limiting)
  4. Mevalonate – IPP

Question 13

Significance of HMG CoA reductase

Answer 13

• Target of statin drugs
• 8 pass transmembrane protein
• Rate limiting step of cholesterol synthesis

Question 14

Cholesterol synthesis (Phase 2)

Answer 14

6 IPP – Squalene
Squalene – Lanosterol (inhibited by azoles)
Lanosterol – Cholesterol

Question 15

Statins

Answer 15

• Strong competitive inhibitors of HMG CoA reductase
• 1000x higher affinity for active site than enzyme
• Also increases SREBP maturation – transcription of LDL receptor and enhance clearance of cholesterol via LDL-receptor mediated endocytosis

Question 16

Statin side effects

Answer 16

• Myotoxic

- Myopathy d/t depletion of muscle levels of CoQ10 and resultant mitochondrial impairment

Question 17

Regulation of Cholesterol Synthesis

Answer 17

• Via HMG CoA reductase
• Direct inhibition (via FFAs, bile acids, STATINS)
• Covalent modification (active as dephospho)
• Transcriptional control (binding of TFs to promoter on HMG CoA reductase increases mRNA levels)
• Translational control
• Post-translatonal control

Question 18

Mechanism of transcriptional control

Answer 18

• HMG CoA reductase w/ sterol regulatory element (SRE) in promoter
• SRE binding proteins bind to SRE
• High [cholesterol] retains SREBP in ER membrane
• Low [cholesterol] triggers translocation of SREBP complex to Golgi
• • enzyme is upregulated w/ increased [cholesterol] + biosynthesis of LDL receptor

Question 19

Antimycotics (cholesterol synthesis inhibitor)

Answer 19

Inhibits 7a hydroxylase

Question 20

Antiestrogens (cholesterol synthesis inhibitor)

Answer 20

Prevents conversion of desmosterol to cholesterol

Question 21

Epileptogenic drugs (cholesterol synthesis inhibitor)

Answer 21

Inhibits conversion of squalene to lanosterol (impairs cholesterol trafficking)

Question 22

Antipsychotic drugs (cholesterol synthesis inhibitor)

Answer 22

Induces dyslipidemia

Question 23

What enzyme degrades sterane ring of cholesterol?

Answer 23

NO ENZYME

Question 24

What makes bile acids/salts strong detergents?

Answer 24

• Amphipathic (polar/nonpolar regions)

- Form micelles which increase surface area of lipids to expose them to more lipases

Question 25

Emulsification by bile salts

Answer 25

1. Cholic acid ionizes, giving cognate bile acid 2. Hydrophobic surface of bile salt associates with TAG and several complexes to form micelles 3. Hydrophobic surface faces outward, so micelle can associate with pancreatic lipases 4. Hydrolytic action of lipase frees FAs to much smaller micelle that is absorbed through intestinal mucosa

Question 26

Effect of pKa on emulsification ability

Answer 26

Lower pKA -- more ionized the molecule -- better the detergent effect -- better emulsifier

Question 27

Primary Conjugated bile acids of Cholic acid

Answer 27

- Glycocholic acid (via glycine) | - Taurocholic acid (via taurine)

Question 28

Primary Conjugated bile acids of Chenodeoxycholic acid

Answer 28

- Taurochenodeoxycholic acid (via taurine) | - Glycochenodeoxycholic acid (via glycine)

Question 29

Secondary Bile acid derivatives

Answer 29

- Deoxycholic acid (cholic acid) | - Lithocholic acid (chenodeoxycholic acid)

Question 30

Bile acid-binding resins

Answer 30

- Cholestyramine causes large increase in excretion of bile acids - Bile acid synthesis increased by induction of 7a hydroxylase - Depletion of liver cholesterol pool (lowers plasma cholesterol levels)

Question 31

Gallstones

Answer 31

- Crystals made up of bile supersaturated with cholesterol - D/t insufficient secretion of bile salts/phospholipids into GB or excess cholesterol secretion into bile * Chronic disturbance in bile salt metabolism -- steatorrhea/ deficiency in fat soluble vitamins

Question 32

Metabolites

Answer 32

Compounds made in body (intermediates or end products)

Question 33

Xenobiotics

Answer 33

Compounds ingested from outside (drugs, pharmacological agents, food additives)

Question 34

Phase I Reactions

Answer 34

- Reduction - Oxidation - Hydroxylation - Hydrolysis * Polarity increased

Question 35

Phase II Reactions

Answer 35

- Conjugation - Sulfation - Methylation - Glucuronidation * Fxnal groups safe for excretion

Question 36

Cytochrome P450 Enzyme

Answer 36

- Superfamily of proteins w/ heme - Metabolism of multiple hydrophobic compinds - Inducible by their substrate - CYP 1, 2, 3 responsible for drug metabolism

Question 37

CYPs and Drug interactions

Answer 37

- Detox pharmacological agents (statins included) - Agents inhibiting CYP increase drug plasma levels - Agents stimulate CYP decreases drug plasma levels

Question 38

Known CYP inhibitors

Answer 38

Citrus/grapefruit juice (increases plasma statin levels)

Question 39

Known CYP inducers

Answer 39

St. John's Wort (decreases plasma statin levels)

Question 40

Key for many liver diseases

Answer 40

- Impairment of free exchange of material between hepatocytes and blood

Question 41

General scheme for xenobiotic detox

Answer 41

Xenobiotic waste -- Phase 1 reaction -- primary metabolite (more polar) -- Phase 2 reaction -- secondary metabolite (suitable for excretion)