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Cardiology > Cholesterol and Lipoprotein Metabolism > Flashcards

Cholesterol and Lipoprotein Metabolism Flashcards

1
Q

What did the Seven Countries Study show?

A

-trend between higher cholesterol levels and 25 year CHD mortality

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2
Q

Lipoprotein structure

A

-hydrophobic, non-polar core region composed mainly of cholesterol ester and triglyceride -hydrophilic polar surface region composed of a phospholipid and free cholesterol shell to which a number of apolipoproteins are associated

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3
Q

Structure of a TG vs a phospholipid

A

-triglyceride is 3 carbon glyceral backbone with 3 FA estified to them -phospholipid: 2 FAs and 1 phosphate, polar, head group attached to glycerol backbone

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4
Q

Trend between lipoprotein subclasses and density

A

-larger lipoproteins have smallest density and more TG to CE ratio -chylomicrons > VLDL>IDL> LDL >HDL

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5
Q

List the apolipoproteins on the chylomicrons, VLDL, IDL, LDL, HDL particles

A
  • chylomicrons: ApoB48, ApoC-II
  • VLDL: ApoB100, ApoC-II, ApoE
  • IDL: ApoB100
  • LDL: ApoB100
  • HDL: ApoA-1, II, ApoE
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6
Q

List the apolipoproteins with ApoB48, ApoB100, ApoA-1, ApoA-II, ApoE, and ApoC-II in their surface

A
  • ApoB48: chylomicrons
  • B100:VLDL, IDL, LDL
  • ApoA1**: HDL
  • ApoA2: HDL
  • ApoE: VLDL, HDL
  • ApoCII: Chylomicrons, VLDL
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7
Q

ApoB-containing lipoproteins are also called ________ lipoproteins.

A
  • atherogenic
  • remember: B is for bad
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8
Q

What lipoproteins contains a B in their outer shell, and are thus atherogenic?

A
  • basically, everything but HDL
  • LDL, IVL, VLDL, chylomicrons and remnants
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9
Q

Explain the exogenous pathway of lipoprotein metabolism

A
  • uptake by gut enterocytes and package TG and CE into chylomicron. Put into lymph
  • chylomicron contains B48 and CII (cofactor for LPL) and delivers FAs to cardiac and skeletal muscle and adipose tissue via enzyme LPL
  • chylomicron remnant: mostly cholesterol B48, E is uptaken by liver via LDLR
  • get fat to muscle and fat tissue then put cholesterol in liver
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10
Q

Explain endogenous pathway of lipoprotein metabolism

A
  • during fasting, liver packages FFAs into TGs in VLDL particles
  • B100 and C-II on VLDL allow LPL in heart and skeletal muscle to uptake FFAs.
  • IDL remnant has less TG now and if further encounter LPL will turn into Cholesterol predominant LDL particle; or remnant (IDL) can be uptaken again to the liver, but this is less likely
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11
Q

Classification of lipoprotein disorders is based on what?

A

-which lipoprotein is elevated

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12
Q

Secondary (non genetic) causes of hyperlipoproteinemia and which is the biggest factor

A
  • dietary influences
  • alcohol use
  • insulin resistance/Type 2 DM!!!! Biggest factor
  • hypothyroidism
  • nephrotic syndrome
  • chronic renal failure
  • medications: HIV, antipsych meds
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13
Q

Describe how T2DM/Insulin resistance can lead to hyperlipoproteinemia

A
  • liver doesnt stop making VLDL particles since adipose tissue keeps sending it FFAs
  • impaired adipose production of LPL also so cannot take up TGs
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14
Q

Familial Chylomicronemia Syndromes (FCS; type 1) mechanisms and signs

A
  • missing LPL or C-II
  • eruptive xanthomas associated with LPL deficiency; reversible, backs of surfaces, tend to come out overnight; leave if low TGs; red base with yellow pustule
  • clinical: acute pancreatitis
  • summary: elevated CM due to LPL or ApoCII deficiency causing eruptive xanthomas and acute pancreatitis from increased TG
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15
Q

Familial Dysbetalipoproteinemia (FD; type III): etiology, xanthomas, clinical, TG level, lipoprotein elevated

A
  • Issue with ApoE2 causing elevated TGs (not as much as FCS) from increased lipoprotein remnants (CM and VLDL, IDL remnants)
  • xanthomas: tubero-eruptive (knees, elbows) or palmar!! (pathognomonic)
  • clinical: CHD and peripheral arterial disease
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16
Q

3 common ApoE alleles in humans and the mutated subtype in FD

A
  • ApoE3 is WT
  • ApoE4: AD
  • ApoE2: issue in FD
17
Q

Familial hypercholesterolemia (FH, type IIa)

A
  • mutation in LDLR leading to increased LDL cholesterol levels
  • corneal arcus, xanthelasma, tendon xanthoma*** of achilles tendon or MCP joints
  • normal TG, elevated LDL
  • CHD
18
Q

Homozygous for Familial Hypercholesterolemia

A
  • cutaneous xanthomas widespread and severe
  • see CHD in children or adolescents
19
Q

Familial defective ApoB-100 (FDB, Type IIa)

A

similar to FH but the mutation is in B-100 not allowing LDL uptake into liver

  • founder effect in amish
  • normal TGs, elevated LDL, tendon xanthomas, CHD,
20
Q

Autosomal dominant hypercholesterolemia 3 (ADH3; Type IIa)

A

very rare

  • gain of function mutation in PCSK9 which causes severe downregulation of LDLR in liver
  • same phenotype as FDB, FH
21
Q

PCSK9

A

-secreted by liver and binds to LDLR externally and causes R uptake and degradation

22
Q

Familial Hypertriglyceridemia (FHTG, Type IV or V)

A
  • essentially elevated TG without IR/T2DM
  • usually clinically unimportant bc VLDL isnt prone to depositing in arteries, but can be tipped over the edge if TGs get too high (from additionally elevated CM)–> acute pancreatitis, CHD and eruptive xanthomas
23
Q

Familial Combined Hyperlipidemia (FCHL: 2b)

A
  • a genetic overproduction of VLDL and consequently, LDL
  • increased LDL and VLDL
  • increase TG
  • no xanthomas
  • clinical: CHD
24
Q

Review the 6 genetic causes of primary hyperlipoproteinemia

A
    1. Familial chylomicronemia syndromes
      1. Familial dysbetalipoproteinemia (FD)
      2. Familial Hypercholesterolemia (FH)
      3. Familial Defective ApoB100 (FDB)
      4. Familial Hypertriglyceridemia (FHTG)
      5. Familial Combined Hyperlipidemia (FCHL)
25
Q

Lipoprotein (a) aka Lp(a)

A
  • independent risk factor for CHD
  • highly genetically determined
  • Apo(a) is homologous to plasminogen
  • function unknown
  • similar to LDL but with Apo(a) attachment
26
Q

True/False: LDL and HDL cholesterol are predictors of CHD risk that depend on eachother

A
  • false; independent risk
  • for example, low HDL is bad, regardless of LDL status (high or low) and high LDL increases risk, regardless of HDL
27
Q

Sites of ApoA-I /HDL production. What else are these sites responsible for with HDL?

A

-liver and intestine: also primarily responsible for lipidating newly secreted lipid-poor ApoA-I via ABCA1-mediated lipid efflux. While liver and intestine ABCA1 may be the most critical for lipidating, substantial additional cholesterol efflux to HDL occurs from other tissues

28
Q

Aside from steroidogenic tissues, cholesterol cannot be used within cells. So, how do we dispose of it then?

A
  • ABCA1 transports it out of macrophages as FREE cholesterol to nascent HDL. LCAT then turns it into a cholesterol ester which brings it back to the liver
  • with in liver, CE turned back into FC and turned/excreted as bile
29
Q

HDL metabolism

A
30
Q

Secondary causes of low HDL cholesterol

A
  • very low fat diet
  • sedentary lifestyle
  • obesity
  • IR/T2DM
  • chronic renal failure
  • medications
31
Q

3 Primary genetic causes of hypoalphalipoproteinemia (low HDL)

A
  1. ApoA-1 mutation: necessary for proper stucture, which when not achieved, leads to rapid degradation of nascent HDLs
  2. Tangier Disease (ABCA1): impaired macrophage cholesterol efflux due to ABCA1 mutation; in its absence, the ApoA1 (made by liver and intestine) cannot be properly lipidated and is rapidly catabolized by the kidney. Mature HDL cannot be formed.
  3. LCAT deficiency: responsible for turning free cholesterol into CEs to form mature HDL particles. Nascent HDL is rapidly catabolized
32
Q

Finding in LCAT deficiency that is pathognomonic. What are these patients biggest issue though?

A
  • Free cholesterol accumulation within corneas–fish eye disease
  • biggest problem in these patients though is kidney disease
33
Q

T/F: genes causing low HDL lead to an increase risk of coronary heart disease.

A

-false! however secondarily low HDL is an independent risk factor for CHD

34
Q

CETP function

A

-transfers cholesterol and TGs between HDL and VLDL/LDL particles

Cardiology (27 decks)

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