cholesterol synthesis and transport

Question 1

what do statins inhibit, and what do they resemble?

Answer 1

inhibit HMG-coA reductase, and resemble mevalonate, the product of reducing HMG-coA with HMG-coA reductase

Question 2

potential side effects of statins (mech not understood)

Answer 2

myopathy and rhabdomyolysis

Question 3

examples of statins

Answer 3

compactin, simvastatin (zocor), pravastatin (pravachol), lovastatin (mevacor)

Question 4

full name HMG coA

Answer 4

3-hydroxy-3-methylglutaryl-coA

Question 5

mevalonate converted to ? which is a type of ?which are added together to make ?

Answer 5

isopentenyl pyrophosphate. C5 isoprene. squalene, and c30 polyisoprene

Question 6

squalene is turned into an epoxide and reacts with itself to form ? which undergoes how many steps and what changes to become cholesterol?

Answer 6

lanosterol which undergoes 19 steps to be converted to cholesterol, including a reduction of a double bond, and isomerization of a double bond, two carbons removed as CO2, and one carbon removed as HCOO- for one-carbon metabolism (eat a dick Tim)

Question 7

HMG-coA reductase regulated (4)

Answer 7

phosphorylation by glucagon (inactive), dephosphorylation by insulin (active), high levels of cholesterol cause proteolysis, transcription by SREBP

Question 8

HMG-coA reductase synthesis inhibition

Answer 8

high cholesterol, cholesterol binds SCAP (SCREB cleavage-activating protein) on ER membrane, which prevents transport of SREBP (Sterol regulatory element-binding proteins) and the attached DNA binding domain to the golgi

cholesterol low, cholesterol unbinds and SCAP and SREBP move to the golgi and DNA binding domain is cleaved off causing to gene transcription

Question 9

formed by cholesterol and isopentenyl pyrophosphate

Answer 9

cholesterol: steroid hormones, bile acids, vitamin D
isopentenyl pyrophosphate: Vitamin A, E, and K, carotenoids, isoprene, quinone e- carriers (ubiquinone, plastoquinone), rubber; phytol chain of chlorophyll…

Question 10

rate limiting step of bile acid to bile acid formation

Answer 10

7alpha-hydroxylase (CYP7A1) which converts cholesterol to 7alpha hydrocholesterol. Inhibited by bile salts

Question 11

bile acids to bile salts and secondary bile salts

Answer 11

add glycine or taurine (the amide bond) to make the bile salt.
secondary bile salts are deconjugated by bacteria and 7-OH removed

Question 12

factors in cholesterol stones

Answer 12

1. bile acid levels
2. biliary cholesterol secretion
3. gallbladder hypomotility

(80% US gallstones are cholesterol stones)

Question 13

In blood, esterifies HDL cholesterol so it is retained in particles

Answer 13

Lecithin: cholesterol HDL cholesterol acyltransferase (LCAT). lecithin is phosphatidycholine (major component of cell membranes)

Question 14

Acyl: cholesterol acyltransferase

Answer 14

Intracellular, packages cholesterol of VLDL and storage in liver for bile production

Question 15

involved in HDL to VLDL transfer of cholesterol

Answer 15

Cholesterol ester transfer protein (CEPT)

Question 16

what does LDL receptor bind to

Answer 16

recognizes apoE and apoB-100. binds to VLDL, IDL, LDL, and chylomicron remnants

Question 17

Where LDL receptor related proteins (LRPs) in the body, what do they bind to, and what is their expression dependent on?

Answer 17

Liver, brain, and placenta.
bind apoE (clears remnants?)
expression increases in response to insulin but independent of [cholesterol]

Question 18

what is SR-B1

Answer 18

scavenger receptor-B1 binds HDL on the liver to accept the cholesterol coming in from the tissue

Question 19

how do foam cells form and where

Answer 19

SR-A1, SR-A2 on macrophages bind oxidized LDL (oxidized by superoxides such as H2O2 and inhibited by vit E, C, and A). macrophage engulfs many of these and becomes engorged in the intima of a blood vessel

Question 20

what causes familial hypercholesterolemia (FH) and what are the symptoms

Answer 20

defective LDL receptor (heterozyotes 200-400mg/dL, homozygotes 500-800mg/dL serum cholesterol). 
-incr. coronary artery disease 
xanthomas (chol rich material on tendons)
corneal arcus (white line on edge of cornea)

Question 21

Familial ligand defective ApoB-100

Answer 21

similar symptoms to FH, but not as severe. (LDL recognizes apoE so VLDL and IDL uptake normal)

Question 22

what transports cholesterol out of macrophages into HDL, what what disease occurs when this does not occur enough because of extremely low HDL levels

Answer 22

ABC A1 (ATP binding cassette family of transporters). defective in Tangier disease.

Question 23

Liver X receptor (LXR) and retinal X receptor (RXR) form a heterodimer transcriptional activator complex and activate what when bound with what?

Answer 23

activate expression of CETP and ABCA1 when cholesterol levels are high and oxysterols (e.g. 25-hydroxycholesterol) are present.

(note: RXR also forms a dimer with PPARalpha and regulates fatty acid metabolism on binding specific lipids)

Question 24

how does cholestyramine lower cholesterol

Answer 24

binds negatively charged bile acids in small intestine, increases bile secretion. liver must then make more bile and increases LDL uptake so total and LDL cholesterol decrease

Question 25

how does eztimibe (Zetia) work to lower cholesterol

Answer 25

prevents cholesterol absorption in the small intestine. showed little benefit in plaque reduction.

Question 26

how do fibrates work

Answer 26

agonist of PPARalphas--activate synth of many proteins on lipid metabolism. lower triglycerides (30%), total and LDL chol (10-15%), and may incr HDL (15-20%)

Question 27

fenofibrate and gemfribrazil are examples of?

Answer 27

fibrates

Question 28

nicotinic acid acts how and does it reduce risk?

Answer 28

water soluble vitamin B3 inhibits hormone sensitive lipase in adipose tissues, reducing plasma triglycerol, and thus reducing VLDL synth. did not lower vascular events.