Regulation of Cholesterol

Question 1

Rate limiting step of cholesterol synthesis

Answer 1

HMG-CoA reductase catalyzes the reduction of HMG-CoA —> Mevalonate

Question 2

Statins

Answer 2

Inhibit HMG-CoA reductase –> decrease cholesterol formation

Question 3

DHCR7 gene mutatino

Answer 3

Codes for 7-DeHydroCholesterol Reductase (last step of cholesterol syth)

Causes Smith-Lemili-Opitz Syndrome

AR

Results in low plasma cholesterol and accumulated precursors –> toxic to brain & retina

Question 4

Metabolic fates of cholesterol

Answer 4

1. Hepatocyte membranes
2. Bile acids, biliary cholesterol, cholesterol esters
3. steroid hormone synthesis
4. Liver/Kidney –> vitamin D synth
5. Small amts oxysterols formed in LIVER –> regulators of cholesterol synth

Question 5

Cholesterol esters

Answer 5

Formed in the LIVER

Catalyzes ACAT
FA from coenzyme A att to cholesterol –>makes cholesterol more hydrophobic –> CE secreted and stored in LIVER in lipid droplets

Question 6

Bile acids

Answer 6

Relatively hydrophilic –> emulsify dietary fats

Helps remove excess cholesterol via excretion (enhanced by dietary fiber, allows more cholesterol to be used to make bile)

Question 7

ApoB-48

Answer 7

Unique to chylomicron –> cholesterol transport/clearance

Core structural protein

Question 8

ApoC -II

Answer 8

Activates lipoprotein lipase (LPL)

Question 9

Exogenous pathway of lipoprotein metabolism

Answer 9

1. Incorporation of dietary fats –> chylomicrons in intestine
2. ApoC-II activates LPL
3. Chylomicron remnants being stored travel to LIVER and enter ApoE ligand

Question 10

VLDL

Answer 10

Lipids from LIVER –> peripheral tissue

ApoC-II activates LPL–> hydrolyzes TAG to glycerol & free FA

Loss of TAG converts VLDL to IDL (VLDL remnants)

Question 11

In fed state

Answer 11

Lipids generating VLDL particles are primarily coming from the diet –> VLDL particles take lipids to adipose –> storage

Question 12

In fasting state

Answer 12

Fatty acids from adipose travel to the LIVER to form VLDL particles –> transport FA to muscle –> make energy

Question 13

LDL Particles

Answer 13

Function to take cholesterol to extrahepatic tissues –> bind apoB-100 (LDL receptor)

Can be taken up by macrophages –> FOAM cells

Question 14

apoB-100 receptor

Answer 14

Recycles cell surface –> bind LDL –> cell surface

Question 15

Proprotein convertase subtilisin/kexin type 9 (PCSK9)

Answer 15

Responsible for degradation of LDL receptor

LOF mutation –> reduced plasma LDL

GOF mutation –> increased plasma LDL

Question 16

PCSK9 inhibitors

Answer 16

Antibodies to PCSK9

Binds PCSK9 to antibody instead of receptor –> allows receptor to continue to be recycled –> decrease plasma LDL levels

Question 17

PCSK9 inhibitors + statin

Answer 17

Statins decrease cell cholesterol concentration –> increased expression of LDL receptor

Antibodies to PCSK9 inhibitor LDLR breakdown, increasing receptor recycling

Question 18

HDL particles

Answer 18

Highest concentration of proteins (low TAG) –> scavenger excess cholesterol in periphery back to the LIVER

Originates in LIVER & Small intestine –> mature in circulation

Contains apoA-1 –> activates LCAT

Question 19

LCAT

Answer 19

Esterifies cholesterol in peripheral cell membranes –> makes them very hydrophobic to allow for integration into HDL particles

Catalyzes addition of free FA to cholesterol from phospholipid -> generates cholesteryl ester

Taken to liver to be stored or converted to bile acids

Question 20

HDL particle function

Answer 20

Take excess cholesterol from periphery and transport it back to LIVER

1. mature HDL particles
2. Bind scavenger receptor (SR-BI)
3. CE in HDL particles can be transferred to LDL via CETP

Question 21

CETP

Answer 21

Cholesterol Ester Transfer Protein

Transfer CE to LDL

Question 22

SR-BI

Answer 22

Scavenger receptor for HDL –> bind and release all contents into the cell and then the HDL particle dissociates and continues moving through circulation

Question 23

ATP-binding Cassette (ABC)

Answer 23

Key transporter of cholesterol out of the cell

ABCA1
ABCG1

Question 24

ABCA1

Answer 24

Interacts with ApoA-1 (on HDL) –> transports cholesterol from inside to outer surface of HDL

Associated with dx: Familial HDL deficiency (HDL extremely low)

Tangier dx (HDL levels undetectable)

Mutation–> loss of ability to transport cholesterol to periphery

Question 25

ABCG1

Answer 25

Interacts with mature HDL particles Promotes the movement of cholesterol into HDL

Question 26

Cholesterol 7a-hydroxylase (CYP7A1)

Answer 26

Catalyzes the catabolism of cholesterol to bile acids Regulated by levels of cholesterol and bile acids Bile acids: detergent that promote formation of micelles

Question 27

Enterohepatic pathway -- cholesterol secretion

Answer 27

Much cholesterol in LIVER is converted to bile salts --> store in gall bladder --> excreted into intestine post meal bile salts reabsorbed (in terminal ileum) by liver and recirculate through gallbladder

Question 28

Bile acid

Answer 28

Bile acids --> exist as bile salts --> amphipathic molecules stored in gallbladder Cholate --> most abundant bile acid (produces more water-soluble bile salts) Secrete excess cholesterol

Question 29

Bile acid binding resins

Answer 29

Cholestyramine --> insoluble resins that bind bile acids with high affinity Increase bile acid secretion and reduce overall cholesterol Excreted bile acid (not recycled) --> liver shunts cholesterol to bile acid synth --> decrease cholesteryl ester pool --> further decreases overall cholesterol

Question 30

Regulation of cholesterol synthesis and secretion

Answer 30

Synth is energy-expensive Regulators: Low ATP, Glucagon, Oxysterol inhibits HMG-CoA reductase Insulin stimulates HMG-CoA reductase

Question 31

HMG-CoA reductase Phosphorylated form

Answer 31

Inactive Glucagon --> HMG-CoA reductase phosphorylated by AMP-dependent protein kinase (AMPK) --> inactivated --> lack of cholesterol synth

Question 32

HMG-CoA reductase Dephosphorylated form

Answer 32

Active Promoted by insulin --> activation of enzyme and cholesterol synthesis Increased cellular cholesterol --> activation of ACAT for esterification to cholesteryl esters

Question 33

Regulation of Cholesterol Synthesis

Answer 33

Cholesterol regulates number of molecules of HMG-CoA Reductase via sterol regulatory element-binding proteins (SREBPs) --> regulate gene expression

Question 34

Niemann-Pick Type-C

Answer 34

Cholesterol is not transported out of lysosomes Accumulates in lysosomes of liver, brain, spleen, and/or lung Pathogenic mutations in NPC1 or NPC2

Question 35

NPC1 or NPC2

Answer 35

Genes encode proteins that act in tandem to transfer cholesterol out of the lysosome and into cytosol

Question 36

SREBP (sterol regulatory element-binding proteins)

Answer 36

Regulate gene expression Held in ER with SCAP (SREBP cleavage-activating protein)

Question 37

SCAP

Answer 37

Interacts with Insig (insulin-induced gene) SCAP & insig act as sterol sensor Increase sterol in the cell Insig-SCAP-SREBP retained in ER

Question 38

Drop in sterol in the cell

Answer 38

Insig is UBIQUITINATED SCAP-SREBP --> golgi Regulatory domain enters the nucleus and activates transcription of target genes (HMG-CoA reductase, LDL receptor, other proteins of lipid synth)

Question 39

Statin drugs inhibit HMG-CoA reductase

Answer 39

De novo cholesterol biosynthesis contributes to elevated LDL Capable of lowering plasma LDL levels Indirectly stimulate LDL receptor expression

Question 40

Ezetimibe

Answer 40

Blocks diet cholesterol import Block cholesterol absorption in the intestine Decrease plasma LDL levels Blocks cholesterol transporter Niemann Pick C1 - like 1 (NPC1L1)

Question 41

Bile acids sequestered in the intestine and excreted --> increase bile acid synth Decrease hepatic cholesterol

Answer 41

Increases LDL receptors Increases uptake of LDL particles Decreases plasma LDL cholesterol Used to tx FH by increasing expression of wild-type allele