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GI Week 6 > Liver Biochemistry > Flashcards

Liver Biochemistry Flashcards

1
Q

True or false; hepatocytes specialize to perform only a few of the liver functions.

A

mostly false - there is some degree of specialization, but in general hepatocytes can do all 10 of the liver biochemical functions

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2
Q

What are the macorpahges of the liver?

A

kupffer cells

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3
Q

What are the NK cells of the liver?

A

pit cells - protect against viruses and tumor cells

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4
Q

What cells are the source of the inflammatory mediators that contribute to liver linjury? What cells actually lay down the collagen in fibrosis?

A

kupffer cells release cytokiens which activate the stellate cells to lay down collagen

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5
Q

What does the liver do with excess proteins and carbs in the fed state?

A

converts them to storage - makes blood proteins, glucose and VLDL

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6
Q

What does the liver do to xenobiotics and metabolites?

A

detoxifies them - processes them for removal

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7
Q

What is phase 1 in the detoxification process?

A

adding a hydroxyl group to the substrate

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8
Q

What is phase 2 in the detoxificaiton process?

A

conjugating that hydroxyl group with a sulfate, methyl group, glutathione, glucuronate

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9
Q

What essentially is the goal of both phase 1 and 2 detoxification?

A

make the substrate more soluble so it can be excreted

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10
Q

Name a hugely important family of phase 1 metabolizing enzymes.

A

cytochrome p450 enzymes

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11
Q

What cofactors are required for cytocrome p450?

A

NADPH, FAD, O2 and heme

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12
Q

Expression of cytpchrome p450 will be ___ by their substrates

A

induced

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13
Q

What big class of drug is metabolized by the cype 3A4 group of p450s?

A

statins

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14
Q

If you give two drugs that are metabolized by cyp 3A4, what happens if one has a higher affinity for it?

A

the cype 3A4 will just deal with that one and the other will build up - potantial toxicity

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15
Q

What effect does grapefruit juice have on cype 3A4?

A

inhibits it!

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16
Q

What occupation exposure from plastic industries can promote angiosarcoma (liver cancer)?

A

vinyl chloride

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17
Q

How does vinyl chloride cause angiosarcoma in relation to the p450s?

A

Its acted on by Cype 2E1 to form an epoxide which is toxic to the liver - it covalently binds to proteins, DNA andcauses cell damage

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18
Q

What is the most common cause of acute liver failure?

A

acetaminophen toxicity - over 100,000 acetaminophen overdoses annualy in the US

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19
Q

What are the symptoms of acetaminophen toxicity?

A

early: nausea and vomiting
24-48 horus: AST and ALT go up, lactate dehydrogenase go up, prothrombin time go up
72-49 hours: jaundice, hepatomegaly, bilirubin increase, encaphalopathy, hypotention, hypoglyecmia and metabolic acidosis, death by general organ failure

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20
Q

What will predict the severity of the acetaminophen poisoning?

A

the serum concentration of acetaminophen after ingestion

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21
Q

How does detoxification of acetaminophen happen in the liver and describe how toxicity can occur in this process?

A

there are two options for acetaminophen because it already has a hydoxyl group on it

  1. it can be a substrate for phase 2 reactions without even going through phase 1. then excreted
  2. it can be oxidized by cype2E1 to a toxic metabolite which can then be a substrate for phase 2 reactions and then excreted
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22
Q

What is the toxic metabolite that cype2E1 turns acetaminophen into?

A

NAPQI - it creates adducts on cell proteins and kills liver cells

23
Q

What effect does alcohol have on acetaminophen toxicity and why?

A

It will increased acetaminophen toxicity because it’s a substrate (and therfor inductor) for cype 2E1, so you get an increase in the NAPQI formation if you drink

24
Q

What product of alcohol metabolism will incude the kupffer cell to secrete cytokines in the pathogenesis of cirrhosis?

A

acetaldehyde

25
Q

What cytokins from the kupffer cell in particular will cause activation of the stellate cell to secrete collagen?

A

TGF-beta

26
Q

WHen the liver breaks down glycogen to glucose, it first makes glucose 1 phosphate and then glucose 6 phosphate, which is then turned to glucose. What enzyme interconverts glucose 1-phosphate to glucose 6-phosphate?

A

phosphoglucomutase (PGM1(

27
Q

What does the liver do in terms of bile salts?

A

It synthesizes bile salts with cholesterol

the bile salts are then stored in the ball bladder and then spit into the duodenum during meals

the ileum will resorb the bile salts to the liver

the liver will reconguate them and then the cycle repeats

28
Q

wHAT ARE THE other three uses for cholesterol in the liver?

A

cell membrane production
storage of fatty acids
steroid hormone production

29
Q

How does the liver deal with nitrogen?

A

Excess nitrogen resulting from amino acid catabolism must be converted to urea

the liver does this with the urea cycle - takes nitrogen in the form of ammonia and aspartate and puts it through the urea cycle to create urea which can be excreted

30
Q

Excess nitrogen is transported fomr peripheral tissues to the liver int he form of what amino acid?

A

glutamine

31
Q

In the liver, what enzyme will convert that glutamine to glutamate, releasing free ammonia?

A

glutaminase

32
Q

Where in the hepatic lobule is glutaminase present?

A

at the periphery (near the portal triad)

33
Q

In the liver, what enzyme will take the free ammonium and create urea?

A

carbamoyl phosphate synthase (CPS1)

34
Q

Where is CPS1 expression highest in the liver lobule?

A

same as glutaminase - in the periporal hepatocytes at the periphery

35
Q

But what if we break too much protein down for CPS1 to handle? How does the liver protect us from the ammonia that owuld build up in that situation?

A

It has another enzyme called glutamine synthase which will take the excess free ammonia and stick it on glutamate to give back glutamine

36
Q

Where is glutamine synthase present in the liver lobule?

A

near the central vein - perivenal hepatocytes

37
Q

What effect does Wnt signalling have on the urea cycle?

A

Wnt signalling is what will allow beta catenin to be stabilized and translocate to the nucleus

there, it turns on transcription of glutamine synthase

so it serves as a protection against excess ammonia escaping the urea cycle

38
Q

Where is Wnt concentration highest in the lobule?

A

near the central vein - because the central vein endothelial cells secrete Wnt

this is why glutamine synthase is highest near the central vein

39
Q

Why is maintaining blood glucose while fasting dependnt on the urea cycle?

A

because the liver will use alanine orother amino acids to make glucose in the presence of glucagon (needs to use the carbon skeletons)

the carbon skeleton is used and the ammonia is released as a byproduct

so the ammonia needs to enter the urea cycle to form excretable urea

40
Q

What will the liver synthesize from fatty cids during extended fasting/starvation?

A

ketone bodies

41
Q

Every tissue requires nucleotides for biosynthesis. Where are those nucleotides made?

A

the liver

42
Q

Why does the liver have an especially high need for the PPP?

A

Because it requires the NADPH for detoxification reactions (cytochromes) and the NADPH and the ribose sugars from it for it’s biosynthesis of nucleotides

43
Q

Many proteins created in the liver (and elsewhere) are glycosylated with carbohydrate modifications linked to what amino acids?

A

asparagine or serine

44
Q

In what organelle does glycosylation occur?

A

endoplasmic reticulum (after the chain has been assembled on a dolichol molecule)

45
Q

What organelle modifies the glycosylation before the protein is released?

A

the golgi apparatus

46
Q

The two siblings in this case had a shared mutation in the gene encoding phosphoglucomutase (PGM1), which is largely responsible for what?

A

interconverts glucose 1 phosphate and glucose 6 phosphate back and forth

also important for generatin UDP-galactose, a glycosylatio intermediate (so many proteins that require glycosylation don’t have it appropriately done in this mutation)

47
Q

What is the phenotype for a typical individual who is homozygous for the PGM1 mutation?

A
  1. hepatopathy
  2. bifid uvula
  3. growth retardation (delayed puberty)
  4. myopathy
  5. hypoglycemia
  6. dilated cardiomyopathy
48
Q

What was the fix for these siblings?

A

just give them lots of galactose supplementation to help out with the glycosylation

49
Q

Why did these siblings have delayed puberty?

A

leutenizing hormone, which is associated with the onset of puberty requires glycosylation in order for it’s to be stable in circulatin

glycosylation also increases its affinity for its receptor

50
Q

What will the AST: ALT ratio be with an acute hepatocellular disorder?

A

AST: ALT will be less than 1 (because ALT is most specific for liver damage)

51
Q

What sill the AST:ALT ratio be in liver damage secondary to alcohol abuse?

A

AST;ALT will be over 2

52
Q

What three enzyme tests will suggest cholestasis (bile duct blockage)?

A

alkaline phosphatase (but not specific for cholestasis)

5- nucleotidase

gamma-glutamyltranspeptidase

53
Q

What proteins could you measure to test the liver’s biosynthetic capcity?

A
  1. serum albumin
  2. serum globulins
  3. coagulation factors

GI Week 6 (14 decks)

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