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Hannah GI 2 > Liver biochem > Flashcards

Liver biochem Flashcards

1
Q

Oxygen rich blood flows into the liver through the ____ and nutrient rich blood from the bowel flows into the liver through the _____

A
  1. hepatic artery

2. portal vein

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2
Q

How tightly packed are endothelial cells lining the sinusoids of a liver lobule

A

endothelial cells have gaps and are loosely packed so that nutrients and oxygen can be exchanged through pores and fenestrations in the plasma membrane with the hepatocytes as blood passes through the sinusoid
**also there is no basement membrane to allow more contact

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3
Q

which liver cell type makes up 80% of the liver cells and carries out most of the metabolic functions of the liver and is capable of regeneration

A

hepatocytes

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4
Q

what are kupffer cells

A

macrophages in the lining of the sinusoid that protect the liver from gut microbes, removed damaged RBCs, secrete cytokines, and have immune function.
-well developed phagocytic and endocytic function with lots of lysosomes present

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5
Q

what is the function of hepatic stellate cells in the liver lobule

A

storage site for vitamin A and other lipids. responsible for the sponginess texture of the liver.

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6
Q

what is the function of pit cells in the liver lobule

A

(lymphocytes)

- NK cells that protect the liver against viruses and tumor cells

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7
Q

what is the function of cholangiocytes in the liver lobule

A

they line bile ducts and control bile flow rate and bile pH

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8
Q

what are the functions of the liver

A
  • primary receiving, distributing, and recycling center
    1. carbohydrate metabolism
    2. lipid metabolism
    3. nucleotide biosynthesis / blood protein biosynthesis
    4. protein and amino acid metabolism
    5. urea cycle
    6. bilirubin metabolism
    7. waste management and detoxification
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9
Q

what is one of the most important aspects of the livers function in relation to glucose metabolism

A

GLUCOSTASIS (maintains glucose levels under fed, fasting, and starvation state)
*also gluconeogensis (making glucose) is a function only in the liver

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10
Q

T/F

the liver is responsible for clottings factors and making albumin

A

TRUE

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11
Q

describe the unique circulation of the liver

A
  • liver receives blood from the enteric system (via hepatic portal vein) and the periphery (via hepatic artery)
  • there is low portal blood pressure in order to maximize the blood/nutrient exchange with hepatocytes
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12
Q

3 acetyl CoA’s come together to form ____. this is an important molecule because ?

A
  • 3 acetyl Co A = 1 IPP (isopentenyl pyrophospahate)
  • IPP is a 5 C compound that is the building block of all isoprenoids (cholesterol, steriods, lipid soluble vitamins, hormones, UBIQUINONE)
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13
Q

what are 3 sources of acetyl coA generated in the mirochondria ? how does it get to the cytoplasm

A
  1. oxidative decarboxylation of pyruvate
  2. beta-ox of fatty acids
  3. breakdown of amino acids
    * gets to cytoplasms via citrate shuttle
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14
Q

what does 6 IPP’s combine to form

A
  1. sterane ring

4-ring structure that is the backbone of most steroids, like cholesterol

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15
Q

what are important structural features of cholesterol

A
  1. allicyclic compound (aliphatic and cyclic)
  2. has 27 carbons
  3. has one hydroxyl (-OH) group on C 3
    * made of sterane ring
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16
Q

what is the most abundant sterol in the body? and it is a precursor to what important compounds?

A

cholesterol

  1. bile acids/salts
  2. vitamin D
  3. steroid hormones
    * only make about 1 g a day
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17
Q

T/F

biosynthesis of cholesterol is inversely proportional to dietary intake

A

TRUE

the more you ingest the less your body makes, and vice versa

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18
Q

what is the molecular equation for the formation of cholesterol

A

18 acetyl co A + 18 ATP + 16 NADPH + 16 H + 4O2 –> cholesterol + 16 NADP + 18 ADP + 18 Pi.

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19
Q

what are the 2 phases of cholesterol synthesis

A
  • phase 1: generation of IPP from acetyl CoA

- phase 2: generation of cholesterol from IPP

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20
Q

describe the Phase 1 pathway of cholesterol synthesis and label the RLS with its stimulators and inhibitors

A

**generation of IPP

acetyl CoA–>acetoacetyl coA– [HMG CoA synthetase]—-> HMG CoA –[HMG CoA reductase] –>mevalonate——–>IPP

**HMG CoA reductase is the RLS
(+ insulin, and thryoxine)
(- glucagon, sterols, high AMP, statins, Vit E)

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21
Q

what is the target of statins in the cholesterol synthesis pathway

A

HMG CoA reductase in phase 1
-simvastatin binds to the active site of HMG CoA reductase therefore it is a competitive inhibitor ( very strong)

  • used to lower cholesterol
  • *long term statin use disrupts ubiquinone and causes problems (myopathy), so think about supplementing ubiquinone
22
Q

describe the Phase 2 pathway of cholesterol synthesis,

A

**generation of cholesterol from IPP

6IPP–>squalene–>Lanosterol–>cholesterol

23
Q

what is Km for HMG coA? what is the Ki for statins ?

A 
Km = 4 uM
Ki = 5 - 45 nM
24
Q

how does statin induce its hypocholesterolemic affect? what is a side effect of long term statin use?

A
  1. increases SREBP maturation which leads to increased transcription of LDL receptors which endocytose cholesterol therefore causing a depletion of cholesterol
    * myotoxic side effect (statin mediated myopathy) bc depletion of ubiquinone (CoQ10) in muscles
25
Q

what inhibitor of cholesterol synthesis will actually increase CoQ10

A

squalene synthesis inhibitors (squalestatins)

26
Q

T/F

cholesterol is packages into VLDL’s in the liver and released into blood

A

true

27
Q

in relation to covalent modification: which form is HMG CoA reductase active and inactive

A

inactive: phospho form
active: dephospho form

28
Q

describe the transcriptional control of HMG CoA Reductase

A
  • **binding of transcriptional factors to promoter (SRE) on HMG CoA reductase gene will increase its mRNA levels
  • SREBP needs SCAP to activate it
  • in presence of cholesterol the SREBP-SCAP complex stays in the ER by binding to INSIG and transcription is low
  • low cholesterol causes SREBP-SCAP release to golgi where SREBP matures and then goes to nucleus to bind to SRE on promotor and promote transcription of HMG CoA reductase which up regulates cholesterol biosynthesis
  • *also up regulates LDL receptor transcription which will act to remove cholesterol and lower its levels
29
Q

what inhibits the RLS of bile acid formation, and what is the enzyme it inhibits

A

Ketoconazole inhibits 7-alpha hydroxylase the RLS in bile acid formation

30
Q

which drugs inhibit the conversion of squalene to lanosterol

A

epileptogenic drugs

31
Q

which drug inhibits lanosterol conversion to cholesterol

A
  • antimycotics like Azoles inhibit Lanosterol forming cholesterol
  • azole is an anti fungal drug that is suppose to inhibit ergosterol production for stablization of fungal plasma membrane but long term use will inhibit mammalian production of cholesterol by blocking conversion of lanosterol to cholesterol
32
Q

what enzymes can degrade the sterane ring of cholesterol ?

A

NONEEEEE

33
Q

function of bile acids/ salts

A
  1. fat digestion and absorption

2. prevention of cholesterol precipitation and its elimination

34
Q

what structural component of bile allows it to aid in fat digestion

A
  • strong detergent

- amphipathic nature allows micelle formation which increase the surface area of lipids thus exposing them to lipases

35
Q

where is bile made and stored

A

bile is made in the liver from cholesterol and released into bile canaliculi to then be stored and concentrated in the gallbladder. from there it is released into the duodenum in response to food

36
Q

describe the synthesis pathway of bile acids from cholesterol

A

cholesterol –[ 7-alpha hydroxylase] –> 7-alpha hydroxycholesterol–> chenodeoxycholic acid or cholic acid (bile acids)
**7- a hydoxylase is the RLS and it is inhibited by bile acids

37
Q

describe the conjugation pathway of bile acids and importance of conjugated bile acids

A
  1. cholic acid —> cholyl coA (pKa 6)
  2. splits into taurine and glycine
  3. makes taurocholic acid (pKa 2 ) and glycocholic acid (pKa 4)
    * *conjugation is used to lower the pKa of the bile acids so they have a better detergent effect due to more ionization of the molecule
38
Q

what id the difference between bile acids and bile salts

A

bile acids = COOH form
bile salts = COO- form
**bile salt is a better detergent bc increase in ionized components

39
Q

what are your 2 primary (unconjugated) bile acids made in the liver

A

cholic acid (3 OH) and chenodeoxycholic acid (2 OH)

40
Q

what is a primary bile acid vs a secondary bile salt

A

primary: made in liver and used in duodenum to emulsify dietary fat (will be conjugated before leaving liver)
secondary: dehydroxylated primary bile acids. dehydroxylated and deconjugated by bacteria in GI tract, which are then absorbed by the ileum and either excreted (5%) or recycled back to liver (95%)

41
Q

what are the 2 main secondary bile acids

A
  1. deoxycholic acid (from cholic acid)

2. lithocholic acid ( from chenodeoxycholic acid)

42
Q

describe the mechanism of the cholesterol lowering drug using bile acid-binding resins

A
  1. bile acid binding resins (like cholestyramine) increase bile acid excretion
  2. low bile acids stimulates 7-alpha hydroxylase and increases rate of bile acid synthesis
  3. subsequent depletion of liver cholesterol
  4. increase in LDL receptor uptake of cholesterol which also decreases cholesterol levels
43
Q

what are gallstones

A

crystals made of bile supersaturated with cholesterol

44
Q

what is cholethiasis

A

insufficient secretion of bile salts or phospholipids into gallbladder or excess cholesterol secretion into bile

  • causes gallstone formation
  • chronic disturbance in bile salt metabolism causes steatorrhea and deficiency of fat soluble vitamins
  • secondary bile acids can be used orally to reduce cholesterol secretion into bile and dissolve small/medium sized stones
45
Q

the liver is primary site for conversion/degradation of metabolites and xenobiotics. what is the difference between the two?

A

metabolites: compounds made in the body
xenobiotics: compounds ingested from outside with no nutritional value and/or potentially toxic (drugs, food additives, etc.)

46
Q

describe the inactivation and detoxification of xenobiotics in the liver

A
  • phase 1: increase polarity (reduction, oxidation, hydrolysis, etc.)
  • phase 2: functional groups are conjugated for safe excretion (conjugation, sulfation, methylation, etc)
  • catalyzed by Cytochrome P450 (CYP enzyme)
47
Q

importance of Cytochrome P450 enzymes

A
  • superfamily of proteins containing heme
  • with cytochrome P450 reductase (RLS) it plays a key role in metabolizing hydrophobic compounds to make them more polar for excretion
  • inducible by their substrate
  • CYP 1/2/3 = responsible for drug metabolism
48
Q

agents that activate CYP will ___ plasma drug levels, and agents that inhibit CYP will ___ plasma drugs levels

A

-activating agents will decrease drug levels
(St. Johns wort, rifampicin)

-inhibting agents will increase drug levels
(citrus juice)

49
Q

what is the detrimental effect of chronic liver disease (i.e. hepatitis)

A

formation of basement membrane with thick collagen closing off the easy exchange of nutrients/blood to hepatocytes. increase in resistance causes portal hypertension and therefore eventual cirrhosis of the liver (cirrhosis = liver fibrosis)

50
Q

what does a marked increase in ALT and AST transamines mean in the assessment of liver function

A

liver damage

Hannah GI 2 (11 decks)

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