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GI Final > Liver Biochemistry > Flashcards

Liver Biochemistry Flashcards

1
Q

What is the largest solid organ in the body?

A

liver

3% body weight

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2
Q

How many lobes are there?

A

2 main lobes which are subdivided into multiple lobes and sinusoids

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3
Q

What is the liver covered by?

A

capsule of CT

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4
Q

What is the blood supply of the liver

A

75% portal vein

25% hepatic artery

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5
Q

What is the biliary components made of?

A

bile ducts and gall bladder

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6
Q

Describe hepatic circulation

A
  • oxygen rich blood flows into the liver through the hepatic artery (25%)
  • nutrient rich blood coming through the bowel flows into the liver through the portal vein (75%)
  • bile flows out of the liver through the bile duct
  • blood flows out of the liver through 3 hepatic veins into a big vein called the IVC
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7
Q

What can be seen in a cross section of a liver lobe?

A
  • hepatic sinusoid
  • hepatocyte
  • central vein
  • interlobar bile duct
  • interlobar vein
  • interlobar artery
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8
Q

What types of cells are in the liver?

A
  • hepatocytes
  • endothelial cells
  • Kupffer cells
  • hepatic stellate cells
  • pit cells (lymphocytes)
  • cholangiocytes
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9
Q

What are hepatocytes?

A

80% of liver cells, carry out most of the metabolic functions of the liver, capable of regeneration

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10
Q

What do endothelial cells do in the liver?

A

allow exchange of material from liver to blood and vice versa via pores and fenstrations in plasma membrane

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11
Q

What are Kupffer cells?

A
  • present in the lining of the sinusoids
  • are macrophages that protect the liver from gut derived microbes, remove damaged/dead RBCs, orchestrate immune response, secrete cytokines.
  • have well developed endocytic and phagocytic functions, lots of lysosomes present in these cells
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12
Q

What are hepatic stellate cells?

A

serve as storage site for vitamin A and other lipids

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13
Q

What are pit cells?

A

lymphocytes

-NK cells, protect liver against viruses and tumor cells

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14
Q

What are cholangiocytes?

A

line bile ducts

control bile flow rate and bile pH

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15
Q

What are the functions of the liver?

A
  • primary receiving, distribution, and recycling center
  • carbohydrate metabolism
  • liver metabolism
  • neucleotide biosynthesis
  • amino acid metabolism, ammonia, and urea cycle
  • protein and amino acid metabolism
  • synthesis of blood proteins
  • bilirubin metabolism
  • waste management
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16
Q

How does the liver participate in carbohydrate metabolism?

A
  • glycolysis
  • glycogenesis and glycogenolysis
  • gluconeogenesis
  • glucostasis (maintains glucose levels under fed, fasting, and starvation state)
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17
Q

How does the liver participate in lipid metabolism?

A
  • biosynthesis of triacylglycerols (TAGs), phospholipids, steroids (cholesterol, bile acids, and bile salts), lipoproteins (VLDL, LDL, HDL)
  • degredation of TAG and plasma lipoproteins
  • regulation of free fatty acid (FFA) metabolism
  • breakdown of FFA via beta oxydation to release energy
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18
Q

What are the blood proteins the liver synthesizes?

A
  • albumin
  • IgGs
  • apoproteins
  • fibrinogen
  • prothrombin
  • blood coagulation factors V, VII, IX, and X
  • CRP
  • alpha 1 antitrypsin
  • alpha 1 antichymotrypsin (acute phase proteins)
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19
Q

How is the liver involved in waste management?

A

-inactivation, detoxification, and biotransformation of metabolites and xenobiotics

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20
Q

What is a majory role fo the liver?

A

monitoring, synthesizing, recycling, distributing, and modifying metabolites

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21
Q

What does the liver do to useful ingested material and harmful products?

A

useful: retrieved by the liver and converted into a useful form
harmful: converted into a safe product and excreted

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22
Q

Describe the unique circulation of the liver

A
  • liver receives blood from enteric circulation via portal vein and from periphery via hepatic artery
  • low portal blood pressure
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23
Q

Does the liver have basement membrane?

A

NO

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24
Q

Does the liver have tight junctions between hepatocytes and endothelial cells?

A

NO

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25
Q

What is between endothelial cells of the liver?

A

gaps

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26
Q

What is unique about the endothelial cell membrane in the liver?

A

fenstrations

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27
Q

What allows greater access and increased contact between liver and blood?

A
  • lack of basement membrane
  • absence of tight junctions btwn hepatocytes and endothelial cells
  • gaps btwn endothelial cells
  • fenstrations in endothelial cell membrane
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28
Q

How many acetyl CoA are used to generate one isopentenyl pyrophosphate (IPP)?

A

3

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29
Q

IPP serves as a building block for synthesis of all ____

A

isoprenoids

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30
Q

What are examples of isoprenoids?

A

lipid-soluble vitamins, prenyl groups attach proteins to plasma membrane, steroids

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31
Q

How many carbons in isoprene?

A

5

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32
Q

Where is acetyl CoA generated?

A

mitochondria

  • oxidative decarboxylation of pyruvate
  • beta oxidation of fatty acids
  • breakdown of amino acids
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33
Q

How is acetyl CoA transported into cytoplasm?

A

citrate shuttle

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34
Q

What is a sterane ring?

A

six units of IPP form tetracyclic sterane ring

  • backbone of most steroids
  • cholesterol and cholic acids
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35
Q

What is the structure of cholesterol?

A
  • allicyclic compound made of 4 fused rings (sterane)
  • MW of 386 g/mol
  • 27 carbons (sterane ring, side chain, one hydroxyl group at C3)
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36
Q

What is the most abundant sterol?

A

cholesterol

0.05% of body weight

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37
Q

What is cholesterol a component of?

A

plama membranes and precursor of biologically active compounds:

  • bile acids and bile salts
  • vitamin D
  • steroid hormones (progesterone, aldosterone, cortisol, testosterone, estradiol)
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38
Q

What is the recommended daily intake of cholesterol?

A

<300 mg

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39
Q

What is the daily production of cholesterol?

A

0.75-1.0 g (mostly in liver, small intestine, adrenal cortex, ovaries, testes, and skin)

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40
Q

What is the daily excretion of cholesterol?

A

5% excreted, 95% reabsorbed

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41
Q

biosynthesis of cholesterol is inversely proportional to _____

A

dietary intake

42
Q

What is the chemical equation for cholesterol synthesis?

A

18 AcetylCoA + 18 ATP + 16 NADPH + 16H+ + 4O2 –> cholesterol + 16 NADP+ + 18 ADP + 18 Pi

43
Q

What are the steps of phase I of cholesterol synthesis?

A

acetyl CoA –> acetoacetyl CoA -HMG CoA synthase->HMG CoA -HMG CoA reductase, insulin, thyroxine, glucagon, sterols, high AMP, vit E, statin-> mevalonate–>IPP

44
Q

What is the rate limiting enzyme in cholesterol synthesis?

A

HMG CoA reductase

45
Q

What are the steps in phase II of cholesterol synthesis?

A

6 IPP –> squalene –> lanosterol -azoles, KCN, tamoxifen, morpholine, triparanol-> cholesterol

46
Q

What is the target for the regulation of cholesterol synthesis?

A

HMG CoA reductase in the membrane of the ER

47
Q

What inhibits HMG CoA reductase?

A

statins: lovastatin, simvastatin, pravastatin, atorvastin

48
Q

What are statins used for?

A

to reduce cholesterol levels significantly (20-60%), prevent CV disease

49
Q

What are statins?

A

strong competitive inhibitors of HMG CoA reductase (rate limiting reaction in cholesterol biosynthesis)

50
Q

Hypocholesterolemic action also due to increase in SREBP maturation which leads to ____ and subsequent enhanced _____ via LDL receptor mediated ____

A

transcription of LDL receptor; clearance of cholesterol; endocytosis

51
Q

What are myotoxic side effects? What causes this?

A

statin-mediated myopathy caused by depletion of muscle levels of ubiquinone (CoQ 10) and resultant impairment of mitochondrial function. inhibitors of squalene synthase (sequalestatins) increase levels of CoQ10.

52
Q

What is the fate of cholesterol?

A
  • packaged into VLDL and released into blood
  • All tissues: cholesterol incorporated into cellular membranes
  • liver: cholesterol used to synthesize bile acids
  • adrenal glands, ovaries, testes: cholesterol used to synthesize steroid hormones
  • skin: cholesterol used to synthesize vitamin D
53
Q

What is cholesterol synthesis directly inhibited by?

A
  • free fatty acids
  • bile acids
  • oxysterols
  • statins
54
Q

What covalent modification inactivates HMG CoA reductase?

A

phosphate inactivates

55
Q

What conditions inactivate HMG CoA reductase?

A
  • low energy
  • high AMP

activates AMPK, phosphorylates enzyme

56
Q

Does insulin activate or inactivate HMG CoA reductase?

A

activates by dephosphorylation

57
Q

Does thyroxine activate or inactivate HMG CoA reductase?

A

inactivates by preventing dephosphorylation

58
Q

Does glucagon activate or inactivate HMG CoA reductase?

A

inactivates by preventing dephosphorylation

59
Q

Describe the transcriptional control of HMG CoA reductase

A

binding of transcription factors to promoter on the HMG CoA reductase gene increases its mRNA levels

60
Q

Describe translational control of HMG CoA reductase

A

protein synthesis level

-reduced by gamma tocotrienol (member of vitamin E family) and oxylanosterols

61
Q

Describe the post-translational control of HMG CoA reductase

A

protein turnover/degredation

-enhanced by sterols, oxysterols, and gamma tocotrienol

62
Q

What is the family of transcription factors for HMG CoA reductase called?

A

sterol regulatory element binding protiens (SREBP)

63
Q

What is the gene in the promoter for HMG CoA reductase?

A

sterol regulatory element (SRE)

64
Q

What are late stage inhibitors of cholesterol synthesis?

A
  • antimycotics (miconazole, ketoconazole) inhibit formation of ergosterol
  • antiestrogens (triparanol, progesterone, tamoxifen) prevent conversion of desmoterol to cholesterol
  • epileptogenic drug inhibits conversion of squalene to lanosterol and impairs cholesterol trafficking
  • antipsychotic drugs (haloperidol, clozapine) induce dyslipidemia
65
Q

What enzyme can degrade the sterane ring of cholesterol

A

NONE
cholesterol is converted to bile acids and stored in bile
some cholesterol and bile are excreted in feces

66
Q

What is bile made from?

A
  • bile acids
  • bile salts
  • cholesterol
  • phospholipids
  • fatty acids
  • proteins
  • bile pigments
  • inorganic salts
67
Q

What do bile acids and bile salts help in?

A
  • emulsification of fats
  • absorption of fat soluble vitamins
  • digestion and absorption of fats
  • prevention of cholesterol precipitation and its elimination
68
Q

What are bile acids and bile salts synthesized from?

A

hepatic cholesterol

69
Q

Where are bile salts and bile acids made? What is the process?

A
  • made in hepatocytes
  • released into bile canaliculi
  • stored and concentrated in gallbladder
  • released into duodenum in response to food
70
Q

What is the commited step in the synthesis of bile acids?

A

cholesterol –7 alpha hydroxylase –> 7 alhpa hydroxycholesterol

71
Q

What are the steps in the synthesis of bile acids?

A

cholesterol –> 7 alpha hydroxycholesterol –> chenodeoxycholic acid OR cholic acid after oxydation of side chain

72
Q

coagulation of bile acids

A

cholic acid–>cholyl CoA pKa 6 –(Taurine) –> Taurocholic acid pKa 2

cholic acid–>cholyl CoA pKa 6 –(Glycine)–>glycocholic acid pKa4

73
Q

primary bile acids and primary conjugated bile acids

A

chenodeoxycholic acid –glycine–>glycochenodeoxycholic acid

chenodeoxycholic acid –taurine–>taurochenodeoxycholic acid

cholic acid –taurine–>taurocholic acid

cholic acid –glycine–>glycocholic acid

74
Q

What is the protonated form?

A

acid

75
Q

What is the deprotonated form?

A

salt

76
Q

What are primary bile salts used for?

A

in the duodenum to emulsify dietary lipids to aid in their digestion and absorption

77
Q

What do bacteria do to primary bile salts?

A

bacteria deconjugate and dehydroxylate primary bile salts into primary and secondary bile acids, which are absorbed by the ileum and are then

  • excreted in feces (5%)
  • recycled to the liver via enterohepatic circulation (95%)
78
Q

What are examples of secondary bile acids?

A
  • deoxycholic acid derived from cholic acid

- lithocholic acid derived from chenodeoxycholic acid

79
Q

What do non-absorbable bile-acid binding resins such as cholestyramine cause?

A

large increase in excretion of bile acids

80
Q

What increases the rate of bile acid synthesis?

A

induction of 7-alpha hydroxylase

81
Q

What are gallstones?

A

-crystals made up of bile supersaturated with cholesterol

82
Q

What is cholelithiasis?

A

insufficient secretion of bile salts or phospholipids into gall bladder or excess cholesterol secretion into bile

83
Q

Chronic disturbance in bile salt metabolism leads to what?

A

malabsorption syndromes (steatorrhea) and deficiency in fat soluble vitamins

84
Q

What reduces cholesterol secretion into bile?

A

oral administration of Ursodeoxycholic acid (secondary bile acid) dissolves small/medium sized stones

85
Q

What are metabolites?

A

compounds made in the body (intermediates and/or end products of metabolism)

86
Q

What are xenobiotics?

A

compounds ingested from outside (with no nutritional value, potentially toxic)

  • pharmacological agents
  • recreational drugs
  • compounds of food (additives, processing)
87
Q

What are phase I reactions of inactivation of detoxification of xenobiotics?

A

polarity is increased

88
Q

What are phase II reactions of inactivation and detoxification of xenobiotics?

A

functional groups are conjugated for safe excretion

89
Q

What are inactivation and detoxification of xenobiotics catalyzed by?

A

cytochrome P450 (CYP) enzymes

90
Q

What are examples of phase I reactions?

A
  • reductions
  • oxidations
  • hydroxylation
  • hydrolysis
91
Q

What are examples of phase II reactions?

A
  • conjugation
  • sulfation
  • methylation
  • glucuronidation
92
Q

What are cytochrome P450 enzymes?

A
  • superfamily of proteins containing heme
  • colocalize with cytochrome P450 reductase
  • play a key role in metabolism of multiple hydrophobic compounds
  • operate via electron transfer system
  • inducible by their substrate
  • 12 gene families
  • CYP1, CYP2, CYP3 responsible for drug metabolism
93
Q

What is the effect of agents that inhibit CYP?

A

cause increase in drug levels in plasma

94
Q

What is the effect of agents that stimulate CYP?

A

cause decrease in drug levels in plasma

95
Q

What are the toxiic effects of statins?

A
  • myopathy

- rhabdomyolysis

96
Q

What are examples of CYP inhibitors?

A

itraconozole, clarithromycin, cyclosporine, citrus juices, grapefruit juice

97
Q

What are examples of agents that induce CYP?

A

rifampicin, carbamazepine, St. John’s Wort

98
Q

What are some diseases of the liver?

A

-hepatits
-jaundice
-viral hepatitis
-alcohol - induced hepatitis
-drug induced hepatitis
=liver cirrhosis

99
Q

What is a major change of the liver with disease?

A

-normally leaky basement membrane btwn endothelial cells and hepatocytes replaced by high density membrane containing fibrillar collagen
-spaces btwn endothelial cells and fenstrations in plasma membrane lost
-increased stiffness of hepatic vascular channels offers resistance to free flow of blood through liver
-elevated intra-sinusoidal fluid pressure
PORTAL HTN
IMPAIRMENT OF FREE EXCHANGE OF MATERIAL BTWN HEPATOCYTES AND BLOOD

100
Q

What are some tests for assessment of liver function?

A
  • albumin
  • transaminases: ALT and AST
  • alkaline phosphatase
  • lactate dehydrogenase
  • urea BUN
  • ammonia
  • prothrombin time (PT)
  • TAG levels
  • cholesterol levels
  • bilirubin levels
  • serum glucose

GI Final (15 decks)

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