Cholesterol and Lipoprotein Metabolism Flashcards
What did the Seven Countries Study show?
-trend between higher cholesterol levels and 25 year CHD mortality
Lipoprotein structure
-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
Structure of a TG vs a phospholipid
-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
Trend between lipoprotein subclasses and density
-larger lipoproteins have smallest density and more TG to CE ratio -chylomicrons > VLDL>IDL> LDL >HDL
List the apolipoproteins on the chylomicrons, VLDL, IDL, LDL, HDL particles
- chylomicrons: ApoB48, ApoC-II
- VLDL: ApoB100, ApoC-II, ApoE
- IDL: ApoB100
- LDL: ApoB100
- HDL: ApoA-1, II, ApoE
List the apolipoproteins with ApoB48, ApoB100, ApoA-1, ApoA-II, ApoE, and ApoC-II in their surface
- ApoB48: chylomicrons
- B100:VLDL, IDL, LDL
- ApoA1**: HDL
- ApoA2: HDL
- ApoE: VLDL, HDL
- ApoCII: Chylomicrons, VLDL
ApoB-containing lipoproteins are also called ________ lipoproteins.
- atherogenic
- remember: B is for bad
What lipoproteins contains a B in their outer shell, and are thus atherogenic?
- basically, everything but HDL
- LDL, IVL, VLDL, chylomicrons and remnants
Explain the exogenous pathway of lipoprotein metabolism
- 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
Explain endogenous pathway of lipoprotein metabolism
- 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
Classification of lipoprotein disorders is based on what?
-which lipoprotein is elevated
Secondary (non genetic) causes of hyperlipoproteinemia and which is the biggest factor
- dietary influences
- alcohol use
- insulin resistance/Type 2 DM!!!! Biggest factor
- hypothyroidism
- nephrotic syndrome
- chronic renal failure
- medications: HIV, antipsych meds
Describe how T2DM/Insulin resistance can lead to hyperlipoproteinemia
- liver doesnt stop making VLDL particles since adipose tissue keeps sending it FFAs
- impaired adipose production of LPL also so cannot take up TGs
Familial Chylomicronemia Syndromes (FCS; type 1) mechanisms and signs
- 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
Familial Dysbetalipoproteinemia (FD; type III): etiology, xanthomas, clinical, TG level, lipoprotein elevated
- 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
3 common ApoE alleles in humans and the mutated subtype in FD
- ApoE3 is WT
- ApoE4: AD
- ApoE2: issue in FD
Familial hypercholesterolemia (FH, type IIa)
- 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
Homozygous for Familial Hypercholesterolemia
- cutaneous xanthomas widespread and severe
- see CHD in children or adolescents
Familial defective ApoB-100 (FDB, Type IIa)
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,
Autosomal dominant hypercholesterolemia 3 (ADH3; Type IIa)
very rare
- gain of function mutation in PCSK9 which causes severe downregulation of LDLR in liver
- same phenotype as FDB, FH
PCSK9
-secreted by liver and binds to LDLR externally and causes R uptake and degradation
Familial Hypertriglyceridemia (FHTG, Type IV or V)
- 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
Familial Combined Hyperlipidemia (FCHL: 2b)
- a genetic overproduction of VLDL and consequently, LDL
- increased LDL and VLDL
- increase TG
- no xanthomas
- clinical: CHD
Review the 6 genetic causes of primary hyperlipoproteinemia
- Familial chylomicronemia syndromes
- Familial dysbetalipoproteinemia (FD)
- Familial Hypercholesterolemia (FH)
- Familial Defective ApoB100 (FDB)
- Familial Hypertriglyceridemia (FHTG)
- Familial Combined Hyperlipidemia (FCHL)
- Familial chylomicronemia syndromes
Lipoprotein (a) aka Lp(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
True/False: LDL and HDL cholesterol are predictors of CHD risk that depend on eachother
- false; independent risk
- for example, low HDL is bad, regardless of LDL status (high or low) and high LDL increases risk, regardless of HDL
Sites of ApoA-I /HDL production. What else are these sites responsible for with HDL?
-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
Aside from steroidogenic tissues, cholesterol cannot be used within cells. So, how do we dispose of it then?
- 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
HDL metabolism
Secondary causes of low HDL cholesterol
- very low fat diet
- sedentary lifestyle
- obesity
- IR/T2DM
- chronic renal failure
- medications
3 Primary genetic causes of hypoalphalipoproteinemia (low HDL)
- ApoA-1 mutation: necessary for proper stucture, which when not achieved, leads to rapid degradation of nascent HDLs
- 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.
- LCAT deficiency: responsible for turning free cholesterol into CEs to form mature HDL particles. Nascent HDL is rapidly catabolized
Finding in LCAT deficiency that is pathognomonic. What are these patients biggest issue though?
- Free cholesterol accumulation within corneas–fish eye disease
- biggest problem in these patients though is kidney disease
T/F: genes causing low HDL lead to an increase risk of coronary heart disease.
-false! however secondarily low HDL is an independent risk factor for CHD
CETP function
-transfers cholesterol and TGs between HDL and VLDL/LDL particles
