4.04 Cholesterol Synthesis Regulation

Question 1

What are the three main sources of cholesterol that enter the liver?

Answer 1

dietary - chylomicron remnants
extrahepatic - HDL
de novo - made in liver

Question 2

What are the forms that cholesterol is excreted from the liver?

Answer 2

Secretion VLDL
Free cholesterol in bile
conversion to bile acids/salts

Question 3

What is cholesterol important for in the body?

Answer 3

membrane components
plasma lipoproteins
bile acid, steroid, Vit D precursor

Question 4

cholesterol structural components?

Answer 4

four fused rings
extremely hydrophobic

Question 5

What form of cholesterol is stored within cells and even more hydrophobic?

Answer 5

esterified cholesterol

Question 6

What makes cholesterol in the body?

Answer 6

nearly all tissues
(but especially liver, adrenal cortex, and reproductive)

Question 7

Production of cholesterol begins with what?

Answer 7

acetyl coA (2)

Question 8

Why do you need NADPH in cholesterol synthesis?

Answer 8

Used to reduce cholesterol and generate energy

Question 9

cholesterol synthesis is responsive to what?

Answer 9

intracellular cholesterol concentration*

Question 10

Where does cholesterol synthesis take place in a cell?

Answer 10

cytosol

Question 11

Describe the key first two steps of cholesterol synthesis

Answer 11

(2) acetyl CoA -> acetoacetyl CoA

+ Acetyl CoA –> HMG CoA
Enz: ** HMG CoA Synthase**

Question 12

Cholesterol synthesis mimics what other reaction within hepatocytes?

Answer 12

ketone synthesis

Question 13

When does NADPH first come into play in cholesterol synthesis?

Answer 13

production of mevalonate from HMG CoA

Question 14

Key regulating step (rate limiting) in cholesterol synthesis?

Answer 14

HMG CoA Reductase**
enzyme inhibited by cholesterol
needed to make mevalonate
NADPH required

Question 15

What drug inhibits HMG COA reductase to lower cholesterol?

Answer 15

statins (inhibit endogenous production and promote more cell uptake from circulation)

Question 16

Mutations in what gene cause Smith Lemli Opitz Syndrome?

Answer 16

DHCR7
needed for final step of cholesterol synthesis

Question 17

AR disorder with a broad phenotypic spectrum including microcephaly, developmental delay, cardiac defects, syndactyly toes, etc. that leads to low cholesterol and accumulated precursors?

Answer 17

SLOS - Smith Lemli Opitz Syndrome

Question 18

What enzyme catalyzes cholesterol storage within a cell?

Answer 18

ACAT acyl-CoA-cholesterol acyltransferase

Question 19

What is the role of bile acids?

Answer 19

emulsify fats after a fatty meal and a way to excrete cholesterol (made more hydrophilic)

Question 20

What can enhance the bile acid cholesterol excretion and lower endogenous cholesterol?

Answer 20

dietary fiber

Question 21

exogenous cholesterol metabolism?

Answer 21

dietary cholesterol packed into chylomicrons

Question 22

endogenous metabolism cholesterol?

Answer 22

lipids packed into VLDL in the liver

Question 23

Reverse cholesterol pathway?

Answer 23

HDL transports cholesterol from extrahepatic tissue (plasma membranes) to the liver

Question 24

What kind of plasma lipoprotein has the highest density of protein?

Answer 24

HDL
(protein > lipids)

Question 25

What kind of plasma lipoprotein has the highest concentration of cholesterol?

Answer 25

LDL

Question 26

What plasma lipoprotein has the highest concentration of TAG?

Answer 26

chylomicrons

Question 27

Where are chylomicrons assembled to transport dietary lipids?

Answer 27

intestine

Question 28

What kind of apolipoprotein do chylomicrons have?

Answer 28

ApoB-48 (first half = APOB gene)

Question 29

What protein helps form teh chylomicron?

Answer 29

MTP microsomal triglyceride transfer protein

Question 30

How do nascent chylomicrons integrate ApoE and ApoC-II to fully form?

Answer 30

HDL in circulation

Question 31

Roles of ApoE and ApoC-II respectively?

Answer 31

ApoE = hepatocyte uptake of chylomicron remnant ApoC-II = activate lipoprotein lipase

Question 32

What protein hydrolyzes 90% of chylomicrons TAG into FA and glycerol in tissues?

Answer 32

lipoprotein lipase

Question 33

VLDLs are generated where?

Answer 33

liver

Question 34

Where does the free glycerol go?

Answer 34

liver for glycolysis

Question 35

What kind of ApoB is in VLDL?

Answer 35

ApoB-100

Question 36

VLDL is degraded in to what post LPL degrading teh TAG?

Answer 36

IDL

Question 37

How can cholesterol ester be moved from HDL to VLDL?

Answer 37

via CETP (trade cholesterol ester for TAG)

Question 38

What does IDL become?

Answer 38

LDL to be taken up by extrahepatic tissue and liver

Question 39

What does ApoB-100 do?

Answer 39

help to stabilize LDL attachment to receptor in clathrin pit to be taken to by hepatocyte

Question 40

Intracellular cholesterol inhibits HMG CoA reductase (endogenous metabolism) and the expression of what gene?

Answer 40

LDL receptor protein (inhibit the uptake of cholesterol)

Question 41

If not needed immeidtaley what esterifies the choelsterol?

Answer 41

ACAT

Question 42

What kind of mutation is in Niemann Pick Type C? What is it responsible for?

Answer 42

NPC1 or NPC2 (transfer cholesterol out of lysosome into cytosol)

Question 43

Where does the cholesterol accumulate in Neiman Pick Type C Syndrome?

Answer 43

lysosomes of liver, brain, spleem, and lung

Question 44

What promotes the degradation of LDL receptors to increase the circulation of LDL?

Answer 44

PCSK9

Question 45

What kind of mutation at PCSK9 is associated with reduced circulating LDL?

Answer 45

loss of function mutation

Question 46

What kind of mutation at PCSK9 is associated with more circulating LDL?

Answer 46

gain of function mutation

Question 47

HDL originates where?

Answer 47

liver and small inestine

Question 48

What kind of Apo in HDL?

Answer 48

ApoA-1

Question 49

What do HDLs do?

Answer 49

cholesterol from periphery to the liver

Question 50

What catalyses teh esterification of cholesterol allowing them to be transported through circulation?

Answer 50

LCAT

Question 51

What mediates the movement of cholesterol within a cell (inside to outside)?

Answer 51

ABCA1

Question 52

What does HDL2 bind to on the liver to pass along the cholesterol (just expel the contents)?

Answer 52

SR-B1

Question 53

What are the cholesterol scavengers to take excess cholesterol to the liver?

Answer 53

HDL

Question 54

What activates LCAT?

Answer 54

ApoA-I

Question 55

What interacts with the mature HDLs to pass along HDL from intracellular to them?

Answer 55

ABCG1

Question 56

What conditions result in low HDL levels or almost undetectable levels? What mutation?

Answer 56

Familial HDL Deficiency Tangier Disease Mutations to ABCA1 (Can't take up cholesterol)

Question 57

What catalyzes the catabolism of cholesterol to bile acids?

Answer 57

CYP7A1

Question 58

Where are 95% of the bile acids secreted by the intestine reabsorbed?

Answer 58

terminal ileum

Question 59

What is enterohepatic circulation?

Answer 59

continuous cycle of bile acid secretion and excretion

Question 60

What is teh most common bile acid?

Answer 60

cholate (water soluble)

Question 61

About how much bile acids are excreted and how?

Answer 61

<3% feces some excess cholesterol too

Question 62

What are bile acid-binding resins?

Answer 62

increase bile acid secretion to reduce overall cholesterol (by binding with high affinity and insoluble so can't be reabsorbed)

Question 63

What to note about using bile acid resins clinically?

Answer 63

patient would need to consume large amounts so used in conjunction with other therapies

Question 64

What regulated cholesterol production overall?

Answer 64

intracellular cholesterol ATP supply glucagon + insulin

Question 65

What makes HMG-CoA reductase inactive?

Answer 65

phosphorylation by AMPK

Question 66

What does glucagon do (cholesterol synthesis)?

Answer 66

promotes the inactive form of HMG-CoA reductase, especially in fasting states

Question 67

What does insulin do (cholesterol synthesis)?

Answer 67

promote the ACTIVE form of HMG-CoA reductase

Question 68

What do oxysterols do?

Answer 68

also inhibit HMG-CoA reductase by indicating a lot of esterified cholesterol (storage)

Question 69

How can you regulate cholesterol long-term?

Answer 69

via SREBPs held in ER with SCAP --> insig (sterol sensors)

Question 70

If there is low cholesterol in the cell how does that influence the expression of the LDL gene?

Answer 70

want to promote LDLR expression (via Insig being ubiquitinated - SCRAP-SREBP cleaved at Golgi - SREBPs domain activated transcription at the nucleus)

Question 71

Statins do what to lower cholesterol levels?

Answer 71

inhibit De novo - endogenous lower plasma LDL indirectly simulate LDLR

Question 72

If statins do not work what else can you use (pharm)?

Answer 72

Ezetimibe blocks NPC1L1 (cholesterol absorption in the intestine)

Question 73

What does Ezetimbie block?

Answer 73

cholesterol absorption in the intestine via NPC1L1