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GI Final > Liver Biochem > Flashcards

Liver Biochem Flashcards

1
Q

Liver Circulation

A

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

Flow out: 100% by IVC

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2
Q

Hepatocytes

A

Metabolic functions of liver (can regenerate)

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3
Q

Endothelial cells

A

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

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4
Q

Kupffer cells

A
  • Present in lining of sinusoids

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

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5
Q

Hepatic stellate cells

A

Storage of lipids (Vitamin A)

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6
Q

Pit cells

A

NK cells (lymphocytes)

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7
Q

Cholangiocytes

A

Line bile ducts, control bile flow rate and bile pH

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8
Q

Isoprenoids

A

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

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9
Q

Sterane ring structure

A

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

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10
Q

Structure of cholesterol (OH group?)

A
  • Allicyclic compound of 4 fused rings

* Hydroxyl group at C3

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11
Q

Cholesterol

A
  • Precursor to bile acids/salts

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

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12
Q

Cholesterol synthesis (Phase 1)

A
  • 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
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13
Q

Significance of HMG CoA reductase

A
  • Target of statin drugs
  • 8 pass transmembrane protein
  • Rate limiting step of cholesterol synthesis
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14
Q

Cholesterol synthesis (Phase 2)

A

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

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15
Q

Statins

A
  • 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
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16
Q

Statin side effects

A
  • Myotoxic

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

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17
Q

Regulation of Cholesterol Synthesis

A
  • 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
18
Q

Mechanism of transcriptional control

A
  • 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
19
Q

Antimycotics (cholesterol synthesis inhibitor)

A

Inhibits 7a hydroxylase

20
Q

Antiestrogens (cholesterol synthesis inhibitor)

A

Prevents conversion of desmosterol to cholesterol

21
Q

Epileptogenic drugs (cholesterol synthesis inhibitor)

A

Inhibits conversion of squalene to lanosterol (impairs cholesterol trafficking)

22
Q

Antipsychotic drugs (cholesterol synthesis inhibitor)

A

Induces dyslipidemia

23
Q

What enzyme degrades sterane ring of cholesterol?

A

NO ENZYME

24
Q

What makes bile acids/salts strong detergents?

A
  • Amphipathic (polar/nonpolar regions)

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

25
Q

Emulsification by bile salts

A
  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
26
Q

Effect of pKa on emulsification ability

A

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

27
Q

Primary Conjugated bile acids of Cholic acid

A
  • Glycocholic acid (via glycine)

- Taurocholic acid (via taurine)

28
Q

Primary Conjugated bile acids of Chenodeoxycholic acid

A
  • Taurochenodeoxycholic acid (via taurine)

- Glycochenodeoxycholic acid (via glycine)

29
Q

Secondary Bile acid derivatives

A
  • Deoxycholic acid (cholic acid)

- Lithocholic acid (chenodeoxycholic acid)

30
Q

Bile acid-binding resins

A
  • 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)
31
Q

Gallstones

A
  • 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
32
Q

Metabolites

A

Compounds made in body (intermediates or end products)

33
Q

Xenobiotics

A

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

34
Q

Phase I Reactions

A
  • Reduction
  • Oxidation
  • Hydroxylation
  • Hydrolysis
  • Polarity increased
35
Q

Phase II Reactions

A
  • Conjugation
  • Sulfation
  • Methylation
  • Glucuronidation
  • Fxnal groups safe for excretion
36
Q

Cytochrome P450 Enzyme

A
  • Superfamily of proteins w/ heme
  • Metabolism of multiple hydrophobic compinds
  • Inducible by their substrate
  • CYP 1, 2, 3 responsible for drug metabolism
37
Q

CYPs and Drug interactions

A
  • Detox pharmacological agents (statins included)
  • Agents inhibiting CYP increase drug plasma levels
  • Agents stimulate CYP decreases drug plasma levels
38
Q

Known CYP inhibitors

A

Citrus/grapefruit juice (increases plasma statin levels)

39
Q

Known CYP inducers

A

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

40
Q

Key for many liver diseases

A
  • Impairment of free exchange of material between hepatocytes and blood
41
Q

General scheme for xenobiotic detox

A

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

GI Final (13 decks)

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