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Unit 8 Abbey > MCP Lecture 1 > Flashcards

MCP Lecture 1 Flashcards

1
Q

What maintains human cholesterol homeostasis?

A

liver

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2
Q

In what forms does cholesterol leave the liver?

A
  • unmodified free cholesterol in the bile
  • conversion to bile acids/salts
  • as VLDL
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3
Q

Describe the structure of cholesterol

A
  • four planar hydrocarbon rings (steroid nucleus)
  • 8 carbon hydrocarbon attached to carbon 17 (D ring)
  • hydroxyl group attached to carbon 3 (A ring)
  • double bond between carbon 5 and 6 (B ring)
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4
Q

How is cholesterol converted to a fatty acid?

A

esterified at carbon 3 (A ring)

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5
Q

What does the presence of cholesterol in the membrane do?

A
  • increases packing within the hydrophobic core
  • increases mechanical strength
  • decreases permeability and fluidity
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6
Q

What are sterols?

A

Family that cholesterol belongs to

-four fused hydrocarbon rings, 8-10 carbon atoms in hydrocarbon tail on carbon 17, hydroxyl at carbon 3

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7
Q

What is sitosterolemia?

A
  • autosomal recessive plant sterol storage disease
  • mutations in ABCG5 and ABCG8 genes (encode ABC transporters sterolin-1 and sterolin-2)
  • characterized by diminished pumping of plant sterols back into the intestine
  • ability of the liver to excrete the phytosterols into the bile
  • result = increased phytosterols found in blood and tissues
  • presentation: tendon and tuberous xanthomas and premature atherosclerosis
  • coronary heart disease
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8
Q

Where is cholesterol synthesized?

A
  • all cells except RBCs - majority in liver, intestine, adrenal cortex and reproductive tissues
  • all reactions on cytoplasmic surface of smooth ER
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9
Q

How is cholesterol synthesis similar to fatty acid synthesis?

A

all carbons in cholesterol are provided by acetyl CoA and NADPH provides reducing equivalents

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10
Q

What is the key regulartory step in cholesterol synthesis?

A

conversion of HMG CoA to mevalonate catalyzed by HMG CoA reductase

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11
Q

What are the steps from acetyl CoA to mevalonate?

A
  1. begin with 2 molecules acetly CoA - condense
  2. third molecule of acetyl CoA added by HMG-CoA synthase (cytosolic - not mitchondrial enzyme) to form HMG-CoA
  3. HMG CoA reductase uses 2 molecules of NADPH to reduce HMG CoA to mevalonate
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12
Q

What are the 8 steps between mevalonate to cholesterol?

A
  1. mevalonate (6C) –> 5-pyrophosphomevalonate in two steps (2 ATPs used, enzyme = kinase)
  2. 5-pyrophosphomovalonate (6C) –> isopentenyl pyrophosphate IPP (5C) (requires 1 ATP, enzyme = decarboxylase)
  3. IPP –> 3,3-dimethylallyl pyrophosphate DPP (5C) (enzyme = isomerase)
  4. IPP and DPP condense to form geranyl pyrophosphate GPP (10C)
  5. second molecule of IPP condenses with GPP –> farnesyl pyrophasphate FPP (15C)
  6. 2 molecules of FPP combine, release pyrophosphate, and are reduced –> squalene (30 C)
  7. Squalene –> lanosterol (ring closure of squalene using 02 and NADPH) enzymes are ER based
  8. lanosterol –> cholesterol (multistep, ER associated process)
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13
Q

How many ATP are used to make squalene?

A

18 ATP (3 ATP hydrolzed per mevalonate converted to IPP - 6 IPP used to make squalene)

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14
Q

Describe what happens during the conversion of lanosterol to cholesterol

A

shortening of side chain, oxidative removal of methyl groups, reduction of double bonds, migration of a double bond

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15
Q

What happens in Smith-Lemli-Opitz syndrome (SLOS)?

A

austosomal recessive disorder, partial deficiency in 7-dehydrocholesterol-7-reductase - the enzyme that reduces the double bond in 7-dehydrocholesterol (lanosterol) to cholesterol

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16
Q

How is HMG CoA reductase regulated?

A
  • sterol dependent transcriptional regulation
  • sterol accelerated enzyme degradation
  • sterol independent phosphorylation-dephosphorylation
  • hormonal control
17
Q

How does the regulation of gene expression of HMG CoA Reductase happen?

A

SREBP-2 in inactive form associates with ER protein SCAP - when cholesterol levels are low, the complex moves to the Golgi - cleavage of SREBP, now activated. SREBP enters the nucleus and binds SRE

When cholesterol levels are high, cholesterol binds to SCAP which anchors the SREBP-2-SCAP complex to the ER membrane

18
Q

What causes degradation of HMG CoA reductase?

A

high cholesterol levels - bind to sterol-sensing domain of the reductase triggering ubiquitination and degradation

19
Q

Is HMG CoA reductase active when it’s phosphorylated or dephosphorylated?

A

dephosphorylated

20
Q

What hormones regulate expression of HMG CoA reductase

A

insulin and thyroxine = upregulation

glucagon and glucocorticoids = down regulation

21
Q

How do statin drugs work?

A

structural analogues of HMG = competitive inhibitors

works to lower plasma levels of cholesterol

22
Q

How is cholesterol degraded?

A
  • eliminated by conversion to bile acids and bile salts (POOP)
  • some is modified by bacteria before excretion
  • primary products are reduced forms of cholesterol (coprostanol and cholestanol)
23
Q

What is the difference between bile acids and bile salts?

A

bile acids are protenated

bile salts are deprotenated

24
Q

Why do bile salts/acids work well as emulsifying agents?

A

polar face (OH groups) and nonpolar face (methyl groups)

25
Q

What is the rate limiting step in bile acid synthesis?

A

addition of the hydroxyl group at carbon 7 of cholesterol (is then converted to either cholic acid or chenodeoxycholic acid - the most common “primary bile” acids

26
Q

What happens to bile acids before they leave the liver?

A

conjugated to glycine or taurine (amide bond forms btw carboxyl group of the bile acid and amino group of serine or taurine)
Why? makes them better detergents because of increased amphipathic nature

27
Q

Why are bile salts better detergents than bile acids?

A

increased amphipathic nature

28
Q

What is the effect of bacteria on bile salts?

A

remove glycine and taurine from conjugated bile salts - also can remove the hydroxyl group from carbon 7 - produces SECONDARY BILE ACIDS

29
Q

Describe the enterohepatic circulation of bile salts

A
  • liver secretes bile acids
  • reabsorbed in terminal ileum by Na+ bile salt cotransporter and returned to the blood
  • albumin binds and transports bile salts in the blood
  • hepatocytes take up bile salts using an isoform of the Na+ bile cotransporter

95% returned to liver, 5% poop

30
Q

What is cholelithiasis?

A

a decrease in bile salt production or increase of cholesterol secretion - imbalance = precipitation of cholesterol and formation of gall stones

treatment: laproscopic cholecystectomy

Unit 8 Abbey (19 decks)

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