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CVB by Minnie (Madeleine) > SM 125a - Lipoprotein Metabolism > Flashcards

SM 125a - Lipoprotein Metabolism Flashcards

1
Q

What are the symptoms of familial hypercholosterolemia?

A

(Achilles) Tendon xanthoma

Eyelid xanthelasma

Arcus corneae in people <45 years old

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2
Q

What is the function of lipoprotein lipase (LPL)?

A

LPL lyses triglycerides to release free fatty acids to peripheral cells

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3
Q

What is the mechanism of action of bile acid binding sequestrants?

A

Bile acid binding sequestrants bind bile acid in the gut to prevent recycling

  • Decrease hepatic cholesterol (more is used to make new bile salts)
  • Inrease LDL receptor production
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4
Q

What is the efficacy of Omega-3 Fatty Acids?

A
  • Decrease triglycerides
  • Slight increase in HDL-C
  • Decrease coronary heart disease deaths in MI survivors

But: Slight increase in LDL-C

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5
Q

Why aren’t PCSK-9 monoclonal antibodies prescribed for everyone with high cholesterol?

A
  • Expensive
  • Must be injected
    • Allergic reactions possible
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6
Q

Which lipoprotiens are the main carriers of triglycerides?

A

Chylomicrons (after a big meal)

VLDL (in the fasted state)

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7
Q

What are the 4 major pathways of lipoprotein transport?

A

Exogenous

Endogenous

Reverse cholesterol transport

Enterohepatic Circulation

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8
Q

What is the clinical efficacy of statin use?

A
  • Decrease LDL-C 20-22% regardless of risk
  • Prevent atherosclerotic CVD
  • Not efficacious if pt. is on hemodialysis or has chronic heart failure
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9
Q

What is “good cholesterol?”

What is “bad cholesterol?”

A

Good cholesterol = HDL-C

Bad cholesterol = LDL-C

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10
Q

What is the recomended lipid-lowering treatment for somebody with acute coronary syndrome?

A

Moderate intensity statin + Ezetimibe

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11
Q

In which pathway of lipoprotein transport does the liver produce VLDL?

A

Endogenous pathway

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12
Q

Which drug is best for lowering triglyceride levels?

A

Fibrates

Omega-3 Fatty Acids

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13
Q

Describe the endogenous pathway of lipoprotein transport

A

Liver production of VLDL

  • VLDL is produced by the liver
  • Lipoprotein lipase converts VLDL to IDL by removing ApoE
  • IDL is converted to LDL
  • LDL is taken up by LDL receptors in the liver
    • If LDL is oxidized, it is instead taken up by macrophages. They are converted to foam cells and contribute to the progression of atherosclerosis
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14
Q

ApoB48 is specific to which lipoproteins?

A

Chylomicrons

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15
Q

What is the inheritance pattern of familial hypercholesterolemia?

A

Autosomal dominant

People who are homozygous for the mutation have a more severe phenotype than heterozygotes

(up to 1000 mg/dL vs. up to 300 mg/dL; Normal < 130 mg/dL)

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16
Q

A lipoprotein contains ApoB100, ApoE, and ApoC

What class of lipoprotein is it?

A

VLDL

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17
Q

What do bile salts do?

A

Solubilize fats so they can be taken up by enterocytes

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18
Q

Which statins are metabolized by CYP2C9?

What substances are contraindicated?

A
  • Statins
    • Fluvastatin
    • Rosuvastatin
  • Contraindicated:
    • Coumadin (warfarin)
    • Fluconazole
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19
Q

Who should fibrates be prescribed to?

A
  • Patients with high triglycerides
  • Patients with mixed hyperlipidemia and/or low HDL
  • Patients intolerant of statins
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20
Q

What is the fate of oxidized LDL?

A

Instead of binding to LDL receptors and being cleared from the circulation, oxidized LDL is recognized as non-self and taken up by macrophages. This causes them to turn into foam cells and contribute to the development of atherosclerosis

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21
Q

What makes some lipoproteins more dense than others?

A

High density = more proteins

Low density = fewer proteins (and more fat)

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22
Q

What would happen to cholesterol levels if fewer bile salts were recycled?

A

Cholesterol levels would decrease, becuase more would be used to make new bile salts

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23
Q

Who should NOT be treated with fibrates?

A
  • Patients wtih severe renal or hepatic disease
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24
Q

What is the mechainsm of action of fibrates?

(Gemfibrozil, fenofibrate)

A

Fibrates have a major triglyceride-lowering effect

  • Block ApoC3 expression to remove inhibition of LPL activity
  • Block liver VLDL secretion
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25
Q

What would happen to HDL-C if CETP were inhibited?

A

HDL-C would increase

(CETP transfers cholesteryl ester from HDL to LDL)

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26
Q

ApoA1 is the major protein of which lipoprotein?

A

HDL

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27
Q

A lipoprotein contains ApoB100 and ApoE

What class of lipoprotein is it?

A

IDL

(VLDL contians ApoC in addition to these two)

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28
Q

Which apolipoproteins are found on HDL?

A
  • ApoA1 (major protein of HDL)
  • ApoA2
  • ApoE
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29
Q

Describe the pathophysiology of Apolipoprotein B Deficiency

A

Abnormal ApoB structure causes increased LDL-C because LDL receptors cannot recognize LDL-C and remove it from the circulation

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30
Q

Describe the pathophysiology of dysbetalipoproteinemia

A

Defect in ApoE2 synthesis

  • IDL is not recognized by its receptors
  • This leads to increased IDL -> increased risk of atherosclerosis
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31
Q

Which apolipoproteins are found on IDL?

A
  • ApoB100 (single copy)
  • ApoE (multiple copies)
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32
Q

What are the possible adverse effects of statin use?

A
  • Muscle myositis
    • Increase creatin kinase (<0.5%)
    • Myalgias are common
    • Rhabdomyolysis is rare
      • Increased incidence fo taking anythign that inhibits CYP3A4
  • Hepatotoxicity
    • Worry if ALT is 3x the upper limit of normal
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33
Q

What is the function of Cholesteryl Ester Transfer Protein (CETP)?

A

CETP transfers cholesterol esters from HDL to LDL

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34
Q

What is the mechanism of action of statin drugs?

A
  • Inhibit HMG-CoA Reductase (primarily)
    • This inhibits the conversion of HMG-CoA to Melevonate, which is the rate-limiting step of cholesterol synthesis
  • Increase the number of LDL receptors
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35
Q

What happens to circulating cholesterol levels if LDL receptors are not working?

A

LDL-C levels in the body increase because they cannot be cleared from the circulation

If they are oxidized, they are taken up by macrophages. The macrophages turn into foam cells and contribute to the progression of atherosclerosis

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36
Q

What should be prescribed if a patient cannot tolerate a full dose of statin?

A

Prescribe a bile acid binding sequestrant in addition to the statin

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37
Q

Describe enterohepatic ciruculation, as it relates to lipoprotein transport

A

Recirculation fo bile salts in the gut

  • Bile salts make fats more solube so they can be taken up by enterocytes
  • Cholesterol is a precursor for bile acid
  • Recycling less bile acid means that more cholesterol will be used to make bile acid
    • This reduces cholesterol levels in the body
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38
Q

Which lipoproteins have one ApoB?

A

There is one ApoB on every atherogenic particle (LDL, IDL, VLDL)

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39
Q

Familial Hypercholesterolemia and Apolipoprotein B Deficiency are both genetic disorders that result in increased LDL-C

How are they different?

A
  • Familial hypercholesterolemia
    • Defect in LDL receptor that prevents uptake of LDL-C
  • Apolipoprotein B deficiency
    • Abnormal ApoB structure that prevents the normal receptor from recognizing and uptaking LDL-C
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40
Q

Why would you want to combine a statin with a bile acid sequestrant?

What is the effect?

A

Combine statin with bile acid sequestrant if they…

  • Can’t tolerate a full dose of statin
  • Have familial hypercholesterolemia

Effect

  • Decrease LDL production
    • ​In addition to decreasing cholosterol syntheisis and increasing LDL receptors (statins)
  • Incresae fractional catabolic rate
  • More powerful lowering of LDL-C
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41
Q

What drug class do gembirozil and genofibrate belong to?

A

Fibrates

(Triglyceride-lowering)

42
Q

A lipoprotein contains only ApoB100

Which class of lipoprotein does it belong to?

A

LDL

43
Q

Describe the presentation of familial hypertriglyceridemia

A
  • Increased triglycerides while fasting without apparent cause
  • VLDL overproduction
  • Pancreatitis
  • Family history
44
Q

Which drug is best for increasing HDL?

Are these likely to be prescribed?

A

Niacin (Vitamin B3), but increasing HDL is not longer a target of therapy

These drugs are unlikely to be prescribed today (lack of evidence supporting use, several side effects)

45
Q

How does cyclosporine affect statin use?

A

Cyclosporine (an immunosuppressant) increases the toxicity of all statins

46
Q

Which drug would you prescribe to lower triglycerides?

A

Fibrates

(Fenofibrate, gemfibrozil)

47
Q

Describe the shape of the statin does-response curve

What does this mean for treatment?

A

Statins have a logrithmic dose-response curve

Statins are effective at relatively low doses, but there is no great benefit for large increases in dose.

Instead of increaseing statin dose, combine with another class of cholesterol-lowering drugs, lifestyle modification, etc.

48
Q

What is the function of Lecithin-Cholesterol Acyltransferase (LCAT)?

A

LCAt takes acyl groups from phospholipids and adds them to cholesterol to form cholesteryl esters

49
Q

What are the effects of statins on…

LDL-C?

HDL-C?

Triglyceride-rich particles?

ApoE? (VLDL, IDL)

A

Statins…

  • Decrease LDL-C 30-60%
  • Increase HDL-C 3-8%
  • Decrease Triglyceride-rich particles
  • Decrease ApoE (Found on VLDL, IDL)
50
Q

Which lipid-lowering drug functions by blocking the enterocyte NPC1L1 transporter to inhibit the uptake of cholesterol form the gut?

A

Ezetimibe

51
Q

Which apolipoprotiens are found on nascent chylomicrons?

Mature chylomicrons?

A
  • Nascent
    • ApoB48 (specific to chylomicrons)
    • ApoA1
  • Mature: Get more Apolipoproteins by interacting with HDL
    • ApoB48
    • ApoA1
    • ApoC
    • ApoE
52
Q

What mutation causes familial hypercholesterolemia?

A

Mutation in the LDL receptor (usually in the LDLR gene)

  • Non-functioning LDL receptors ->
  • Insufficient clearance of LDL particles ->
  • LDL is oxidized ->
  • Oxidized LDL is taken up by macrophages ->
  • Premature atherosclerosis
53
Q

Which disorder of lipoprotein metabolism is most likely to present in adulthood with high IDL levels?

A

Dysbetalipoproteinemia

(A defect in ApoE2 synthesis means that IDL cannot be recognized and taken up by its receptor)

54
Q

Describe the presentation of familial chylomicronemia syndrome

A

High chylomicrons

High triglyceride levels (>2000; cloudy plasma)

55
Q

Which apolipoproteins are found on LDL?

A

ApoB100

56
Q

Describe the presentation of dysbetalipoproteinemia

A
  • High IDL levels
  • Adulthood presentation
  • Hyperlipidemia
  • Xanthoma
  • Premature CVD
57
Q

Which apolipoproteins are found on VLDL?

A
  • ApoB100
  • ApoE
  • ApoC
58
Q

What are the pleiotropic (non-LDL) effects fo statins?

A
  • Improve endothelial dysfunction
  • Reduce inflammatory response
    • lower CRP
  • Increase plaque stability
  • Decrease thrombus formation
59
Q

What is the rate-limiting step of cholesterol synthesis

A

HMG CoA -> Mevalonate

Catalyzed by HMG CoA Reductase

60
Q

What is the mechanism of action of PCSK9 monoclonal antibodies?

A

PCSK9 monoclonal antibodies prevent the removal of LDL receptors

  • Antibody against the protein that removes the receptors
61
Q

What is the Friedwald equation?

A

Total Cholesterol = LDL-C + HDL-C + 0.2*TG

Total cholesterol, HDL-C and TG are measured

LDL-C is derived from everything else

Total cholesterol = Cholesterol + Cholesteryl Ester

62
Q

What are the 3 key enzymes of lipoprotein transport?

A

Lipoprotein Lipase (LPL)

Lecithin Cholesterol Acyltransferase (LCAT)

Cholesteryl Ester Transfer Protein (CETP)

63
Q

Which drugs increase the chances of adverse statin effects?

A
  • CYP3A4 inhibitors
    • Grapefruit juice
    • Clarithromycin
    • Erythromycin
    • Ketoconazole
    • Protease inhibitors
  • CYP2C9 inhibitors (or users)
    • Coumadin (warfarin)
    • Fluconazole
64
Q

What are the major lipoprotiein classes?

List them from least dense to most dense

A

Least dense

  • Chylomicrons
  • Chylomicron remnants
  • VLDL
  • IDL
  • LDL
  • HDL

Most dense

65
Q

Describe the pathophysiology of familial chylomicronemia syndrome

A

Deficiency of lipoprotein lipase or ApoC2

  • Both are necessary for the hydrolysis of triglycerides and delivery to tissues
  • Deficiency results in high cholesterol and high triglycerides
66
Q

Which statins are metabolized by CYP3A4?

What substances are contraindicated?

A
  • Statins
    • Lovastatin
    • Simvastatin
    • Atorvastatin
  • CYP3A4 inhibitors
    • Grapefruit juice
    • Clarithromycin
    • Erythromycin
    • Ketoconazole
    • Protease inhibitors
      ​
67
Q

Which patients would most benefit from PCSK-9 monoclonal antibody treatment?

A

Patients with homozygous or heterozygous familial hypercholesterolemia. Combine with maximum statin does

It works well, but it is expensive and must be injected; not great for 1st line for everyone

68
Q

Which lipid-lowering drug is best for lowering LDL-C?

A

Statins (first line)

If very high LDL-C, combine with ezetimibe or bile acid resin

69
Q

Which lipid-lowering drugs lower LP(a), a lipoprotein rich in ApoA?

A

PCSK-9 monoclonal antibodies

Niacin

70
Q

Which pathway of lipoprotein transport metabolizes chylomicrons?

A

The exogenous pathway

71
Q

Who should ezetimibe be prescribed for?

A

People who are already taking statins, who have acute coronary syndromes

72
Q

What would happen to LDL-C if bile salts were removed from the circulation (ex: by a bile acid binding sequestrant)

A

LDL-C would decreses; the body woudl use more cholesterol to synthesize new bile salts

73
Q

What would happen to LDL-C if NPC1L1 were inhibited?

A

LDL-C would decrease; there would be less uptake from the gut

(This is how Ezetimibe works)

74
Q

Which drugs prevent the removal of LDL receptors?

A

PCSK-9 Monoclonal antibodies

75
Q

What is the inheritance pattern of familial hypertriglyceridemia?

A

Autosomal dominant

(patients who present with familial hypertriglyceridemia typically have a family history of the disorder)

76
Q

Which pathway of lipoprotein transport disposes of extra cholesterol?

A

The reverse cholesterol transport pathway

77
Q

Why is it important to decrease triglyceride levels if they are too high?

A

Decrease risk of pancreatitis

78
Q

Describe the reverse cholesterol transport pathway of lipoprotein transport

A

Cholesterol from the periphery is taken up by HDL and delivered to the liver - This is the “vacuum cleaner” that disposes of extra cholesterol

  • Liver or intestine produce and secrete ApoA1
  • ApoA1 is lipidated to become pre-beta-HDL
  • LCAT turns the pre-beta-HDL into mature HDL by adding acyl groups to cholesterol to make choelsteryl ester
    • Mature HDL delivers cholesterol or cholesterol ester to the liver directly
  • *OR**
    • CETP transfers cholesterol to LDL
      • ​LDL is uptaken by the liver (indirect pathway)
79
Q

What is the efficacy of statins?

A

Lower LDL-C 30-60%

80
Q

What is the association between statins and diabetes risk?

A

Statins increase the risk of a new diabetes diagnosis

But only in people wiht existing risk factors. Typically, the benefits fo preventing heart attack and stroke are greater than the risk of diabetes

81
Q

What is the effect of PCSK9 Deficiency?

A

The protein product of the PCSK9 gene normally degrades teh LDL receptor

A mutation in this gene results in…

  • Increased persistence of LDL receptors
  • -> Decreased LDL-C levels
  • -> Decreased risk of coronary artery disease
82
Q

What is the clinical efficacy of ezetimibe?

A

20% decrease in LDL-C

Typically a 2nd line treatment (1st = statin)

  • Combine with moderate intesity statins in people with acute coronary syndrome
    • Decreases risk of heart attack and stroke
83
Q

What is the function of lipoproteins:?

A
  • Deliver triglycerides as fuel
  • Transport cholestrol and phopholipids throughout the body
84
Q

Which fibrate can be combined with stains safely?

A

Fenofibrae (better than gemfibrozil)

85
Q

What are the effects of Niacin (Vitamin B3) on lipid levels?

A
  • Decrease LDL
  • Increase in HDL ApoA1
    • ​Inhibits hepatic removal
  • Decrease VLDL
    • Decrease flux of free fatty acids that the liver uses for VLDL production
    • Inhibit VLDL synthesis
  • Inhibit adipose tissue lypolysis
  • Decrease assembly of ApoB-containing lipoproteins
  • Decrease in LP(a)

But no effect on heart disease progression

86
Q

Who should bile acid binding sequestrants be prescribed to?

A

Patients with high cholesterol only; use in concert with statins

Not to patients with high (>250-300) triglycerides
May increase triglyceride levels

87
Q

What kind of drugs are cholestyramine and colesevelam?

A

Bile acid binding sequestrants

88
Q

What are the effects of fibrates on…

Triglycerides?

LDL-C?

HDL-C?

Other?

A
  • Triglycerides (primary function)
    • Major decrease
  • LDL-C
    • If normal TG, increased LDL-C: will lower LDL-C
    • If high TG, normal LDL-C: will increase LDL-C
  • HDL-C
    • If baseline levels are lower: will increase HDL-C
    • Increases ApoA1, ApoA2 (lipoproteins on HDL)
  • Other
    • Decrease uric acid
    • Increase homocystein (fenofibrate only)
89
Q

What is the primary reason for treating people with high cholesterol?

A

To reduce/slow/prevent the progression of atherosclerosis

90
Q

Which lipid species are ampipathic?

A

Phospholipids

Cholesterol

91
Q

Which lipid species are hydrophobic?

A

Free fatty acids

Triglycerides

Cholesteryl ester

92
Q

Describe the exogenous pathway of lipoprotein transport

A

Chylomicrons deliver triglycerides from the gut to the peripheral cells via the thoracic duct

  • Micelles from food are digested via bile acid
  • Cross enterocytes
  • Packaged into nascent chylomicrons
  • Chylomicron matures
  • Chylomicron delivers triglycerides to peripheral cells
  • Lipoprotein lipase lyses triglycerides to release free fatty acids + Chylomicron remnant
    • Apo-C acts as a cofactor
  • The chylomicron remnanat is taken up by the liver
93
Q

What is the efficacy of PCSK-9 monoclonal antibodies?

A

50-60% reduction in LDL-C in addition to statin

Decrease LP(a)

94
Q

What is the mechanism of action of ezetimibe?

A

Ezetimibe blocks the enterocyte NPC1L1 transporter, thus inhibiting gut uptake of cholesterol

  • Ezetimibe is absorbed, undergoes glucuronidation, and goes to the intestinal villi
  • It decreases biliary and dietary cholesterol
95
Q

Which lipoproteins have the most electrophoretic mobility?

Are there exceptions?

A

HDL (alpha) migrate furthest

VLDL (Pre-beta) migrate the least far

*Some HDLs migrate to the pre-beta position

96
Q

Which statin does not have CYP activity?

A

Pravastain

(This is the best one to use if the patient is on other drugs)

97
Q

Which pathway of lipoprotein transport recycles bile salts?

A

Enterohepatic circulation

98
Q

What is the purpose of apoliproteins?

Where are they found?

A

Apolipoproteins are found in lipoproteins

  • Structural scaffold
  • Cofactor for enzymes
  • Specificity for receptors
99
Q

Describe the general structure of a lipoprotein

A
  • Apolipoproteins
    • Structural scaffold
    • Cofactor for enzymes and receptors
    • Confer specificity
  • Ampipathic surface
    • Phospholipids
    • Cholesterol
  • Hydrophobic core
    • Triglycerides
    • Cholesteryl Ester
100
Q

What is the mechanism of action of Omega-3 Fatty Acids?

A

Inhibit hepatic production and utilization of triglyceride-rich particles (Chylomicrons, VLDL)

  • Block liver VLDL, ApoB synthesis

CVB by Minnie (Madeleine) (43 decks)

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