Lecture 44

Question 1

Cholesterol is a major component in:

Answer 1

Cell plasma membranes

Question 2

Describe plasma membrane cholesterol

Answer 2

Cholesterol is an amphipathic molecule, meaning, like phospholipids, it contains a hydrophilic and a hydrophobic portion. It slightly immobilizes the outer surface of the membrane and makes it less soluble to very small water-soluble molecules that could otherwise pass through more easily

Question 3

In order of very low levels to very high levels, what cellular components (4) have cholesterol?

Answer 3

1) Rough ER (Lowest amount of cholesterol)
2) Smooth ER
3) Golgi
4) Plasma membrane

Question 4

What are 5 major classes of steroid hormones derived from cholesterol?

Answer 4

1) Progestagens
2) Glucocorticoids (subclass of progestagens)
3) Mineralocorticoids (subclass of progestagens)
4) Androgens (subclass of progestagens)
5) Estrogens (subclass of Androgens)

Question 5

What are key characteristics of cholesterol?

Answer 5

1) Made up of 27 carbons, all derived from acetate
2) C3 has a hydroxyl group
3) C17 has a side chain with 8 carbons

Question 6

Where does cholesterol come from?

Answer 6

1) Synthesized primarily in the liver & intestine
2) Not required in the diet
3) Intestinal uptake from diet

Question 7

How is cholesterol eliminated from the body?

Answer 7

1) Converted into bile acids & bile salts in the liver
2) Stored in gall bladder or secreted into the intestine
3) Small % excreted in feces

Question 8

What are cholesterol esters?

Answer 8

1) Esterification at C3 with fatty acid
2) Primary form transported in plasma
3) Packaged in lipoprotein particles (LDL, HDL, etc.)

Question 9

How is HMG CoA synthesized?

Answer 9

1) 2 Acetyl CoA undergo a reaction catalyzed by thiolase to release CoA and transfer the acetyl group to form 2-acetoacetyl CoA
2) 2-acetoacetyl CoA undergoes a reaction with acetyl CoA catalyzed by HMG CoA synthase to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA) and release CoA
3) Reactions occur in the cytosol, mitochondria, & peroxisomes

Question 10

How is Mevalonic Acid synthesized?

Answer 10

1) HMG CoA undergoes a reaction catalyzed by HMG CoA reductase, oxidized 2 NADPH, releases a CoA, & forms Mevalonic acid in the ER (rate limiting step)
2) Mevalonic acid can undergo a series of reactions to form cholesterol

Question 11

How is cholesterol synthesized from Mevalonic Acid?

Answer 11

Mnemonic: My Porsche Is Darn Good For Seeing London

1) Kinases phosphorylate mevalonic acid using ATP to produce 5-pyrophosphomevalonic acid (cytosol, mitochondria & peroxisomes)
2) A decarboxylase uses ATP to produce Isopentyl pyrophosphate (IPP) from 5-pyrophosphomevalonic acid (Produces 3 ATP + 2 NADPH) (ER)
3) An isomerase produces 3,3-Dimethylallyl pyrophosphate (DPP) (Produces 3 ATP + 2 NADPH) (peroxisomes)
4) An FPP transferase uses inorganic phosphate to produce Geranyl pyrophosphate (GPP) (Produces 3 ATP + 2 NADPH) (peroxisomes)
5) An FPP transferase uses inorganic phosphate to produce Farnesyl pyrophosphate (FPP) (peroxisomes)
5) A squalene synthase produces squalene from Farnesyl pyrophosphate (FPP) (peroxisomes)
6) Squalene monoxygenase produces lanosterol from squalene (peroxisomes)
7) Cholesterol is produced from lanosterol (ER + peroxisomes)

Question 12

How is cholesterol regulated through gene expression?

Answer 12

1) Increase in intracellular cholesterol causes a decrease of transcription of nearly all genes encoding proteins in the cholesterol synthesis pathway
2) A decrease in intracellular cholesterol causes an increase in transcription of cholesterol synthesis proteins

Question 13

What is the transcription factor responsible for cholesterol gene expression?

Answer 13

The transcription factor regulating cholesterol synthesis genes is SREBP-sterol responsive element binding protein

Question 14

What is Sterol Regulatory Element Binding Protein (SREBP)?

Answer 14

1) a transmembrane protein
2) has a DNA binding domain
3) has a SCAP interacting domain

Question 15

What is SREBP Cleavage Activating Protein (SCAP)?

Answer 15

1) a transmembrane protein
2) has a sterol sensing domain
3) binds to SREBP in the ER
4) when ER sterols are low, SCAP-SREBP move to the Golgi

Question 16

What do protease 1 and 2 do?

Answer 16

1) localized to the golgi

2) responsible for the two step cleavage of SREBP resulting in soluble, cytosolic SREBP

Question 17

What is mature, proteolytically processed SREBP?

Answer 17

1) translocates from the Golgi to the nucleus

2) Activates the expression of cholesterol synthesis genes

Question 18

What are the steps to?

Answer 18

1) When sterol levels are low, SCAP and SREBP are transported to the golgi
2) Protease 1 cuts a connection to SREBP
3) Protease 2 releases SREBP
4) SREBP translocates to the nucleus causing transcriptional activation of sterol responsive element (SRE) controlled genes

Question 19

How does cholesterol regulate the stability of HMG CoA reductase?

Answer 19

1) Increased intracellular cholesterol causes a reduction in the stability of HMG CoA reductase (misfolding and degradation)
2) Decreased intracellular cholesterol causes an increase in the stability of HMG CoA (proper protein folding)

Question 20

What happens when HMGR is phosphorylated?

Answer 20

1) HMGR is phosphorylated by an AMP activated kinase (AMP kinase - not the same as cAMP kinase)
2) Low levels of ATP & high levels of AMP causes AMP activated kinase activation, HMGR phosphorylation, & decreased cholesterol synthesis

Question 21

How is HMGR expression hormonally regulated?

Answer 21

1) Insulin stimulates HMGR expression & activity

2) Glucagon inhibits HMGR expression & activity

Question 22

What are competitive drug inhibitors of HMGR?

Answer 22

1) Statins competitively inhibit HMGR because they mimic the transient intermediate mevadyl CoA
2) Examples: Mevacor, altocor, pravachol, zocor, lipitor, baycol, & lescol

Question 23

What does zetia (ezetimibe) do?

Answer 23

1) acts on small intestine brush border)
2) does not enter the bloodstream, no side effects
3) inhibits absorption of cholesterol
4) does not block absorption of triglycerides or fat soluble vitamins

Question 24

What does vytorin (ezetimibe + simvastatin) do?

Answer 24

1) ezetimibe is administered in combination with a simvastatin
2) further reduces total cholesterol levels as compared
to statin alone
3) blocks cholesterol absorption in the intestine and
cholesterol synthesis in the liver
4) permits reduced doses of statins, which have
side effects

Question 25

What do bile acids & bile salts do?

Answer 25

1) cholesterol is the precursor of bile acids and bile salts
2) synthesized in the liver
3) stored in the gall bladder
4) secreted into intestine
5) aid digestion by emulsifying dietary lipids making them accessible to pancreatic lipases
6) aid intestinal absorption of fat-soluble vitamins (A, D, E, K)
7) ~95% are reabsorbed in ileum and returned to liver; 5% excreted in feces

Question 26

What is enterohepatic circulation?

Answer 26

1) synthesis in liver
2) storage in gall bladder
3) secretion into intestine
4) recirculation to liver

Question 27

What is the principal mechanism of excreting cholesterol from the body?

Answer 27

Excretion of bile salts is the principal mechanism

for eliminating cholesterol from the body

Question 28

What are the steps in forming primary bile acids from cholesterol?

Answer 28

1) 7-alpha-hydroxylase converts cholesterol to 7-alpha-hydroxycholesterol (rate limiting step; negative feedback from cholic acid; positive feedback from cholesterol)
2) 7-alpha-hydroxycholesterol breaks apart into cholic acid & chenodeoxycholic acid

Question 29

What are the steps in forming secondary bile acids?

Answer 29

1) Cholic acid is converted to deoxycholic acid

2) Chenodeoxycholic acid is converted to lithocholic acid

Question 30

How is hypercholesterolemia treated?

Answer 30

Hypercholesterolemia is often treated with compounds that sequester bile acids in the intestine.
Sequestrants:
1) prevent reabsorbtion of bile acids
2) increase conversion of cholesterol to bile acids
3) increase bile salt elimination in feces
4) dietary fiber also sequesters bile acids

Question 31

What are bile salts?

Answer 31

Bile salts are bile acids conjugated to glycine or taurine in liver

Question 32

How are bile acid receptors as targets for drug development?

Answer 32

1) Farnesoid X receptor and TGR5 a G protein-coupled receptor respond to bile acids by activating transcription and/or signaling cascades that mediate: metabolism of bile acid, cholesterol, lipid and carbohydrates inflammation fibrosis carcinogenesis
2) agents modulating these receptors are potentially a new class of drugs for treating metabolic diseases chronic liver disease hepatocellular cancer extrahepatic inflammatory