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Biochemistry Block 3 > Cholesterol Metabolism > Flashcards

Cholesterol Metabolism Flashcards

1
Q

Main function of cholesterol

What 3 things do cholesterol synthesize

A

Structural component in cell membrane (helps control fluidity)

Steroid hormones, bile acids, and vitamin D

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2
Q

What is the biggest source of cholesterol

A

De novo synthesis

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3
Q

Which cells in the body require cholesterol

A

All of them since it is a major component of cell membranes

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4
Q
  1. Main site of de novo cholesterol synthesis

2. 4 other places where de novo cholesterol synthesis occurs

A
  1. Liver

2. Adrenal cortex, skin, placenta, and testes/ovaries

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5
Q

Starting molecule for cholesterol synthesis

A

Acetyl CoA

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6
Q

What other two things are required to start cholesterol synthesis

A

Citrate (to shuttle acetyl CoA from mitochondria to cytoplasm) and NADPH

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7
Q

What is the main idea of the first two steps of cholesterol synthesis

A

Both steps involve adding a CoA

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8
Q

2 major steps to know about in cholesterol synthesis are doing what?

A
  1. Synthesis of HMG CoA (6 carbons)

2. Formation of mevalonate (6 carbons)

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9
Q

What is the rate limiting enzyme in cholesterol synthesis

What is clinically significant about it

A

HMG CoA reductase (turns HMG CoA to mevalonic acid)

Statin drugs target this

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10
Q

What kind of inhibitor are statins to HMG CoA reductase?

What does this type of inhibitor do to Km/Vmax

~what happens with noncompetitive inhibition

A

Competitive

Km increases, Vmax unchanged

~Km unchanged, Vmax decreases

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11
Q

What is the next significant thing to be formed after mevalonic acid

2 of these condense to form

A

Farnesyl pyrophosphate (15 carbons)

Squalene (30 carbons)

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12
Q

Squalene is converted to

A

Lanosterol

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13
Q

What two things need to happen in order for lanosterol to be converted to cholesterol

A

Shortening of carbon chain from 30-27; requires 7-dehydrocholesterol reductase (formed by farnesyl)

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14
Q

Smith-Lemli-Opitz syndrome (SLOS) is a defect in ?

Defect in this enzyme causes?

A

7-dehydrocholesterol reductase

Increase in vitamin D (7-dehydrocholesterol reductase converts 7-dehydrocholesterol into cholesterol. 7-dehydrocholesterol is precursor for vitamin D, so if it is not being converted to cholesterol, vitamin D will be made in excess)

~increased levels of 7-dehydrocholesterol/ vitamin D and decreased levels of plasma cholesterol

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15
Q

Clinical findings in SLOS

A

Microcephaly, distinctive faces, cleft palate, organ malformations, syn/polydactyly, fork toe, and genital abnormalities

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16
Q

How is SLOS treated

A

With statins

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17
Q

Farnesyl pyrophosphate is building blocks for which 3 biological molecules

A

Dolichol, heme A, and ubiquinone

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18
Q
  1. Where is dolichol used

2. Where are Heme A and Ubiquinone used?

A
  1. N-linked oligosaccharide synthesis/ lipid anchors proteins in intracellular membranes
  2. ETC
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19
Q

Difference in energy state of the body for cholesterol synthesis / ketone body synthesis

What enzyme does each use thats different

A

Cholesterol happens in well fed, ketone bodies happens in fasting

Cholesterol= cytoplasmic HMG CoA synthase
Ketone= mitochondrial HMG CoA synthase
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20
Q

What is prenylation of proteins

A

Attaches proteins to any surface

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21
Q

When would dolichol, heme a, ubiquinone and prenylation of proteins be reduced

A

Anything that blocks HMG CoA reductase will reduce amount of these intermediates - myoglobinuria

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22
Q

What else can happen if HMG CoA reductase is blocked?

A

Rhadomyolysis- excess muscle breakdown

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23
Q

Cholesterol synthesis requires __ and is enhanced by ___

A

Requires acetyl CoA and enhanced by insulin

24
Q

What is the most important factor for determining rate of cholesterol produced

A

Amount of cholesterol taken up by cells during lipoprotein metabolism

25
Q

Hepatic synthesis of cholesterol is inhibited by

A

Dietary cholesterol

26
Q

How does insulin induce the key enzyme

A

By upregulating HMG CoA reductase gene (mRNA production) and activating key enzyme

27
Q

So what activates and inhibits HMG CoA reductase

A

Activated by insulin / dephosphorylation

Inactivated by phosphorylation

28
Q

Explain the sterol dependent regulation of HMG CoA reductase gene expression

A

Sterol dependent regulation requires the presence of SREBP which is always under the control of SCAP. Both are usually in SER, then go to golgi apparatus which has proteases to break the bond between SCAP and SREBP, thus releasing SREBP to nucleus where it acts as a transcription factor that increases the expression of the gene for HMG CoA reductase - to form more cholesterol

29
Q

What will happen to SREBP when cholesterol is high

A

When cholesterol is high, SREBP will bind with SCAP again to remove transcription factor

(So high cholesterol puts them together, low cholesterol breaks them apart)

30
Q
  1. What are the two primary bile acids?

2. What are the two secondary?

A
  1. Cholic acid and chenodeoxycholic acid

2. Deoxycholic acid and lithocholic acid

31
Q

4 functions of bile acids

A
  1. Provides mechanism for excess cholesterol excretion
  2. Prevents precipitation of cholesterol in gallbladder
  3. Facilitates digestion of dietary triacylglycerols
  4. Facilitates intestinal absorption of fat soluble vitamins
32
Q

3 components of bile

A
  1. Bile acids (85%)
  2. Cholesterol (10%)
  3. Phospholipids (5%)
33
Q

What is the starting point for bile acid synthesis

Site of bile acid synthesis?

A

Cholesterol

Liver

34
Q

What is the rate limiting enzyme in bile acid synthesis

A

7 alpha hydroxylase

35
Q

Name 4 bile salts produced from bile acid synthesis

What are these 4 considered

A

Glycochalic acid, taurocahlic acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid

Primary bile acids

36
Q

How do bile acids form bile salts

A

Bile acids are conjugated in the liver by glycine and taurine to form bile salts

37
Q

How much bile acids do adults produce a day from cholesterol in the liver

A

3-5 grams

38
Q
  1. Where are bile salts stored

2. What secretes bile

A
  1. Gallbladder

2. Hepatocytes

39
Q

What are the 2 secondary bile acids

A

Deoxycholic acid and lithocholic acid

40
Q

Whats the difference between primary and secondary bile acids

A

Secondary are ones that have already traveled to the small intestine and are now being reused in the liver to complete process again (along with more primary)

41
Q

What does the rate limiting enzyme of bile acid synthesis (7 alpha hydroxylase) require

A

O2 and NADPH

42
Q

Allosteric activator of bile acid synthesis?

A

Cholesterol (induces transcription of enzyme)

43
Q

What is an allosteric inhibitor of bile acid synthesis

A

Increased bile acids

~bile acids regulate HMG CoA reductase activity via SREBP pathway

44
Q

Main function of cholestyramine

What effect would this have

A

It is a bile acid sequestrant that prevents absorption of bile acid and promotes their excretion

Removing bile acids relieves inhibition so now more cholesterol can be diverted to bile acid synthesis

45
Q

What increases LDL receptor expression?

A

Decreased cholesterol in the cells (allows hepatocytes to remove more LDL from blood)

46
Q

4 pharmacological effects of cholestyramine

A
  1. Prevents cholesterol recycling
  2. Increases fecal loss of LDL
  3. Lowers serum LDL
  4. Treatment for hypercholesterolemia
47
Q

What causes gallstone formation (cholelithiasis)

A

If more cholesterol enters the bile than can be solublised by bile salts and phospholipid
~so decreased bile acids in the bile

48
Q

Since decreased bile acids in the bile cause gallstones, what are some factors that could contribute to not have enough bile acids?

A

Malabsorption of bile acids from intestine, obstruction to biliary tract, hepatic dysfunction (decreases bile salt synthesis), or accelerated recycling of bile acid

49
Q

Risk factors for cholelithiasis

A

Fat, forty, fertile, female, and flattulent

50
Q

Function of 21-hydroxylase

A

Enzyme used in steroid hormone synthesis

51
Q

What are the 3 main hormones of steroid synthesis (in order that they are seen in the pathway)

A

17 alpha hydroxylase
21 alpha hydroxylase
11 beta hydroxylase

52
Q

Deficiency in 21 alpha hydroxylase will prevent

A

Synthesis of aldosterone and cortisol

53
Q

What effects will 21 hydroxylase deficiency have on the body

A

Will increase testosterone (exaggerated external genitalia), hypoglycemia, lack of glucocorticoids/mineralcorticoids

54
Q

17 alpha hydroxylase deficiency leads to

How does this present

A

No cortisol produced, diminished sex hormones produced

Males-ambiguous genitalia, females- no 2nd sex characteristics; increased corticosterone secretion causes salt/fluid retention resulting in hypertension (ringing in ears) and increased aldosterone(progesterone will make more since it cannot make anything else)

55
Q

11 beta hydroxylase deficiency has similar symptoms to

How does it present

A

21 alpha hydroxylase deficiency

Decrease in serum cortisol and aldosterone, hypertension, exaggerated genitalia

56
Q

Function of glucocorticoids

A

Maintain blood glucose levels

Biochemistry Block 3 (11 decks)

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