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GEM > 4.04 Cholesterol Synthesis Regulation > Flashcards

4.04 Cholesterol Synthesis Regulation Flashcards

1
Q

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

A

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

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2
Q

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

A

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

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3
Q

What is cholesterol important for in the body?

A

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

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4
Q

cholesterol structural components?

A

four fused rings
extremely hydrophobic

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5
Q

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

A

esterified cholesterol

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6
Q

What makes cholesterol in the body?

A

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

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7
Q

Production of cholesterol begins with what?

A

acetyl coA (2)

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8
Q

Why do you need NADPH in cholesterol synthesis?

A

Used to reduce cholesterol and generate energy

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9
Q

cholesterol synthesis is responsive to what?

A

intracellular cholesterol concentration*

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10
Q

Where does cholesterol synthesis take place in a cell?

A

cytosol

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11
Q

Describe the key first two steps of cholesterol synthesis

A

(2) acetyl CoA -> acetoacetyl CoA

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

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12
Q

Cholesterol synthesis mimics what other reaction within hepatocytes?

A

ketone synthesis

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13
Q

When does NADPH first come into play in cholesterol synthesis?

A

production of mevalonate from HMG CoA

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14
Q

Key regulating step (rate limiting) in cholesterol synthesis?

A

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

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15
Q

What drug inhibits HMG COA reductase to lower cholesterol?

A

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

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16
Q

Mutations in what gene cause Smith Lemli Opitz Syndrome?

A

DHCR7
needed for final step of cholesterol synthesis

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17
Q

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

A

SLOS - Smith Lemli Opitz Syndrome

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18
Q

What enzyme catalyzes cholesterol storage within a cell?

A

ACAT acyl-CoA-cholesterol acyltransferase

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19
Q

What is the role of bile acids?

A

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

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20
Q

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

A

dietary fiber

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21
Q

exogenous cholesterol metabolism?

A

dietary cholesterol packed into chylomicrons

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22
Q

endogenous metabolism cholesterol?

A

lipids packed into VLDL in the liver

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23
Q

Reverse cholesterol pathway?

A

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

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24
Q

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

A

HDL
(protein > lipids)

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25
Q

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

A

LDL

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26
Q

What plasma lipoprotein has the highest concentration of TAG?

A

chylomicrons

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27
Q

Where are chylomicrons assembled to transport dietary lipids?

A

intestine

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28
Q

What kind of apolipoprotein do chylomicrons have?

A

ApoB-48
(first half = APOB gene)

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29
Q

What protein helps form teh chylomicron?

A

MTP microsomal triglyceride transfer protein

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30
Q

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

A

HDL in circulation

31
Q

Roles of ApoE and ApoC-II respectively?

A

ApoE = hepatocyte uptake of chylomicron remnant

ApoC-II = activate lipoprotein lipase

32
Q

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

A

lipoprotein lipase

33
Q

VLDLs are generated where?

A

liver

34
Q

Where does the free glycerol go?

A

liver for glycolysis

35
Q

What kind of ApoB is in VLDL?

A

ApoB-100

36
Q

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

A

IDL

37
Q

How can cholesterol ester be moved from HDL to VLDL?

A

via CETP (trade cholesterol ester for TAG)

38
Q

What does IDL become?

A

LDL to be taken up by extrahepatic tissue and liver

39
Q

What does ApoB-100 do?

A

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

40
Q

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

A

LDL receptor protein
(inhibit the uptake of cholesterol)

41
Q

If not needed immeidtaley what esterifies the choelsterol?

A

ACAT

42
Q

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

A

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

43
Q

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

A

lysosomes of liver, brain, spleem, and lung

44
Q

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

A

PCSK9

45
Q

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

A

loss of function mutation

46
Q

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

A

gain of function mutation

47
Q

HDL originates where?

A

liver and small inestine

48
Q

What kind of Apo in HDL?

A

ApoA-1

49
Q

What do HDLs do?

A

cholesterol from periphery to the liver

50
Q

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

A

LCAT

51
Q

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

A

ABCA1

52
Q

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

A

SR-B1

53
Q

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

A

HDL

54
Q

What activates LCAT?

A

ApoA-I

55
Q

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

A

ABCG1

56
Q

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

A

Familial HDL Deficiency
Tangier Disease

Mutations to ABCA1
(Can’t take up cholesterol)

57
Q

What catalyzes the catabolism of cholesterol to bile acids?

A

CYP7A1

58
Q

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

A

terminal ileum

59
Q

What is enterohepatic circulation?

A

continuous cycle of bile acid secretion and excretion

60
Q

What is teh most common bile acid?

A

cholate (water soluble)

61
Q

About how much bile acids are excreted and how?

A

<3% feces
some excess cholesterol too

62
Q

What are bile acid-binding resins?

A

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

63
Q

What to note about using bile acid resins clinically?

A

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

64
Q

What regulated cholesterol production overall?

A

intracellular cholesterol
ATP supply
glucagon + insulin

65
Q

What makes HMG-CoA reductase inactive?

A

phosphorylation by AMPK

66
Q

What does glucagon do (cholesterol synthesis)?

A

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

67
Q

What does insulin do (cholesterol synthesis)?

A

promote the ACTIVE form of HMG-CoA reductase

68
Q

What do oxysterols do?

A

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

69
Q

How can you regulate cholesterol long-term?

A

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

70
Q

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

A

want to promote LDLR expression

(via Insig being ubiquitinated - SCRAP-SREBP cleaved at Golgi -
SREBPs domain activated transcription at the nucleus)

71
Q

Statins do what to lower cholesterol levels?

A

inhibit De novo - endogenous
lower plasma LDL
indirectly simulate LDLR

72
Q

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

A

Ezetimibe
blocks NPC1L1 (cholesterol absorption in the intestine)

73
Q

What does Ezetimbie block?

A

cholesterol absorption in the intestine via NPC1L1

GEM (29 decks)

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