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Biochem 1 > Cholesterol and bile acid Metabolism & Function > Flashcards

Cholesterol and bile acid Metabolism & Function Flashcards

1
Q

What is the structure/characteristic of cholesterol

A
  • fused rings
  • very non-polar
  • even more non-polar when esterified to fatty acid
  • extremely water insoluble
  • stabilizing component of cell membranes
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2
Q

What is cholesterol synthesized out of?

A

acyl-CoA

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3
Q

What are the major sites of cholesterol synthesis?

A

Liver

Intestine epithelial

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4
Q

What is cholesterol a precursor of?

A 
Bile salts (liver)
steroid hormones (endocrine glands)
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5
Q

Can cholesterol be degraded?

A

No.

There are no enzymes that degrade cholesterol

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6
Q

Why sis cholesterol associated with vascular disease?

A
  • Can’t be degraded

- High non-polarity

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7
Q

is cholesterol synthesized in plants?

A

no

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8
Q

how is cholesterol transported?

A

In the blood in lipoproteins

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9
Q

How is cholesterol excreted from the body?

A

by converting it to bile salts

this is why it is essential to transport cholesterol from peripheral tissues to the liver

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10
Q

What are the 4 phases in the pathway of cholesterol synthesis?

A
  1. Acetyl-CoA units condense to form mevalonate
  2. Mevalonate is converted to 5C isoprene units
  3. Six C5 isoprene units condense to form the C30 squalene
  4. Squalene cyclizes to form the 4 ring lanosterol. Carbons are released to convert lanosterol to 27C cholesterol
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11
Q

What are the 3 ways HMG-CoA reductase is regulated?

A
  1. Transcription control
  2. Regulation by proteolysis
  3. Regulation by phosphorylation
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12
Q

How is HMG-CoA reductase regulated by transcription control?

A

High levels of cholesterol negatively regulate the rate of synthesis of HMG-CoA mRNA via repression of transcription of HMG-CoA gene

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13
Q

How is HMG-CoA reductase regulated by proteolysis?

A

Rising level of cholesterol and bile salts (in the liver) makes enzyme more susceptible to proteolysis

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14
Q

How is HMG-CoA reductase regulated by phosphorylation?

A

Phosphorylated HMG-CoA reductase is inactive

Dephosphorylated HMG-CoA reductase is active

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15
Q

How is cholesterol esterified?

A

Cholesterol OH at position 3 is esterified to form cholesterol ester (CE)

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16
Q

Where does the enzyme LCAT esterifies cholesterol?

A

in HDL particles

LCAT is located in the blood

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17
Q

Where does the enzyme ACAT esterifies cholesterol?

A

In cells

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18
Q

Which enzyme hydrolyzes CE?

A

CEH - cholesterol ester hydrolase

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19
Q

What is the purpose of esterification?

A
  • Causes cholesterol to become more hydrophobic to facilitate incorporation into lipoproteins
  • Contributes to govern free cholesterol levels in blood and cells
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20
Q

What is the fate of chylomicron cholesterol from the diet to the liver?

A
  1. Dietary cholesterol is absorbed from bile salts micelles into intestinal epithelial cells
  2. It is packaged into nascent chylomicrons
  3. Nascent chylomicrons enter the blood via the lymph system and are converted into chylomicrons by obtaining apoCII & apoE from HDL
  4. In the blood, chylomicrons TGs are digested by LPL
  5. Chylomicrons remnants bind to liver receptors and are internalized by endocytosis
  6. In the liver cells, chylomicrons remnants are digested in lysosomes where proteins are degraded, FA cleaved from CE and free cholesterol enters the cholesterol pools in liver cells
21
Q

What is the fate of VLDL cholesterol?

A
  • Liver cholesterol, TG, phospholipids and apoB-100 are packaged to VLDL and secreted to blood
  • In the blood, HDL transfers CE, apoCII and apoE to VLDL
  • TG carried in VLDL are metabolized by LPL and converted to IDL

Fate of VLDL:

  • IDL either endocytosed into liver cells thus returning VLDL cholesterol back tot the liver
  • IDL TG degraded to produce LDL which delivers VLDL cholesterol to peripheral cells or liver
22
Q

What is the fate of LDL (bad) cholesterol?

A
  • LDL produced in blood from IDL
  • Major role of transporting cholesterol to several tissues including liver, peripheral tissues
  • Uptake of oxidized LDL into macrophages plays a major role in atherosclerosis - thus “bad” cholesterol
23
Q

Describe the uptake of LDL by the LDL receptor?

A
  • LDL receptors synthesized in the ER and golgi travel to the cell surface
  • Membrane LDL receptor brings LDL into cell by endocytosis. Receptors recycled to the surface
  • In the endosome, decreased pH, LDL dissociate from receptor
  • Endosomes fuse to lysosomes containing hydrolytic enzymes that digest lipoproteins releasing AA, FA, CE
  • CE further hydrolyzed to cholesterol, joining intracellular pool
24
Q

What is the effect of cholesterol on HMG-Co reductase?

A

elevated cholesterol reduces synthesis of HMG-Co reductase

25
Q

What is the effect of cholesterol on ACAT?

A

elevated cholesterol stimulates the activity of ACAT converting C to CE

26
Q

What is the effect of cholesterol on HLDL receptors?

A

elevated cholesterol reduces synthesis of LDL receptors

27
Q

Where is HDL synthesized?

A

liver and intestinal cells

28
Q

How does HDL transport cholesterol? “Reverse C transport

A
  1. HDL picks up cholesterol from cell membranes,
  2. Cholesterol is converted to CE by LCAT
  3. HDL transfers apoCII/apoE to chylomicrons & VLDL
  4. HDL transfers CE to VLDL in exchange for TG, mediated by CETP
  5. Hepatic lipase hydrolyzes HDL, allowing release of CE to liver
  6. VLDL degraded by LPL are converted to IDL/LDL endocytosed by liver
29
Q

Why is HDL-C good cholesterol?

A

Because HDL-C from peripheral cells is returned to the liver by “reverse C transport”. It’s then converted to bile salts and eliminated from the body as feces

30
Q

How does the body get rid of cholesterol

A

converting it to bile salts

31
Q

Where does the conversion of cholesterol to bile salts occur (synthesis of bile salts from cholesterol)

A

In the liver

32
Q

How is cholesterol transferred from peripheral tissue to the liver?

A

HDL

33
Q

How is bile salts synthesized?

A
  1. An a-hydroxyl group is added to C7.
  2. Double bond is reduced
  3. Hydroxylation of 2 sets of compounds
  4. # C removed by oxidation - remaining 5C is attached to ring structure and carboxyl
34
Q

What rate limiting step of bile salt synthesis?

A

a-hydroxyl group is added to C7 catalyzed by 7a-hydroxylase

35
Q

How is the rate limiting step of bile salt synthesis regulated (7a-hydroxylase)

A

activity of the enzyme is decreased by bile salts

ie bile salts negatively regulate biosynthesis

36
Q

What are bile salts conjugated to?

A

glycine or taurine (derived from cysteine)

37
Q

What is the role of conjugation of bile salts?

A

Conjugation lowers the pH of bile salts so that a greater percentage of the molecules are ionized in the lumen of the gut, making them better detergents for lipid digestion

38
Q

What is the importance of ionized bile salts?

A

Only ionized bile salts have sufficient polarity to function as a natural detergent that emulsifies (as micelles) dietary fat so that it can be digested by pancreatic enzymes

39
Q

How are bile salts conjugated?

A
  • The carboxyl at the end of the side chain reacts with CoA- reaction requires ATP
  • The acetyl CoA derivatives react with either glycine or taurine forming amides
40
Q

What is the enterohepatic system?

A

Bile salts circulate from the liver to the intestine and back with 95% efficiency

41
Q

After secretion into the intestine, what happens to primary bile salts?

A

they are deconjugated and dehydroxylated forming secondary bile salts

42
Q

How does bile salt deficiency occur?

A

prolonged obstruction of common duct that carries secretions from the gallbladder into the intestine

43
Q

What are some consequences of bile salt deficiency?

A
  • Decreased fat soluble vitamin (A,D,E,K) uptake –> vitamin deficiency
  • Decreased fatty acid uptake –> calorie uptake
  • increased passage of FA into colon (steatorrhea ie fatty stools)
  • induced water secretion
  • diarrhea
44
Q

How do statins lower cholesterol & TG levels?

A

eg Lipitor

HMG-CoA reductase inhibitors that inhibit cholesterol biosynthesis

45
Q

How do bile acid resins lower cholesterol & TG levels?

A

eg cholestyramine
bind bile acid in the intestine causing increased excretion of bile salts in feces and consequently increase in cholesterol elimination

46
Q

How do ezetimibe lower cholesterol & TG levels?

A

by inhibiting intestinal cholesterol absorption

47
Q

How do niacin lower cholesterol & TG levels?

A

activates LPL;
reduces hepatic production of VLDL;
reduces catabolism of HLDL;
suppresses mobilization of FA from adipose tissue

48
Q

How do fibrates lower cholesterol & TG levels?

A

Increase LPL activity thereby increasing VLDL turnover

Inhibit VLDL secretion from the liver

Biochem 1 (22 decks)

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