Cholesterol Metabolism

Question 1

Main function of cholesterol

What 3 things do cholesterol synthesize

Answer 1

Structural component in cell membrane (helps control fluidity)

Steroid hormones, bile acids, and vitamin D

Question 2

What is the biggest source of cholesterol

Answer 2

De novo synthesis

Question 3

Which cells in the body require cholesterol

Answer 3

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

Question 4

1. Main site of de novo cholesterol synthesis

2. 4 other places where de novo cholesterol synthesis occurs

Answer 4

1. Liver

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

Question 5

Starting molecule for cholesterol synthesis

Answer 5

Acetyl CoA

Question 6

What other two things are required to start cholesterol synthesis

Answer 6

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

Question 7

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

Answer 7

Both steps involve adding a CoA

Question 8

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

Answer 8

1. Synthesis of HMG CoA (6 carbons)

2. Formation of mevalonate (6 carbons)

Question 9

What is the rate limiting enzyme in cholesterol synthesis

What is clinically significant about it

Answer 9

HMG CoA reductase (turns HMG CoA to mevalonic acid)

Statin drugs target this

Question 10

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

Answer 10

Competitive

Km increases, Vmax unchanged

~Km unchanged, Vmax decreases

Question 11

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

2 of these condense to form

Answer 11

Farnesyl pyrophosphate (15 carbons)

Squalene (30 carbons)

Question 12

Squalene is converted to

Answer 12

Lanosterol

Question 13

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

Answer 13

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

Question 14

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

Defect in this enzyme causes?

Answer 14

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

Question 15

Clinical findings in SLOS

Answer 15

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

Question 16

How is SLOS treated

Answer 16

With statins

Question 17

Farnesyl pyrophosphate is building blocks for which 3 biological molecules

Answer 17

Dolichol, heme A, and ubiquinone

Question 18

1. Where is dolichol used

2. Where are Heme A and Ubiquinone used?

Answer 18

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

Question 19

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

What enzyme does each use thats different

Answer 19

Cholesterol happens in well fed, ketone bodies happens in fasting

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

Question 20

What is prenylation of proteins

Answer 20

Attaches proteins to any surface

Question 21

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

Answer 21

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

Question 22

What else can happen if HMG CoA reductase is blocked?

Answer 22

Rhadomyolysis- excess muscle breakdown

Question 23

Cholesterol synthesis requires __ and is enhanced by ___

Answer 23

Requires acetyl CoA and enhanced by insulin

Question 24

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

Answer 24

Amount of cholesterol taken up by cells during lipoprotein metabolism

Question 25

Hepatic synthesis of cholesterol is inhibited by

Answer 25

Dietary cholesterol

Question 26

How does insulin induce the key enzyme

Answer 26

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

Question 27

So what activates and inhibits HMG CoA reductase

Answer 27

Activated by insulin / dephosphorylation Inactivated by phosphorylation

Question 28

Explain the sterol dependent regulation of HMG CoA reductase gene expression

Answer 28

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

Question 29

What will happen to SREBP when cholesterol is high

Answer 29

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)

Question 30

1. What are the two primary bile acids? | 2. What are the two secondary?

Answer 30

1. Cholic acid and chenodeoxycholic acid | 2. Deoxycholic acid and lithocholic acid

Question 31

4 functions of bile acids

Answer 31

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

Question 32

3 components of bile

Answer 32

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

Question 33

What is the starting point for bile acid synthesis Site of bile acid synthesis?

Answer 33

Cholesterol Liver

Question 34

What is the rate limiting enzyme in bile acid synthesis

Answer 34

7 alpha hydroxylase

Question 35

Name 4 bile salts produced from bile acid synthesis What are these 4 considered

Answer 35

Glycochalic acid, taurocahlic acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid Primary bile acids

Question 36

How do bile acids form bile salts

Answer 36

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

Question 37

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

Answer 37

3-5 grams

Question 38

1. Where are bile salts stored | 2. What secretes bile

Answer 38

1. Gallbladder | 2. Hepatocytes

Question 39

What are the 2 secondary bile acids

Answer 39

Deoxycholic acid and lithocholic acid

Question 40

Whats the difference between primary and secondary bile acids

Answer 40

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)

Question 41

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

Answer 41

O2 and NADPH

Question 42

Allosteric activator of bile acid synthesis?

Answer 42

Cholesterol (induces transcription of enzyme)

Question 43

What is an allosteric inhibitor of bile acid synthesis

Answer 43

Increased bile acids | ~bile acids regulate HMG CoA reductase activity via SREBP pathway

Question 44

Main function of cholestyramine What effect would this have

Answer 44

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

Question 45

What increases LDL receptor expression?

Answer 45

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

Question 46

4 pharmacological effects of cholestyramine

Answer 46

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

Question 47

What causes gallstone formation (cholelithiasis)

Answer 47

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

Question 48

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

Answer 48

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

Question 49

Risk factors for cholelithiasis

Answer 49

Fat, forty, fertile, female, and flattulent

Question 50

Function of 21-hydroxylase

Answer 50

Enzyme used in steroid hormone synthesis

Question 51

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

Answer 51

17 alpha hydroxylase 21 alpha hydroxylase 11 beta hydroxylase

Question 52

Deficiency in 21 alpha hydroxylase will prevent

Answer 52

Synthesis of aldosterone and cortisol

Question 53

What effects will 21 hydroxylase deficiency have on the body

Answer 53

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

Question 54

17 alpha hydroxylase deficiency leads to How does this present

Answer 54

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)**

Question 55

11 beta hydroxylase deficiency has similar symptoms to How does it present

Answer 55

21 alpha hydroxylase deficiency Decrease in serum cortisol and aldosterone, hypertension, exaggerated genitalia

Question 56

Function of glucocorticoids

Answer 56

Maintain blood glucose levels