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Cardiovascular > SM 125 Lipoprotein Metabolism and Pharmacology > Flashcards

SM 125 Lipoprotein Metabolism and Pharmacology Flashcards

1
Q

What are side effects of statins?

A

Hepatotoxicity up to 3x normal AST/ALT

Rhabdomyolysis or Myalgia of arm and leg muscles with elevated CK

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2
Q

What role does LCAT play?

A

Lecithin Cholesterol Acetyltransferase acts on pre-B-HDL to acylate Cholesterol, leading to internalization of Cholesterol esters and forming a cuboidal shape

LCAT is activated by binding to HDL surface and uses a Phospholipid as an Acyl donor

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3
Q

What is Cholesterol?

A

A sterol in the Eukaryotic membrane which maintains membrane fluidity and is a precursor to steroids and hormones

Free -OH

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4
Q

What is the fate of LDL?

A

LDL uses ApoB100 to bind LDLR in either the Liver or Peripheral tissues, allowing it to deliver Cholesterol and lower the amount of Cholesterol in the bloodstream

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5
Q

What are oxidized LDL and how do they form?

A

Oxidized LDL is a derivative of LDL that cannot be taken up using LDLR

Oxidized LDL is taken up by macrophages and results in the formation of foam cells and eventually Atherosclerosis

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6
Q

How are PCSK9 inhibitors administered?

A

IV, second line to statins

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7
Q

What is direct transport of HDL?

A

HDL binds to SR-B1 in the Liver and enters directly

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8
Q

What does LDL contain?

A

ApoB100 alone, and Cholesterol

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9
Q

What is indirect transport of HDL?

A

HDL is acted on by Cholesterol Ester Transfer Protein (CETP) to form LDL which enter the Liver via LDLR

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10
Q

What is LRP and what does it do?

A

LRP is Lipoprotein Receptor Protein; binds ApoE and ApoB48 on Chylomicron remnants

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11
Q

How are lipoproteins characterized?

A

They are characterized by differences in electrophoretic mobility, due to differences in size/charge ratio’s and density that arise from the relative amount of protein:lipid in their composition

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12
Q

How does Cholesterol flow through the Exogenous pathway?

A

Micelles in the small intestine are emulsified by Bile Acids

Micelles are then taken up into Enterocytes using the transporter NPC1L1

Enterocytes then package TG, Cholesterol, and Phospholipids into the Micelles and release them into Lymph ducts as Nascent Chylomicrons

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13
Q

What are the four major pathways of Cholesterol flux?

A

Cholesterol flux is primarily mediated by:

Exogenous Pathway (dietary intake)
Endogenous Pathway (Liver production of VLDL)
Reverse Cholesterol Transport (Peripheral to Liver)
Enterohepatic Circulation (Recirculation of Bile)
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14
Q

How do nascent Chylomicrons enter circulation?

A

They are released by enterocytes into circulation at the Lymphatic duct and enter circulation using the left brachiocephalic vein

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15
Q

What is the Friedwald Equation?

A

Approximation used to derive LDL-c

0.2 * TG + HDL-c + LDL-c = TC

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16
Q

What should be done to lower High LDL-c?

A

Statin = first line

Second line varies = Ezetimibe or Bile Acids (poorly tolerated)

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17
Q

What are lipids and what is their common underlying feature?

A

Lipids are a group of heterogeneous compounds with varied structures

They are all insoluble in water

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18
Q

What statins are unaffected by CYP?

A

Pravastatin

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19
Q

How do Bile Acid sequestrants work?

A

They bind bile acids in the gut to prevent their reuptake and force Cholesterol to be used to replenish them, lowering Cholesterol in the Liver and inducing hepatocyte expression of LDLR to lower serum Cholesterol

Second line to statins

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20
Q

What lipoproteins do nascent Chylomicrons contain?

A

Nascent Chylomicrons contain Apo-B48 and Apo-A1

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21
Q

What are high intensity statins?

A

Statins that lower LDL-c by 50% or more

Atorvastatin 40 or 80mg/day
Rosuvastatin 20 or 40mg/day

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22
Q

What effects do Fibrates have?

A

Normal TG + Elevated LDL = lower LDL
Elevated TG + Normal LDL = lower TG + increase LDL

Always raises HDL

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23
Q

What is Familial Chylomicronemia Syndrome?

A

Due to a defiency in either Lipoprotein L or ApoC-II, which are needed for the hydrolysis of TG into FA

Leads to very high levels of Chylomicrons and high TG since they are unable to deliver FA

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24
Q

How does reverse Cholesterol transport progress?

A

ApoA1 produced by the Liver is lipidated to form pre-B-HDL, which is discoid in shape

Pre-B-HDL is acted on by LCAT to transfer esters to it’s Cholesterol groups, making them more hydrophobic and leading to internal aggregation that forms a spherical shape overall; direct or indirect transport of HDL ensues

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25
Q

What is Familial Hypertriglyceridemia?

A

Autosomal dominant, family history of overproduction of VLDL leading to high levels of TG

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26
Q

What should be done to lower high TG?

A

Check to make sure patient does not have DM or hypothyroidism

Fibrates and Omega-3 fatty acids to reduce risk of Pancreatitis

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27
Q

What are Free Fatty Acids?

A

A fatty acid chain that may be saturated or unsaturated

Carboxylic acid head group, ampiphathic

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28
Q

What is PCSK9 deficiency?

A

Deficiency of PCSK9 disinhibits LDLR expression, leading to elevated levels of LDLR on Hepatocytes and lowered LDL levels in the blood

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29
Q

What transports TG from Liver to tissues?

A

Chylomicrons and VLDL transport TG from Liver to tissues via LPL

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30
Q

What are Phospholipids?

A

Diverse and complex group of lipids with 2FA linked to a glycerol along with a phosphate and head group

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31
Q

What is a Cholesterol Ester?

A

Cholesterol with an ester that covers the Free -OH, less hydrophilic and more hydrophobic

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32
Q

What is the risk of elevated TG?

A

Pancreatitis, common in Familial Hypertriglyceridemia

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33
Q

What drug increases the toxicity of all statins?

A

Cyclosporine

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34
Q

What is enterohepatic circulation?

A

The recirculation of bile salts in the gut

Bile salts are formed from Cholesterol, and loss of bile salts uses up Cholesterol to reform them, so they are normally recycled

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35
Q

What levels of HDL, LDL, and TG are associated with disease?

A

High LDL, High TG, low HDL = disease

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36
Q

What is Apolipoprotein B deficiency?

A

Genetic disorder affecting ApoB resulting in elevated LDL-c since LDLR do not uptake LDL normally

37
Q

Order the lipoprotein classes by size:

A

Small to large:

HDL < LDL < IDL < VLDL < Chylomicron Remnants < Chylomicrons

38
Q

What is the mode of action of Ezetimibe?

A

Inhibits NPC1L1 in enterocytes to block reuptake of Cholesterol

Second line after statins

39
Q

What is reverse Cholesterol transport?

A

The uptake of Cholesterol by HDL from peripheral sites and delivery to the Liver

40
Q

What is Dysbetalipoproteinemia?

A

Defect in ApoE2 synthesis, an LDL cofactor, that prevents binding to Lipoprotein receptors

Results in accumulation of IDL that cannot be converted into LDL, increases risk of atherosclerosis

41
Q

What groups do statins effect the most?

A

High risk groups gain the most benefit from statins

42
Q

What statins are affected by CYP3A4?

A

ASL

Atorvastatin
Simvastatin
Lovastatin

43
Q

What does LDL-c refer to?

A

LDL-c = LDL cholesterol = amount of Cholesterol and Cholesterol Ester found on LDL in the blood

44
Q

What is the relationship between size and density in a lipoprotein?

A

Increasing size leads to decreasing density and vice versa

45
Q

Why do PCSK9 inhibitors work?

A

PCSK9 inhibitors disinhibit LDLR expression, allowing the Liver to express more LDLR and take more LDL out of circulation to lower blood Cholesterol

46
Q

What statins are affected by CYP2C9?

A

Fluvastatin

47
Q

Describe the response to decreased Cholesterol in the Liver?

A

Decreased cholesterol is detected by SREBP

SREBP induces transcription of LDLR mRNA to upregulate LDLR

SREBP also induces PCSK9 to inhibit expression of LDLR

Overall LDLR is expressed, with some inhibition, to pull more LDL/Cholesterol out of the circulation

48
Q

How do statins works?

A

Statins inhibit HMG CoA Reductase to inhibit Cholesterol synthesis, leading to more LDLR expression and lower amounts of cholesterol carrying LDL in the circulation

49
Q

What are the clinical manifestations of Familial Hypercholesteremia?

A

TEPA

Tendon Xanthomas = bumps near Achilles tendon
Eyelid Xanthelasma = scrunched eyelinds
Premature Atherosclerosis
Arcus Corneae = white deposit in Iris

50
Q

What is measured in clinic for Triglycerides?

A

Chylomicrons and VLDL

51
Q

What is measured in clinic for LDL-c?

A

Chylomicron remnant, IDL, LDL

52
Q

How does Cholesterol flow through the endogenous pathwway?

A

Liver produces VLDL which is metabolized essentially the same way as Chylomicrons, but produces LDL instead; also delivers FA as TG and Cholesterol to the tissues

53
Q

How do VLDL deliver FA and Cholesterol to tissues?

A

VLDL also interacts with Lipoprotein Lipase in peripheral tissues using ApoC as a tissue-specific cofactor

VLDL’s deliver FA as TG and deliver Cholesterol

VLDL lose ApoC to form IDL

54
Q

Why are lipids Amphipathic and what is the functional significance of this property?

A

Lipids are amphipathic due to having polar heads and hydrophobic tails

Allows them to create macromolecular complexes such as liposomes and micelles

55
Q

What does grapefruit juice do?

A

Interferes with CYP 450

56
Q

How are IDL formed?

A

IDL form after VLDL is acted on by Lipoprotein Lipase and loses ApoC

57
Q

What are the side effects of PCSK9 inhibitors?

A

MDD

Myalgia
Delerium
Dementia

58
Q

What are the components and structure of a lipoprotein?

A

Apolipoproteins, amphipathic surface and hydrophobic core containing hydrophobic molecules (FA, Cholesterol)

59
Q

How do nascent Chylomicrons mature?

A

They are exposed to HDL in circulation and obtain ApoC and ApoE from the HDL

60
Q

Where is NPC1L1 found and what does it do?

A

NPC1L1 is found in the enterocytes and mediates uptake of dietary cholesterol from the gut

61
Q

What reaction is the rate limiting step of Cholesterol synthesis?

A

HMG CoA to Melavonate

Catalyzed by HMG CoA Reductase

62
Q

What are the four major classes of lipids?

A

Free fatty acids, Triglycerides, Phospholipids, and Cholesterol

63
Q

What are the three key enzymes to Lipoprotein transport?

A

Lipoprotein Lipase
Lechitin-cholesteroal Acyltransferase
Choseteryl Ester Transfer Protein

64
Q

What are the risks for Rhabdomyolysis in statins?

A

Potentiated by drugs that inhibit CYP-3A4

65
Q

What is PCSK9?

A

PCSK9 is expressed after SREBP senses a decrease in Hepatocyte intracellular Cholesterol concentration

PSCK9 inhibits expression of LDLR on Hepatocytes

66
Q

What is the Lipoprotein Lipase and what is it’s cofactor?

A

Lipoprotein Lipase is an enzyme in peripheral tissues that recognizes ApoC as a cofactor on Chylomicrons

It is used to mediate tissue specificity for Chylomicron delivery and converts Triglycerides into Free FA

67
Q

What do nascent VLDL contain and where are they made?

A

Nascent VLDL made in the Liver and released into circulation, where it interacts with HDL

Nascent VLDL = ApoC, ApoE, ApoB100

68
Q

How are Triglycerides released from Chylomicrons?

A

Lipoprotein Lipase in peripheral tissues recognizes tissue-specific ApoC on mature Chylomicrons

ApoC is returned to HDL upon binding

Triglycerides in the Chylomicron are converted into free FA by Lipoprotein Lipase and taken up by the cell

69
Q

What do Omega 3 fatty acids do and how do they work?

A

3 blocks V + B to Lower T

EPA blocks VLDL and ApoB synthesis in the Liver to decrease TG

70
Q

How are TG “converted” to Cholesterol?

A

Each TG = 0.2 Cholesterol aka 5TG = 1 Cholesterol

71
Q

What protein is mutated in Familial Hypercholesteremia?

A

LDL receptor is mutated leading to insufficient clearance of LDL particles

72
Q

What transports Cholesterol from Liver to tissues?

A

LDL transports Cholesterol from Liver to tissues via LDLR as a breakdown product of VLDL

73
Q

What is the fate of IDL?

A

IDL interacts with HDL in circulation to lose ApoE and form LDL

74
Q

What is the fate of a Chylomicron remnant?

A

Chylomicron remnants form after a Chylomicron delivers Triglycerides to peripheral tissue

Chylomicron remnants use ApoE and ApoB48 to bind LRP in the Liver and re-enter the Liver

75
Q

What is Familial Hypercholesteremia?

A

Genetic disorder arising from mutations in LDLR, haploinsufficiency leads to Heterozygotes (300mg/dL Cholesterol) and Homozygotes (1000mg/dL)

76
Q

Approach to treating low HDL-c?

A

No evidence based therapy exists, can use Niacin

77
Q

How do Fibrates works?

A

CLT AAH

Fibrates = PPARa agonists, primarily aim to lower TG levels, also raises HDL

Block ApoC-III to activate Lipoprotein Lipase and lower TG from VLDL
Activate ApoA-I and ApoA-II to increase HDL

78
Q

What is ApoE2

A

An ApoE isoform that acts as an LDL cofactor, implicated in Dysbetalipoproteinemia

E3 = normal, E2 = abnormal; E2/E2 + second hit = disease

79
Q

What drug class is used to lower LDL-c?

A

Statins are the first line for lowering LDL-c

80
Q

What side effects and contraindications do Fibrates have?

A

GM

Side effects = gallstones and myopathy

Contraindications = renal or hepatic disease

81
Q

What are Triglycerides?

A

3FA + glycerol backbone

82
Q

What are the primary functions of lipoproteins?

A

They deliver TG as fuel and transport Cholesterol and Phospholipids

83
Q

What is measured in clinic for HDL-c?

A

Pre-B-HDL, HDL3, HDL2

84
Q

What is the goal of Niacin and how does it work?

A

Aims to lower TG by blocking Adipose TG mobilization and blocking Liver TG synthesis

May not actually work

85
Q

What drugs are statins often combined with?

A

Bile Acid sequestrants and Ezetimibe

86
Q

What is the mode of inheritance of Familial Hypercholesteremia?

A

Autosomal Dominant

87
Q

What enzyme catalyzes the rate limiting step of Cholesterol synthesis?

A

HMG CoA Reductase

88
Q

What is the hallmark feature of Familial Hypercholesteremia?

A

Premature atherosclerosis

Cardiovascular (25 decks)

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