Cholesterol and Lipoprotein Metabolism

Question 1

What did the Seven Countries Study show?

Answer 1

-trend between higher cholesterol levels and 25 year CHD mortality

Question 2

Lipoprotein structure

Answer 2

-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

Question 3

Structure of a TG vs a phospholipid

Answer 3

-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

Question 4

Trend between lipoprotein subclasses and density

Answer 4

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

Question 5

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

Answer 5

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

Question 6

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

Answer 6

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

Question 7

ApoB-containing lipoproteins are also called ________ lipoproteins.

Answer 7

• atherogenic
• remember: B is for bad

Question 8

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

Answer 8

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

Question 9

Explain the exogenous pathway of lipoprotein metabolism

Answer 9

• 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

Question 10

Explain endogenous pathway of lipoprotein metabolism

Answer 10

• 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

Question 11

Classification of lipoprotein disorders is based on what?

Answer 11

-which lipoprotein is elevated

Question 12

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

Answer 12

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

Question 13

Describe how T2DM/Insulin resistance can lead to hyperlipoproteinemia

Answer 13

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

Question 14

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

Answer 14

• 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

Question 15

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

Answer 15

• 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

Question 16

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

Answer 16

• ApoE3 is WT
• ApoE4: AD
• ApoE2: issue in FD

Question 17

Familial hypercholesterolemia (FH, type IIa)

Answer 17

• 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

Question 18

Homozygous for Familial Hypercholesterolemia

Answer 18

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

Question 19

Familial defective ApoB-100 (FDB, Type IIa)

Answer 19

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,

Question 20

Autosomal dominant hypercholesterolemia 3 (ADH3; Type IIa)

Answer 20

very rare

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

Question 21

PCSK9

Answer 21

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

Question 22

Familial Hypertriglyceridemia (FHTG, Type IV or V)

Answer 22

• 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

Question 23

Familial Combined Hyperlipidemia (FCHL: 2b)

Answer 23

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

Question 24

Review the 6 genetic causes of primary hyperlipoproteinemia

Answer 24

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

Question 25

Lipoprotein (a) aka Lp(a)

Answer 25

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

Question 26

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

Answer 26

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

Question 27

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

Answer 27

-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

Question 28

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

Answer 28

- 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

Question 29

HDL metabolism

Answer 29

Question 30

Secondary causes of low HDL cholesterol

Answer 30

- very low fat diet - sedentary lifestyle - obesity - IR/T2DM - chronic renal failure - medications

Question 31

3 Primary genetic causes of hypoalphalipoproteinemia (low HDL)

Answer 31

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

Question 32

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

Answer 32

- Free cholesterol accumulation within corneas--fish eye disease - biggest problem in these patients though is kidney disease

Question 33

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

Answer 33

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

Question 34

CETP function

Answer 34

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