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GI2 > Liver Biochemistry > Flashcards

Liver Biochemistry Flashcards

1
Q

what are the two ways into the liver? (what are each rich in?)

way out?

A

75% through the portal vein (from the GI) –> nutrient rich

25% from the hepatic artery (systemically) –> oxygen rich

Hepatic Vein (three veins that meet up with the IVC)

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2
Q

Main cell type of the liver?

What’s between the lobules of the liver?

What are present between hepatocytes and sinusoids?what’s interesting to know about these?

what’s within the lobules?

A

hepatocyte

sinusoids (close contact between blood and liver cells)

endothelial cells. very loosely packed to facilitate exchange of material from blood to hepatocytes and the other way around too

Bile canniliculi!

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3
Q

What do endothelial cells have that allow for exchange of material from the liver to blood and vice versa?

A

pores/fenestrations in the plasma membrane!

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4
Q

Kupffer cells?

what do they have inside?

A

macrophages of the liver.. their function is to protect the liver from microbes!

they have lots of lysosomes to engulf and destroy them.

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5
Q

What are Hepatic Stellate Cells?

important factoid about hepatic stellate cells?

A

storage site for Vitamin A and other lipids.

if you’ve touched a liver it’s pretty squishy, the stellate cells contribute to the squishyness

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6
Q

Pit cells (lymphocytes)?

A

NK cells pretty much, protecting the liver against virus and tumor cells

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7
Q

Cholangiocytes?

A

Line bile duct, control bile flow rate and bile pH

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8
Q

What is the biggest function fo the liver?

what are the next biggest thing?

what does the liver do to toxins?

A

primary receiving, distribution, and recycling… any process in the body is presented to the liver. so it’s the gateway to distributing stuff and recycling.

Glucostasis (maintains glucose levels under fed, fasting, and starving state) –> remember we did most of our carbohydrate metabolism in the liver too!

Waste Management –> inactivation, detox, and biotransformation for secretion

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9
Q

What is the unique circulation of the liver?

what’s the blood pressure in the liver like? why is this important?

A

it gets all the blood from the enteric circulation via the portal vein and the periphery from the hepatic artery!

low, so it maximizes the exchange occurring!

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10
Q

What structural features of the liver are important to know? (3) (2 of them are regarding endothelial cells)

why are these important!

A

lack of a basement membrane and absence of tight junctions between hepatocytes and endothelial cells!

Gaps between endothelial cells

Fenestrations in endothelial cells

INCREASE A GREATER access and increased contact between liver and blood

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11
Q

What are Isoprenoids?

what do these do?

important one to know?

A

Acetyl Coa –> generates IPP, which is the backbone to many compounds.

IPP forms a bunch of compounds like steroids, lipid soluble vitamins, and ubiquinone, all of which are a broad category named isoprenoids

create a bunch of stuff

the important one to know is ubiquinone as well, but they also produce steroids, and lipid soluble vitamins.

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12
Q

Where do we get our acetyl coa

how do we get it? (3 ways)

where does it go once it’s made?

A

generated in the mitochondria from breakdown of pyruvate, or beta oxidation of fatty acids, or breaking down amino acids.

it’s then sent into the cytoplasm via the citrate shuttle!

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13
Q

What generates the sterane ring?

what is this common for?

A

6 units of IPP (from acetyl CoA) form the tetracyclic (4-ring) sterane ring

backbone of most steroids

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14
Q

What is the structure of cholesterol?

where’s the hydroxyl group located

A

it’s called an “allicyclic compound… hydrocarbon chain + sterane ring”

OH in the 3rd Carbon of the sterane ring.

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15
Q

Why is cholesterol so important?

A

component of plasma membranes

and

major precursor of bile acids, bile salts, vitamin d, steroid hormones.

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16
Q

in the biosynthesis to cholesterol, what’s important to know about dietary intake?

hint: counterintuitive

A

if you’re trying to lose weight so you ingest less, so your body makes more

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17
Q

Equation for cholesterol?

A

18 AcetylCoA + 18 ATP + 16NADPH + 16H + 4O2 –> Cholesterol

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18
Q

What is phase 1 of of cholesterol synthesis?

A

Acetyl CoA –> IPP

2 Acetyl CoA –> Acetoacetyl CoA

a third Acetyl coA comes in to form HMG CoA (by HMG CoA synthase)

NADPH comes in to form Mevalonate (HMG CoA reductase)

add 3 ATP and you form IPP

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19
Q

What’s the rate limiting step of cholesterol synthesis?

what is this also an important target for?

A

HMG CoA reductase

statins

20
Q

if you are taking statins, what are you inhibiting?

A

statins inhibit HMG CoA reductase, which makes IPP… IPP makes all isoprenoids for cholesterol metabolism, but also lipid soluble vitamins ADEK and ubiquinone (which is for energy metabolism), so people are super tired all the time.

21
Q

What is Phase 2 of cholesterol synthesis?

A

start with 6 IPP –> Squalene –> Lanosterol (here the cycling occurs)–> isomerizes to cholesterol

22
Q

What inhibits lanosterol to cholesterol?

what are these used for usually?

what happens if you use them for long periods of time and at high doses?

A

(azoles) anti fungal drugs

they’re supposed to inhibit the fungal form, but at prolonged use and high concentration they can inhibit mammalian cholesterol

23
Q

What kind of protein is HMG CoA reductase?

where does statins bind to?

A

located in the ER but kind of is an integral membrane weaving in and out.

the catalytic domain in the Cytosol!

24
Q

What are Statins?

A

cholesterol lowering drugs

competitive inhibitors of HMG CoA reductase

Km for HMG CoA is 4 microMolar, Ki is 5-45 nM (1000x higher!!)

25
Q

what cool thing also happens with statins and LDL??

bad thing when using statins?

A

when you inhibit HMG CoA reductase with statins, it goes into crisis mode upregulates activating like 30 enzymes, one of which is the LDL receptor, so picking up cholesterol from the plasma to endocytose to be used!

ubiquinone which results in impaired mitochondrial function… so people get super tired. (myotoxic side effects, myopathy)

26
Q

What is the mechanism of transcriptional control and using statin?

A

SREBP is normally bound to SCAP and these two are attached to INSIG, and held together in the ER membrane when cholesterol levels are high! so they stay in the ER.

when the cholesterol levels go down (from statins or whatever), SCAP loses its hold on INSIG and it migrates to the Golgi, broken down, and the N terminus of SREBP is released as a transcription factor.. this then dinds to SRE on HMGR promoter, promoting cholesterol synthesis!!

this up regulates tons of enzymes including LDL receptor!!

27
Q

What do Antimycotics do?

A

inhibit the formation of ergosterol (needed to maintain plasma membrane of fungal cells)

28
Q

What happens when you have the sterane ring with degradation?

A

no enzyme can degrade it at all.

cholesterol is converted to bile acids and stored in bile.

some excreted in feces

29
Q

What do bile acids / bile salts do?

where are they made?

A

emulsify the lipids! (strong detergents!!.. they have polar and non-polar regions and form micelles which increase the surface area of lipids and expose them to lipase.

hepatocytes

30
Q

How are bile acids made?

what’s the 2 bile acids that can from from this?

A

a second hydroxyl group is added to the 7th carbon of the sterane ring (rate limiting step by 7a-hydroxylase)

this makes 7a-hydroxycholesterol!

then the hydrocarbon chain is cleaved and two options happen:

a carboxyl acid is introduced to that cut hydrocarbon forming chenodeoxycholic acid

or the same thing plus another OH at the 12th carbon, making cholic acid!

31
Q

What can then happen to cholic acid

A

they can then be conjugated with amino acids to make the conjugated forms.

it sticks a CoA on it to form Cholyl CoA

then it can either stick a taurine or a glycine on it to form Taurocholic Acid or Glycocholic Acid

32
Q

What’s good to know about the Cholyl CoA to Taurocholic or glycocholic acid?

which one is most efficient?

A

it goes from a higher pKa to a lower pKa, making it more ionized and a better detergent effect! (better emulsification!)

Taurocholic (2) vs glycolic which was (4)

33
Q

What are bile salts?

A

the Coo- form.

if it becomes deprotonated, it’s the salt because sodium can bind to it.

34
Q

where are bile acids and bile salts made usually?

A

the liver.

35
Q

What happens to the bile?

what do bacteria do to bile in the gut?

A

it is released in the response of food.. and then in the same way it emulsify fat and aid in absorption

there are bacteria that deconjugate bile, they remove the taurine, glycine, or dehydroxylate (remove the OH-)

36
Q

What is the difference between a primary and secondary bile acid?

what happens to these secondary bile acids?

A

secondary has an absence of the hydroxyl group in the bile acid/salt.

95% of them are sent back to the liver to be used over again, 5% to feces.

37
Q

If it’s derived from cholic acid, what is the secondary bile acid?

what about if its derived from chenodeoxycholic acid?

A

deoxycholic acid

chenodeoxycholic acid

38
Q

What are bile acid-binding resins?

what happens when there is a shortage?

A

resins can bind to bile salts and they’re non-absorbable. they don’t go back to the liver they’re just excreted out into the feces.

the liver gets nervous so it generates more and it’s generating more from cholesterol, so you delete cholesterol, so it starts taking cholesterol from blood!

cleaner system than statins

39
Q

gallstones?

A

cholesterol precipitates out of solution.

impairment of metabolism is why it happens.

leads to malabsorption syndromes (steatorrhea), and deficiency in fat soluble vitamins!

40
Q

Liver can detoxify harmful products, even if they’re not (pharmacological), they are detoxed.

Metabolites vs. xenobiotics?

A

metabolite = made in the body

xenobiotics = ingested from the outside

41
Q

What happens during the first phase of detoxification of xenobiotics?

Second phase?

How is this catalyzed?

A

Polarity of the compound is raised because a lot of the compounds tend to be hydrophobic and tend to stick to the membrane and evade excretion

conjugate them with different caps to make them safer for secretion.

catalyzed by Cytochrome P450 (CYP) enzymes

42
Q

What are Cytochrome P450 enzymes?

what do they contain?

what do they work with?

which ones metabolize drugs

A

contain heme

you have a Cytochrome P450 protein and it works with the cytochrome p450 reductase.

they are 12 gene families that helps make tons of compounds

CYP1, 2, or 3 are responsible for drug metabolism

43
Q

How does the reductase work with the cytochrome p450 to increase the polarity of a drug?

A

The reductase helps in the flow of the electrons, which gives it to the cytochrome p450 which then moves it to the drug which alters the drug (electron chain kind of)

Ferric –> Ferrous

Oxygen is introduced

drug becomes OH form of the drug and now its more polar.

44
Q

How do CYPS effect the drugs you’re taking?

A

Everybody’s composition of CYPs are different, so the ability to metabolize different drugs will be different.

if you’re taking multiple drugs, the binding of one will influence the metabolism o the other.

If you’re taking a drug that’s inhibiting the CYP, the drug will be increased in levels in the plasma. the opposite would be the case for stimulating the CYP… there would be decreased levels of the drug.

45
Q

grapefruit juice and CYPs?

A

Grapefruit juice inhibits CYPs!

if you take statin and CYPs, the statins won’t be metabolized as well, leading to higher levels of statin which can be toxin!

46
Q

St. John’s Wort and CYPs?

A

Induces CYP! so statins will be metabolized faster so your overall statin levels will be less!

47
Q

Chronic Hepatitis does what to our bodies?

A

Chronic hepatitis develops a basement membrane between endothelial cells and hepatocytes… so the free flow of material is impaired and impacted so it elevates portal pressure and you aren’t getting the free flow.

GI2 (20 decks)

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