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PATH 406 > Lecture 9: Lipids > Flashcards

Lecture 9: Lipids Flashcards

1
Q

What are the 3 parts of a lipoprotein?

A
  1. Hydrophobic core
    - Cholesterol esters
    - TG
  2. Lipid membrane
    - Free cholesterol
    - Phospholipids
    - Apolipoprotein
    • Serve as ligands for cell receptor and enzymes attached to
      endothelia
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2
Q

What are the different pathways for lipoprotein metabolism/

A
  1. Exogenous pathway
  2. Endogenous pathway
  3. Reverse cholesterol pathway
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3
Q

How does the exogenous pathway metabolise lipoproteins?

A
  1. Enterocytes absorb cholesterol & TG from gut as free cholesterol & FA
  2. FC and FA are esterified & packaged into chylomicrons (CM)
    • ApoB48, ApoA-I, ApoA-II & ApoA-IV form surface of CM
    • ApoB48 is necessary for CM secretion
  3. CM released into intestinal lymphatics a.k.a circulation
    • ApoB48 stays on CM
  4. Hydrolyzed by LPL
    • ApoC-II allows for activation of LPL
    • Hydrolyzes FA to be used as energy/storage in adipose tissue
  5. Convert to CM remnants
    • As FA are hydrolyzed, CM gets smaller
    • CM remnants taken up into liver remnants
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4
Q

How does the endogenous pathway metabolise lipoproteins?

A
  1. TGs and cholesterol secreted with phospholipids and ApoB 100 as VLDL
  2. LPL mediated lipolysis produce cholesteryl esters and ApoE rich remnant particles
  3. VLDL remnants can be taken up by liver or can be further hydrolyzed by hepatic lipase to form LDL
  4. LDL is taken up by liver or other peripheral cells and is degraded to unesterified cholesterol and aa
  5. Cholesterol can be stored/used to make steroids, bile acid or cell membranes

May cause atherosclerosis (AS)

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5
Q

How does the HDL metabolism a.k.a reverse cholesterol pathway metabolise lipoproteins?

A
  1. Apo A1 secreted into circulation by liver and intestinal cells combines with phospholipid to form preβ1-HDL
  2. FC from peripheral cells is exported and binds to preβ1-HDL
  3. LCAT esterifies FC so that it can migrate to the centre of the particle which allows HDL to accept more cholesterol
  4. Particle can be taken up by liver and cholesterol secreted in bile
  5. HDL can also transfer cholesterol to TG rich lipoproteins in exchange for TGs which is catalyzed by CETP and helps the hepatic clearance of cholesterol

Atheroprotective function

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6
Q

What methods are available to measure lipoproteins?

A
  1. Total cholesterol
  2. Enzymatic method
  3. HDL
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7
Q

How does the enzymatic method work?

A
  1. Cholesterol esterase + cholesterol ester -> FC
  2. Cholesterol oxidase + FC + O2 -> cholest-4-ene-3-one + peroxide
  3. Peroxide + 4-aminoantipyrine + DAOS -> oxidized dye
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8
Q

How does the HDL method work to measure lipoproteins?

A
  1. Other forms of cholesterol blocked with PEG or antibodies
  2. Then use enzymatic method
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9
Q

What may interfere with the measurement of HDL?

A
  1. Bilirubin
  2. Reducing agents (Vit C)
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10
Q

How to measure TG?

A
  1. TG hydrolyzed to glycerol and FA
    • Rxn actually measures glycerol
  2. Glycerol phosphorylated to glycerol phosphate
  3. Glycerol phosphate oxidized to dihydroxyacetone and peroxide
  4. Peroxide reacts with dye
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11
Q

***What can interfere with the measurment of TG? How do they interfere?

A
  1. Extremely elevated TG levels
  2. Metamizole
    • Can cause falsely low results
  3. Ascorbic acid (>20 mg/dL)
    • Interfere with peroxidase-based oxidation of chromophore
  4. Bilirubin (>40 mg/dL)
    • Interferes with peroxidase-coupled assays
  5. Hemolysis (>500 mg/dL)
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12
Q

How to estimate LDL?

A

Freidwald equation
LDL = total cholesterol - HDL - TG/2.2

NIH equation (2020)
LDL-C = TC/0.948 - HDL-C/0.971 - (TG/8.56 + [TG x NonHDL-C]/2140 - TG^2/16100) - 9.44

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13
Q

What are the requirements for using the Freidwald equation for estimating LDL? What happens to the calculated value if you ignore this requirement?

A

TG<4.5 mmol/L

If TG > 4.5 mmol/L, this will overestimate the amount of VLDL and underestimate LDL

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14
Q

What is the new NIH equation used for?

A
  1. TG value up to 800 mg/dL

If TG > 800 mg/dL, LDL-C will not be reported

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15
Q

What is the use of apoB and Lp(a)?

A
  1. Values are generally stable through life, no need to repeat measurement
  2. Lp(a) > 30 mg/dL associated w/ high risk of CVD
  3. Useful in younger patients that don’t meet traditional criteria for treatment
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16
Q

What are the types of inherited disorders of lipoprotein metabolism?

A

Type I:
LPL or Apo C-II deficiency, increased CM

Type II:
LDLR deficiency, increased LDL

Type II-B:
Overproduction of apoB-100
Mutation in LDLR gene, increased LDL & VLDL
Increased risk for ASCVD

Type III:
Apo E deficiency
Increased IDL and remnant

Type IV:
Increased VLDL
Acquired/Familial

Type V:
LPL deficiency
Increased CM and VLDL

Hypoalphalipoproteinemia:
Apo-AI deficiency
Decreased HDL
Tangier - ABCA1 deficiency

17
Q

What is familial hypercholesteremia (FH)?

A

Disease caused by a defect in the LDL-receptor pathway

18
Q

What are the clinical characteristics of familial hypercholesterolemia?

A

LDL-R is involved in the recognition and removal of LDL from circulation

Clinical characteristics:
1. Cholesterol deposits
2. High LDL, apo B elevated, HDL slightly low, TG normal
3. Can have elevated Lp(a)

19
Q

What are the causes of FH?

A
  1. Defect in LDL-R (main)
  2. Familial defective apoB
    - Hypercholesterolemia less pronounced than classic FH
    - Reduced binding of particle to LDL-R
  3. Gain of function PCSK-9
    - Increases rate that PCSK-9 degrades LDL receptors
  4. Loss of function LDLRAP-1
    - Defect in endocytosis of LDL
    - Phenotype resembles classic FH
20
Q

What is the general profile for hypertriglyceridemia?

A

Very high TG
High LDL
Low or normal HDL

21
Q

What are the causes of hypertriglyceridemia?

A
  1. LPL deficiency
    - Can be present in childhood with recurrent abdo pain
    - Heterozygotes can dvlp severe hypertriglyceridemia and pancreatitis
  2. Apo C-II deficiency
    - Presents later and milder than LPL deficiency
    - *ApoC-II required for activation of LPL
  3. LPL inhibitor
  4. Remnant hyperlipoproteinemia
    - Associated with apoE2
    - Adulthood
    - Xanthomata in palmar creases
    - Increased CAD risk
22
Q

What is fish eye disease caused by?

A

Partial LCAT deficiency:
1. LCAT is involved in the esterification of cholesterol and maturation of HDL
2. If cholesterol is not esterified, HDL breaks down
3. Unesterified cholesterol accumulates in tissues

23
Q

What diseases cause low HDL?

A
  1. Familial LCAT deficiency
  2. Apo A1 deficiency
  3. Apo A1 variants
  4. Tagnier disease - defect of cholesteryl ester storage in macrophages
24
Q

What disease cause high HDL?

A
  1. CETP deficiency
    - HDL > 3 mmol/L
    - Low LDL and apoB
  2. Hepatic lipase deficiency
    - Increased HDL and TG
    - Eruptive xanthomas
    - Phenotype similar to remnant hyperlipidemia
25
Q

What is dysbetalipoproteinemias?

A

A rare familial dyslipidemia characterized by appoximately equally elevated serum cholesterol and TG levels due to accumulated remnant lipoproteins in apolipoprotein E2/E2 homozygotes.

26
Q

What are examples of dysbetalipoproteinemias?

A
  1. Familial hypobetalipoproteinemia
  2. Abetalipoproteinemia
  3. Chylomicron retention disease
27
Q

What are the cause(s) and characteristics of familial hypobetalipoproteinemia?

A

Premature stop codon in apoB gene

Cannot bind lipids or to a lesser extent

28
Q

What are the cause(s) and characteristics of abetalipoproteinemia?

A

No apoB and 50% apoA

  1. Chronic diarrhea
  2. Night blindness
  3. Acanthocytosis and atypical retinitis pigmentosa
29
Q

What are the cause(s) and characteristics of chylomicron retention disease?

A

Lack of apoB 48 in plasma

CM retained in enterocytes, cannot get out

PATH 406 (24 decks)

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