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262 Cards in this Set
- Front
- Back
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In general terms, explain how a atherosclerotic plaque forms?
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Endothelial damage attracks monocyte to the sight of inflammation.
Monocytes adhere and transfers across the endothelium into the tissue intima - convert into macrophages. Modified (oxidized, glycosylated) LDL cross the endothelium into the intima and are digested by the marcrophages forming foam cells. These foam cells cause the formation of a plaque. |
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What are SNPs?
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Single nucleotide polymorphisms.
They are the most common type of sequence variation observed in humans. |
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What is the difference between Mendelian and complex inheritance?
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Mendelian = rare mutation that causes a obvious phenotype and disease (may be a single gene mutation.
Complex = multiple combination of polymorphisms (SNPs) of which individually have very weak phenotypic effect. The more polymorphisms, the increased effect. - environmental influences. |
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What are two causes of cardiovascular genetic variants which can lead to atherosclerosis?
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1) Mendelian - rare mutation cause phenotype
2) Complex - common polymorphisms with weak effects individually |
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What processes are implicated in the development of atherosclerosis?
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1) Lipoprotein metabolism
2) Thrombosis 3) Inflammation 4) Oxidative stress 5) Vascular biology |
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What is the pathogenesis of atherosclerosis?
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Highly complex interaction of multiple genes and environmental factors.
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What are some environment risk factors for atherosclerosis/CAD?
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1) Diet
2) Exercise 3) Smoking 4) Alcohol 5) Pollution. 6) Fetal environment 7) Infection (chronic) |
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What are some genetic risk factors (heritability) of CAD?
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1) Elevated VLDL or LDL
2) Elevated cholesterol 3) Elevated TAG 4) Low HDL 5) Elevated Lp(a) 6) Elevated systolic and diastolic BP 7) Type 2 DM 8) Elevated homocysteine 9) Elevated CRP 10) Increased BMI 11) Elevated fibrinogen 12) Gender 13) Family Hx |
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What is another name for LDL receptor? Where is it found?
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LDL = AKA Apo B/E receptor
Found on the liver and most peripheral tissue - expressed when the cell needs cholesterol. |
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What type of mutation causes familial hypercholesterolemia (FH)? Which lipids are elevated?
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Defect, reduced or absent LDL receptor therefore LDL remnants are not able to supply cholesterol to tissues.
With less LDL uptake by tissue there will be more free floating LDL therefore raising the LDL and total cholesterol .evels. |
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What are some P/E findings that might indicate FH?
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Corneal arcus
Xanthomas - fat deposits in the skin. Tendon xanthomas - Achielles tendon. |
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How is FH inherited?
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Autosomal dominant
1:500 gene frequency (heterozygous) |
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What ethnicities have higher frequency of LDL receptor gene mutations?
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French Canadians
South Africans with dutch or french descent. |
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What disease is caused by a mutation in Apo B?
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Familial Defective Apo B
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Where are apoprotein B100 molecules found? What are they involved in?
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Apo B100 is a ligand found on VLDL, IDL, LDL and Lp(a) lipids.
Apo B100 binds to LDL receptors and allow cholesterol to be dropped off to tissues. |
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What changes in lipids will be observed in someone with familial defective Apo B?
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Very similar to FH - the mutation prevents binding of LDL to LDL receptor therefore increased LDL levels and total cholesterol levels.
Not as severe LDL as FH. |
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What role does proprotein Conertase subtilisin/Kexin 9 (PCSK9) have in lipid metabolism?
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PCSK9 regulates the amount of LDL receptors by degrading them.
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How is a PCSK9 mutation inherited?
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Autosomal dominant - usually due to a missense mutation.
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What effect does a PCSK9 defect have on lipid profile?
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PCSK9 mutation can either cause a gain of function or loss of enzyme function.
If a gain- of function mutation, PCSK9 will degrade more LDL receptors and therefore increase LDL and total cholesterol levels. A loss of function mutation will decrease LDL receptor degradation and therefore more LDL particles will be uptaken and therefore reduction in LDL and total choletserol = cardioprotective. |
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How is familial combine hyperlipidemia inherited (FCHL)?
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Autosomal dominant
Frequency = 1:50 (common) |
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What causes familial combined hyperlipidemia (FCHL)?
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Mutation in a upstream transcription factor (USF-1) involved in regulating many genes in lipid metabolism.
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What will the lipid profile of someone with FCHL look like?
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Depends on what gene(s) expression in lipid metabolism are effected.
Elevated TAG and plasma cholesterol. |
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When would you suspect FCHL?
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Premature CAD in a middle age man or women
- very common disease. |
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What is the more common cause familial chylomicronemia?
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Mutation/defect in the lipoprotein lipase (LPL) enzyme located on the surface of tissue.
LPL binds Apo CII on chylomicrons and VLDL and allows TAG uptake. |
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Besides LPL mutation, what other mutation can cause familial chylomicronemia?
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Apo CII mutation prevent chylomicron (or VLDL) binding to the LPL.
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How is familial chylomicronemia inherited?
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Autosomal recessive
Frequency 1:million |
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What will the lipid profile of someone with familial chylomicronemia look like?
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Elevated chylomicrons in the fasting state - no intake of lipids.
Elevated plasma TAG. |
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Familial chylomicronmia causes recurrent episodes of what?
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Pancreatitis
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With familial chylomicronemia, what sort of things might be observed on P/E?
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1) Eruptive xanthoma
2) Hepatosplenmegaly 3) Lipemia retinalis (rentinal veins/arteries appear white) |
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What mutation causes Tangier disease?
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Mutation in the ABCA1 transporter responsible for moving cholesterol out of the tissue into the plasma to be uptaken by HDL.
No nascent discoid HDL particle can be made, nor mature HDL. Build up of cholesterol in the peripheral tissues (liver, spleen, tonsils, etc.) |
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How is Tangier disease inherited?
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Autosomal recessive - on 40 patients worldwide.
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What will you be looking for on P/E to confirm suspicion of tangier disease?
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Yellow-orange tonsils
Hepatosplenomegaly Peripheral neuropathy |
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What will the lipid profile of someone with Tangier disease look like?
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Absent HDL - no cholesterol
Low LDL High TAG |
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What other inborn error disease is ABCA1 mutation linked to?
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Familial Hyperalphalipoproteinemia (autosomal dominant)
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What role does the ABCA1 gene have in lipid metabolism?
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ABCA1 is a transporter responsible for unidirectional transfer of cholesterol and phospholipid to ApoA1.
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What effect does the ABCA1 mutation have on macrophage cells?
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Without ABCA1 transporter, the marcophage is less likely to be able to refulx LDL-cholesterol out of the cell therefore increases FOAM cell formation.
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What effect does the recessive mutation ABCA1 have on carriers of the mutated gene (heterozygous)
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Heterozygotes have increased risks of atherosclerosis.
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What disease is episodic in someone with Tangier disease?
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Episodic and recurrent peripheral neuropathy due to accumulation of CE in the nerve sheaths.
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How would you treat someone with Tangier disease?
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Restriction of dietary fats and cholesterol.
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What familial disease causes an decrease in cholesterol esterification?
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Familial Lecithin-cholesterol acyltransferase (LCAT) deficiency.
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What purpose does the LCAT enzyme serve in lipid metabolism?
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LCAT is responsible for esterifying (and therefore solubilzing cholesterol for transport) cholesterol in the HDL particle. This will form mature HDL particles.
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What does the lipid profile look like in someone with familial LCAT deficiency?
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Elevated unesterfied cholesterol
Elevated plasma phospholipid concentration Severe HDL deficiency (because no CE can be added to mature the lipoprotein particle) |
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How would you treat someone with familial LCAT deficiency hypolipidemia?
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Marked restriction of dietary fat and cholesterol.
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What diseases are caused/associated with familial LCAT deficiency?
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1) Corneal opacities
2) hemolytic anemia 3) Renal failure - due to CE and PL deposits in the kidneys. |
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How is familial LCAT deficiency inherited?
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Autosomal recessive - only homozygous express disease.
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What role does the cholesterol esterase transport protein (CETP) play in lipid metabolism?
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CETP is responsible for tranfering of CE from HDL to LDL or chylomicrons and the transfer of TAG from LDL and chylomicrons to HDL.
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How is familial CETP deficiency inherited?
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Autosomal co-dominant; due to mutations in both alleles of the CETP gene.
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What does the lipid profile of someone with CETP deficiency look like?
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Enlarged HDL-C particles, enriched with CE.
Markedly elevated HDL-C and ApoA1 levels. |
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Is a familial CETP deficiency atheroprotective?
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Although HDL-C are markedly elevated, there is no evidence of protection against atherosclerosis.
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What role does Apo E play in lipid metabolism?
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Apo E is found on the surface of chylomicrons, VLDL and HDL particles and is the ligand bound by the receptor on the liver for uptake of these lipoproteins back into the liver.
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What are the 3 isoforms of Apo E? What affect do they each have on total cholesterol levels?
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Apo E2, E3 and E4
Apo E4 is associated with increased cholesterol (~0.2mmol/L) Apo E2 is associated with decreased cholesterol (~0.4). E4 carriers have a 40% higher risk of CHD compared to E3 homozygotes. |
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What type of lipid profile is seen in someone with Apo E2 homozygous mutation?
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Modest elevation in TAG.
Reduced LDL due to E2 decreased affinity for cell surface receptor, causing remnant accumulation and reduced LDL formation. |
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If someone inherits two Apo E2 isoforms (homozygous), what disease forms?
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Dysbetalipoproteinemia (AKA Type III Hyperlipoproteinemia)
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What does the lipid profile of someone with dysbetalipoproteinemia look like?
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Apo E2 has decreased affinity for the hepatic receptors therefore accumulating chylomicron and VLDL remnants.
Elevated cholesterol and TAG. |
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Which disease causes yellow creases to form on the palm of your hands?
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Dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
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If someone has dysbetalipoproteinemia, what can you look for on the P/E?
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1) Tubero-eruptive xanthomas on the elbow and knees
2) Palmar xanthomas (orange creases of the palm). |
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What was the logic behind developing a CETP inhibitor for hyperlipidemia treatment?
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Elevated HDL-C have been shown to atheroprotective.
If you inhibit CETP you inhibit transfer of CE to LDL or chylomicron remanants therefore increasing the HDL pool. Research however, has shown that this is not affective therapy. |
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What are 3 familial diseases that cause primary hypertriglyceridemia?
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1) Familial chylomicronemia = deficiency of Lipoprotein lipase (LPL - more common) or Deficiency of Apo CII (cofactor)
3) Dysbetalipoproteinemia - defect in Apo E2 required of hepatic remnant uptake. 4) Familial combined hyperlipidemia - overproduction of VLDL |
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What is the most common cause of primary hyperlipidemia?
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Familial combined Hyperlipidemia.
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What tests would confirm a primary LPL deficiency? Apo CII deficiency?
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LPL - measure lipolytic activity of plasma after injection of heparin. Heparin releases LPL (if present) so its activity can be measured.
Apo CII - can be determined by electrophoresis |
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What mutations occurs in familial combined hyperlipidemia (FCHL)?
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Mutation in USF-1 which is a upstream transcription factor known to regulate many important genes involved in lipid metabolism.
This results in overproduction of VLDL. |
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What are 3 familial diseases that causes primary hypercholesterolemias?
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1) Familial hypercholesterolemia - LDL receptor mutation
2) Familial combined hyperlipidemia - USF-1 mutation, increased VLDL 3) Familial defective ApoB - mutation in the Apo B100 ligand |
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What familial disease can present with MI in young children (<5 yo)?
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Familial hypercholesterolemia - mutation in LDL receptor (homozygous) causes early onset of atherosclerosis and CHD due to excessive cholesterol.
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What are 2 causes of primary hypolipidemia due to HDL deficiencies?
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1) Tangier disease - defective ABCA1 transporter
2) LCAT deficiency - needed to esterify cholesterol in HDL. |
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What are the general classes of lipid lowering drugs?
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1) Statins
2) Fibrates 3) Resins 4) Niacin 5) Ezetimibe 6) Salmon oil (omega 3) |
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What is the MOA of statins?
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Statins inhibit the HMG CoA reductase enzyme responsible for converting HMG-CoA to mevalonic acid in cholesterol synthesis.
Statins block endogenous hepatic cholesterol production (reducing VLDL). |
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What other pathways are affected by statins?
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Coenzyme Q10 comes off of the same pathway as cholesterol therefore CoQ10 production will also be decreased.
CoQ10 is required for the ETC therefore reduced ATP production. |
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How are statins classified?
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Low and high potency.
Water of fat soluble. |
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Why are water soluble statins thought to have less side effects?
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The tought is that water soluble statins are less able to penetrate muscle and therefore is less likely to cause statin-induced myopathy.
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What are 3 low potency statin drugs? Are they lipid or water soluble?
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1) Lovastatin - lipid
2) Pravastatin - water 3) Fluvastatin - water |
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What is 1 medium potency statin drugs? Are they lipid or water soluble?
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Simvastatin - lipid
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What are 2 high potency statin drugs? Are they lipid or water soluble?
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1) Atorvastatin (Lipitor) - lipid
2) Rosuvastatin (Crestor) - water |
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What effect do statins have on lipid profile?
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Decreases LDL-C and Apo B100 levels
High potency statins have a weak HDL-C raising effect. |
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What is the "pleiotropic effect" of statins (not related to lowering lipids)?
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1) Decreases inflammation
2) Improvement of endothelial function 3) Stabilizes vulnerable endothelial plaques |
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LDL-C measurements can not be determined directly from the blood. How does the lab determine the LDL levels? When does this equation NOT work?
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LDL = Total cholesterol - (HDL-C + Trig/2.2)
If the Triglycerides are >4.5mmol/L then this equation can not be used. |
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How can you measure LDL directly?
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Measure the Apo B100 levels.
There is one apoprotein B100 protein on each LDL lipoprotein however it does not tell you the size of the LDL cholesterol and how much is in it. |
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Do statins work better for primary or secondary prevention?
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Both - however their is stronger evidence for secondary prevention.
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When are statins the ideal choice for treatment?
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1) Familial hypercholesterolemia (usually in combination with niacin or ezetrol)
2) Familial combined hyperlipidemia (in combination with Salmon Oil) 3) Dysbetalipoproteinemia (used if fibrates don't work) 4) Metabolic Syndrome or DM |
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What are the two big side effects of statins that you must be aware of?
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1) Myopathy - causing muscle pain, weakness and rhabdomyolysis which can lead to renal failure
2) Hepatic failure |
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What blood work should be tested before starting someone on a statin?
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CK levels
Liver enzymes (GGT, ALT, AST, Alk Phos). |
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How often should the CK, AST and ALT be checked on someone taking statins?
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Checked within the first 6 weeks, then 3 months and every 6 months to a year after that.
Discontinue if get muscle cramps/aches or flu-like symptoms. |
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What levels of CK are tolerated on someone on a statin?
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<3x the normal limit (200U/L) is asymptomatic elevations and are fairly common and tolerable.
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Besides myopathy and hepatoxicity, what other side effects may occur with Statins?
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GI - nause, vomiting, diarrhea
CNS - headache Dermatological - pruritis |
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What are some secondary causes of hyperlipidemia?
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1) Obesity
2) Diet / Exercise 3) DM 4) HTN 5) Smoking / Drinking 6) Hypothyroid 7) Renal disease 8) Choliothiasis 9) Exogenous estrogens 10) HIV |
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When are statins contraindicated?
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1) Chronic hepatic disease
2) previous sensitivity 3) Pregnant or lactating * Start all women in reproductive age on BCP when starting statins. |
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What other lipid modifying drugs must you be cautious of using with statins and why?
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Niacin and fibrates because increased risk of rhabdomyolysis.
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How are most statins metabolized?
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Cytochrome dependent.
Most are metabolized via the CYP3A4 or the 2C9. Therefore avoid drugs that may act/metabolized via these cytochromes. |
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What are some common 3A4 drug interactions that can occur with statins?
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1) Antifungal
2) Azole 3) Erythromyocin 4) Immunosuppressants 5) Methotrexate 6) grapefruit juice |
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What is the MOA of fibrates?
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Activators of the peroxisome proliferator activated receptor alpha (PPAR alpha).
They increase lipolysis by activating LPL enzyme and inhibiting Apo CIII, which inhibits LPL. |
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What overall effect does fibrates have on the lipid profile?
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Lower Triglycerides, LDL-C and Apo B100 while raising HDL-C
Fibrates cause increased VLDL loss of TAG and therefore decreases the density of LDL (larger in size). This increases the affinity of LDL for the hepatic receptors to remove it from circulation. |
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What are the two fibrate drugs being used to tx hyperlipidemia?
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Fenofibrate
Gemfibrozil |
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When are fibrates used?
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1) Metabolic syndrome and DM
2) Familial hypertriglyceridemia 3) Dysbetalipoproteinemia 4) Familial combined hyperlipidemia when statins are tolerated (second-line of choice). |
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In general, when would you chose a statin and when would you choice and fibrate?
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LDL problem = statin
dyslipidemia = fibrate |
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What are some side effects of fibrates?
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S/E similar to statins - myopathy (rhabdomyoslis), hepatitis, GI, rash
- Can exacerbate gout - Can exacerbate renal failure |
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When is fibrate use contraindicated?
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1) Previous sensitivity
2) Lactating 3) Severe Renal failure 4) Hepatic failure 5) Preexisting cholelithiasis |
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When must you be "cautious" about using fibrates?
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1) Pregnancy
2) Renal disease 3) Combination with statins - rhabdomyolysis 4) Combination with warfarin 5) Combination with cyclosporin. |
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What is another name for niacin?
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Nicotinic acid - water soluble vitamin B3.
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What is the MOA of niacin and how it lowers hyperlipidemia?
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Niacin inhibits lipolysis at the level of the liver and therefore there is a reduction in the the amount of FFA available to VLDL particle production.
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What affect does niacin have on the lipid profile?
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It decreases Triglycerides because less VLDL available harboring TAG.
* Increases HDL-C levels. It also decreases LDL and Apo B. |
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What action is niacin primarily prescribed for?
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To raise HDL-C levels (i.e LCAT deficiency or ABCA1)
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What diabetic drug must be used in with caution in a patient taking fibrates?
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TZD (insulin sensitizers)
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How does niacin increase HDL-C levels?
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Niacin blocks lipolysis therefore decreased FFA = decreased VLDL production.
With decreased VLDL = decreased CETP to transfer CE from HDL to VLDL. Less transfer means that the HDL-C will be higher, containing more cholesterol. |
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What are niacines used to treat?
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Excellent adjunct to statins.
1) Familial hypercholesterolemia 2) Familial combined hyperlipidemia 3) People with low HDL-C |
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What are some side effects of niacin?
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1) Skin - Flushing (most common), pruritis, acathosis nigricans
2) GI 3) CNS - headache 4) Metabolic - decreased insulin sensitivity, hyperuricemia/gout |
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When is niacin contraindicated?
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1) Hepatic disease
2) Active peptic ulcer disease 3) Arterial bleeding |
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When should you be cautious when using niacin?
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1) May increase myopathy or hepatitis if used with a statin
2) worsens glycemic control 3) worsens gout 4) avoid with unstable angina |
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Why must you be careful when ppx niacin to DM?
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Niacin to decrease insulin sensitivity therefore reducing glycemic control in IGT or diabetics.
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What are the two types of resin drugs?
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Cholestyramine
Colestipol. |
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What is the MOA of resins?
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Resins are anion exchange resins.
They are too large to be reabsorbed in the gut but will bind the anionic bile salts which contain cholesterol thereby interrupting the enterohepatic reciruclation and decreased total cholesterol. |
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What effect does resins have on the lipid profile?
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Reduce LDL-C levels
GI side effects therefore not used very much anymore |
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What is the MOA of Ezetimibe?
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Ezetimibe acts on the brush border NPCL-1 cholesterol transporter preventing cholesterol from being absorbed in the gut.
It blocks uptake of dietary cholesterol and that which is secreted into the bile. |
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What effect does ezetimibe have on lipid profile?
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15-30% reduction in total cholesterol and LDL-C and a 8% reduction in TG.
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When is ezetimibe used?
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In conjuction with statins - never used as monotherapy
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What component of salmon oil are we interested in for lower lipids?
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omega-3 polyunsaturated fatty acids (PUFAs).
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What is the MOA of salmon oil?
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Inhibits VLDL production which leads to a corresponding decrease in serum TAG.
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What is the general overall effect that salmon oil has on the lipid profile?
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Reduces TAG.
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What is salmon oil used to treat?
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Primary conditions causing hypertriglyceridemia:
- Familial combined hyperlipidemia - Familial hypertriglyceridemia - metabolic syndrome and DM |
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What is the timeline of atherosclerosis development and the steps involved?
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1) Endothelial damage
2) Build up of FOAM cells 3) Fatty streak 4) Intermediate lesion 5) Atheroma 6) Fibrous plaque 7) Complex lesion with calcification, hemorrhage, ulcer or thrombosis. Steps 1-5 involve accumulation of lipids. Steps 6 and 7 involve smooth muscle and collagen. |
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What are some major risk factors for CAD?
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1) High LDL (Apo B) and low HDL (Apo A1)
2) Age (>40 for men or > 50 or postmenopause for women) 3) Family histor 4) HTN 5) Smoking 6) DM 7) Diet - lack of veggies or fruit 8) Exercise 9) Psychosocial factors 10) Alcohol intake 11) Abdominal obsesity |
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What did the Interheart study determine was the #1 & 2 risk factors for AMI?
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Apo B/Apo A ratio (Ratio of LDL/ HDL)
and smoking |
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What are some features of a vulnerable atherosclerotic plaque?
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1) Thin fibrous cap
2) low grade stenosis 3) Large lipid core 4) Rich in cholesterol 5) Rich in macrophages 6) Poor in smooth muscle |
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What can cause endothelial damage and initiate plaque formation?
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1) Smoking
2) Elevated LDL 3) HTN 4) DM |
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Compare and contrast a normal endothelium compared to a injured, abnormal endothelium?
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1) Vasotone vs vasoconstriction
2) Retards adhesion of platelets & leukocytes vs. Increased adhesion 3) Inhibits smooth muscle migration vs. SMC migration and growth 4) Barrier to LDL, cholesterol - degrades VLDL and chylomicrons vs. Increased lipid deposition reduced clearance |
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Which bacterium has been shown to be associated with atherosclerosis?
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Chylamydia pneumoniae - found in 70% of lesions.
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What does the CRP measure? Elevated level are a risk factor for what?
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C reactive protein is a sign of inflammation - the effects of inflammatory cytokines such as IL-6 on hepatic production.
Elevated levels have an increased risk of a CV event. |
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Is it better to have large LDL particles with fewer total # (decreased ApoB) or better to have more but smaller LDL particles (more Apo B)?
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Better to have fewer but larger LDL particles because they are less dense.
The smaller LDL particles will be greater in density = increase athrogenic. |
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Why are small LDL particles (increased density) more atherogenic then large ones?
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They size allows them to get into the endotheilum, increased the marcophage scavenging pathway, increased FOAM cells.
Less will bind to the LDL receptor. |
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What is the criteria to have metabolic syndrome?
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You need 3 out of the following 5:
1) Waist circumference >102cm for men and >88 cm for women 2) Serum triglycerides >1.7 mmo/L 3) HDL -C <1.05 for men and <1.3 for women 4) BP <130/85 mm Hg 5) Serum glucose >6.1 mmol/L |
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Based on the Framingham cardiac study, what 10 year risks are considered low, medium and high?
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Low = <10%
Medium = 10-19% High = >20% |
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What parameters are included in the Framingham study to determine cardiac risk?
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Age
Gender Systolic BP HDL Smoking Total cholesterol |
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If someone was a low risk for CAD (<10%) when would you start treatment?
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TC/HDL >6
or LDL-C >5 |
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If someone was a medium risk for CAD (<10-19%) when would you start treatment?
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TC/HDL > 5
or LDL-C >3.5 |
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What are the LDL-C and TC/HDL targets for someone with high risk factors for CAD (>20%)?
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Primary target = LDL-C <2
Secondary target = TC/HDL <4 |
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What is the definition of a lipid? What are the common types of lipids found in the body?
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Lipid = a biological compound soluble in non-polar solvent.
1) FFA 2) Mono/Di/Triglycerol 3) Phospholipids 4) Cholesterol (vit D, testosterone, progesterone, aldosterone) |
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Define lipoprotein?
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Lipoprotein = protein + phospholipid + lipid complex that allows transport of lipids in the water phase of plasma
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Define apoprotein?
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Apoprotein = protein on the surface of the lipoprotein that allows metabolism and/or receptor mediated endocytosis of plasma lipoproteins.
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What is the core of a lipoprotein composed mostly of?
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Cholesteryl esters and Triacylglycerols.
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What happens to dietary fat following intake?
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1) Dietary lipids enter the stomach where they are acidified.
2) In the duodenum the lipids are hydrolyzed and emulsified via bile salts 3) Pancreatic lipase and the conditions help to digest TAG into MAG and FFA. 4) The MAG and FFA combine with bile salts and form a micelle |
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How are micelles absorbed into the enterocyte?
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From the micelle, FFA and MAGs can diffuse across the brush border or the micelle can be transported via specific transporters.
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How do short and medium FFAs cross from the lumen into the enterocyte?
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They do not require micelle assistance to be absorbed. They can diffuse directly in the mucosal capillaries.
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How does cholesterol get from the lumen of duodenum into the enterocyte?
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Cholesterol does not diffuse well therefore it is transported via the NPC1L1 specific transporter.
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What happens to the digested (FFA and MAG) once they are inside the enterocyte? How are chylomicrons made?
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The FFA and MAG are formed back into TAG in the ER of the enterocyte and then combined with cholesterol and apoproteins in the golgi. They are all packaged together to form the chylomicron.
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From the enterocyte, how do chylomicrons get into the blood?
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Chylomicrons are too big to diffuse into the mucosal capilliaries therefore they are exocytosed in the the lacteals and transported via lymph to the thoracic duct to the subclavian vein and into circulation.
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What apoproteins are found on the chylomicron?
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Apo B48 - specific
Apo CII Apo E |
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What does the Apo CII do?
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Apo CII is a cofactor for lipoprotein lipase (LPL) enzyme on the vascular endothelium. Its interaction allows TAG from the lipoprotein to release FFA and glycerol to the tissues.
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What is a chylomicron remnant?
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After chylomicron binds to LPL and releases TAG, it is cholestryl ester rich (CE).
Chylomicron without TAGs. |
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What is the exogenous pathway in lipid metabolism?
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Exogenous is the transport and metabolism of lipids that are obtained from the diet.
Transported as chylomicron. |
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What is the Apo E used for?
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Apo E is require for hepatic uptake of remnants.
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Explain the steps in the exogenous pathway?
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1) Chylomicrons are released from the intestine following lipid digestion.
2) Chylomicrons ApoCII bind to the LPL on the surface of the endothelium and release FFA into the tissue. 3) The lack of TAG forms the chylomicron remnant which can then either pick up CE from HDL particle and trasnport cholesterol to tissues or it can be uptaken back to the liver via ApoE. |
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What is the action of LPL?
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Lipoprotein lipase (LPL) is non-covalently bound enzyme on the endothelium.
It hydrolyzes the ester linkages of TAG, DAG and MAGs on chylomicrons and VLDL to produce glycerol and FFA. |
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What is the cofactor for lipoprotein lipase (LPL)?
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Apo CII
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What protein is required to immobilize the chylomicron on LPL so that the TAG could be hydrolyzed?
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GPIHBP1
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How do you measure LPL activity?
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Administer a small dose of heparin.
Heparin is a cofactor for LPL therefore it will disrupt the anchoring of LPL and release it into the plasma where its quantity and activity can be measured. |
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What is the purpose of the endogenous pathway?
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Endogenous pathway is a way for the body to generate and transport cholesterol and other lipids during periods of fasting.
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Explain the steps in the endogenous lipid pathway?
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1) Liver secretes VLDL particles.
2) Apo CII on the VLDL binds the LPL on the endothelium and releases FFA and glycerol from TAG producing a TAG-deficient IDL particle 3) Once the TAG is removed from the IDL completely, the LDL is formed. 4) HDL transfers CE to the LDL (and chylomicon remnant) in exchange for TAG. 5) Cholesterol rich LDL can then either return to the liver or distribute the cholesterol to peripheral tissues that require cholesterol. This occurs via the Apo B100 and LDL receptors. |
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What apoproteins are found on VLDL?
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Apo B100 - specific
Apo CII Apo E |
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What role does HDL play in lipid transport?
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HDL picks up free cholesterol released by the peripheral tissues into the plasma and transports it either back to the liver or to LDL or chylomicron remnants.
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Explain the steps in reverse cholesterol transport?
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1) Excess cholesterol is released from peripheral tissue via ABCA1 transporter
2) Liver and intestine release a immature Apo A1 molecule 3) Apo A1 picks up phospholipids to form the nascent discoid HDL particle 4) HDL picks up cholesterol from the plasma. The LCAT enzyme in the HDL particle esterifies the cholesterol to form the mature HDL. particle. 5) The HDL then transfers the CE to LDL or chylomicron remnants via the CETP in exchange for TAG. 6) Or the HDL can return the excess cholesterol directly to the liver. |
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What specific apoprotein is found on the surface of the HDL particle?
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Apo A1
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What does the CETP do?
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Cholesterol esterase transport protein transfers CE from HDL to LDL or chylomicron remnants.
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What does LCAT enzyme do?
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Esterfies the cholesterol in the HDL particle to mature it.
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What receptor allows for uptake of HDL at the liver and peripheral tissue?
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SRB1
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Which lipoproteins are large, small, dense, etc?
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Chylomicrons are the larger yet the least dense.
HDL is the smallest but the most dense. The larger the size the less the dense. |
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How does the liver get rid of excess cholesterol?
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Via excretion of cholesterol in bile salts.
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What type of lipids are routinely measured and what technique do they use to measure them?
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1) Total cholesterol - enzymatic colorimetric
2) HDL cholesterol - enzymatic colorimetric 3) Triglycerides - enzymatic colorimetric 4) LDL cholesterol - calculated 5) Lipoprotein (a) - colorimetric ELISA 6) Apo B100 - nephelometric 7) Apo A1 - nephelometric 8) Apo E - genotyping |
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What does the LDL-C levels really tell us?
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It tells us the concentration of cholestrol in the plasma that is associated with LDL particles.
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What is Lp(a)?
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Lipoprotein (a) is indentical to LDL except it has an extra apoprotein called apoprotein (a).
Apo (a) is attached to the Apo B100 by a single disulphide bridge. |
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Why is the apo (a) protein length variable?
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Apo (a) kringles forming various loops in the protein thereby varying the length.
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Why is elevated Lp(a) an increased risk of atherosclerosis?
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Lp(a) has been identified in plaques
Apo(a) has homology to plasminogen and therefore may inhibit fibrinolysis and increase clot formation. |
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If Lp(a) levels are high, what other test might it be interfering with?
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Lp(a) will end up being quantified in the LDL level.
If you try to measure apo B levels, Lp(a) may interfere depending on the method. |
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How would you treat someone with high Lp(a) levels?
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Statins do not work well.
Treat with niacin (vitamin B3) |
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What are the major types of lipids?
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1) Fatty acids
2) Glycerolipids (TAG, MAG, DAG) 3) Glycerophospholipids 4) Sphingolipids 5) Steroids 6) Isoprenoids (Vit A, E, K) |
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What are the major types of lipids?
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1) Fatty acids
2) Glycerolipids (TAG, MAG, DAG) 3) Glycerophospholipids 4) Sphingolipids 5) Steroids 6) Isoprenoids (Vit A, E, K) |
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What is the basic structure of triglycerides?
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Glycerol backbone with three fatty acids attached via an ester linkage.
The fatty acids are heterogenous. |
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What is the basic structure of triglycerides?
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Glycerol backbone with three fatty acids attached via an ester linkage.
The fatty acids are heterogenous. |
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What is an unsaturated fatty acid?
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A fatty acid with a double bond within its carbon chain.
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What is an unsaturated fatty acid?
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A fatty acid with a double bond within its carbon chain.
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What is better for you? Cis unsaturated fa or trans?
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Cis
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What is better for you? Cis unsaturated fa or trans?
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Cis
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How do we classify triacyglycerols?
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Long or short chain
Saturated vs Unsaturated Essential vs. Non-essential |
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How do we classify triacyglycerols?
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Long or short chain
Saturated vs Unsaturated. |
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What are the major types of lipids?
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1) Fatty acids
2) Glycerolipids (TAG, MAG, DAG) 3) Glycerophospholipids 4) Sphingolipids 5) Steroids 6) Isoprenoids (Vit A, E, K) |
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What is the basic structure of triglycerides?
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Glycerol backbone with three fatty acids attached via an ester linkage.
The fatty acids are heterogenous. |
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What is an unsaturated fatty acid?
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A fatty acid with a double bond within its carbon chain.
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What is better for you? Cis unsaturated fa or trans?
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Cis
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How do we classify triacyglycerols?
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Long or short chain
Saturated vs Unsaturated. Essential vs. Nonessential |
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What are the lengths of fatty acids for short, medium, long and very long?
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a) short = 2-5 carbons
b) medium = 6-12 c) long = 12-18 d) very long = >18 carbons |
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What does it mean when a fatty acid is monounsaturated? Polyunsaturated?
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Mono means that there is only one double bond someone where in the fatty acid chain.
Poly means there is more then one double bond. |
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Which fatty acids are essential and why?
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Essential fatty acids can not be made therefore you must get them from your diet.
They include Linoleic, linolenic and arachidonic. |
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What does trans fats refer to?
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Trans fats are fatty acids which have a double bond in the trans formation, as opposed to the cis double bound which occurs in plants.
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Where do trans fats arise from?
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Ruminant animal fat
Partially hydrogenation of plant oils Rancid plant oils. |
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What fats are the worse for your lipid profile?
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Saturated and trans fats.
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What is the basic structure of a phospholipid?
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Glycerol backbone with two fatty acids and a phosphorylated head group
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What are the various components that can form the head group on phospholipids?
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1) choline
2) ethanolamine 3) serine 4) inositol 5) Glycerol 6) Phosphatidylglycerol |
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What is another name for phosphatidylcholine?
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Lecithin = LCAT enzyme source.
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What is lecithin (phosphatidylcholine) a marker for?
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Marker for fetal lung maturity.
Take amniotic fluid and measure the ratio of lecithin:syphingomyelin ratio (L:S) via thin layer chromatography. Mature result is L:S >2 Immature is L:S <1.5 If immature, treat with steroids. |
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What is phosphatidyl glycerol a component of?
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Component of mitochondrial membranes
Component of pulmonary surfactant along with DPG. |
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What is phosphatidyl glycerol a marker for clinically?
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Marker for fetal lung development?
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What are cardiolipins?
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Cardiolipins are diphosphatidylglycerols (DPG).
They are the antigens recognized by autoantibodies in the antiphospholipid antibody syndrome, a cause of recurrent fetal loss and maternal hypercoagulability. Associated with phosphatidly glycerol. |
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What disease(s) arise due to problems with sphingolipids?
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Metabolic diseases due to defects in sphingolipid metabolism (i.e. loss of one of the enzymes responsible for removal of sugars or modified sugars)
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What is one type of disease that arises due to defects in sphingolipid metabolism?
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Fabry's disease.
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What is Fabry's disease?
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X-linked disease due to loss of alpha-glactosidase A causing accumulation of lysosomes upstream of glycoshpingolipid due to lack of metabolism (i.e. ceramide thrihexoside).
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What affect does Fabry's disease on the endothelium?
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The accumulation of ceramide trihexoside causes swelling and poliferation of the endothelium, disturbances in intraluminal pressure and angiectasia (dilation of blood vessels)
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What symptoms and/or signs will be observed in someone with Fabry's disease?
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1) Stroke - due to elongated, dilated and distorted vessels subject to occlusions
2) Deposition of ceramide thriheosie in podocytes causing proteinurea. 3) Chronic HTN associated with renal and heart failure. |
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What are some features that will help you diagnosis Fabry's disease?
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1) Family history of early strokes
2) Complaint of pain in distal extremities (i.e do to endothelial swelling). 3) Angiokeratomas around the speedo region 4) HTN 5) Corneal opacities. |
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How do you treat someone with Fabry's disease?
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Replace the alpha-galactosidase A enzyme so that sphingolipids are metabolized.
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What hormones are responsible for increasing lipolysis (break down of TAG)?
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1) Epinephrine
2) GH 3) ACTH 4) alpha-MSH |
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What hormones decrease lipolysis?
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Insulin
(For example: if you have hyperinsulinism, even though you are hypoglycemic, you still do not have lipolysis occurring and no ketone production due to the inhibitory effects of insulin on lipolysis) |
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What roles does the hormone sensitive lipase (HSL) have in lipolysis?
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HSL is located in the adipocyte cytoplasm.
It is activated via phosphorylation and recruited to the lipid droplet. HSL cleaves the TAG at the ester linkage releasing FFA and glycerol into the blood. |
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What happens with the end products of lipolysis?
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Glycerol is used by the liver and kidney for gluconeogenesis to make glucose
FFA are transported being bound to albumin and either oxidized for energy or stored as TAG in the muscle and liver. |
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What tissues primarily metabolize FFA?
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Skeletal muscle
Myocardium Liver |
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How are FFA used to make energy?
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FFA are metabolized via beta oxidation producing Acetly CoA, NADH or FADH2.
NADH and FADH2 enter the ETC and make ATP. Acetly CoA enters the citric acid cycle and make ketonse or is used to remake TAG or other lipids. |
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How do FFA get into the cytosol?
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Once released from adipocytes into the blood, the FFA is taken up by the target cell (liver, muscle, heart) passively via diffusion and transport proteins.
Once inside the target cell, the FFA are esterfied to Coenzyme A and bound to fatty acid binding protein. |
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How are FFA transferred through the blood?
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Bound to albumin
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How does FFA get into the mitochondria?
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1) Acyl-CoA from the cytosol passes freely into the permeable outer mitochonrial membrane.
2) To cross the inner membrane, Acetyl-CoA is couple to carnitine via CPT-1 enzyme to form Acyl-carnitine 3) Transported across inner mitochondiral membrane where it is converted back to fatty acid CoA via CPTII. |
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What happens if there is a CPT-1 or II enzyme deficiency?
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CPT-1 is required to couple carnitine to CoA
CPT-2 is required to convert acyl-carnitine back to fatty acid CoA once across the mitochondrial membrane. If deficient, you will be able to utilize FFA as a energy source - wasting muscles. |
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What are some clinical signs that someone may have a CPT-1 or CPT-II deficiency?
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Recurrent attacks of myoglobinuria and rhabdomyolysis.
Unable to use FFA as an energy source therefore muscle break down occurs during exercise causing muscle pain, stiffness, and tenderness triggered by exercise or fasting. |
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Where does beta-oxidation of FFA occur in the cell?
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In the mitochondria.
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Explain briefly, the steps in beta oxidation of fatty acids?
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Fatty acid Coenzyme A is converted to Acetyl CoA via acyl CoA dehydrogenases.
Acetyl CoA then enters the CCA to make ATP or ketones or is used for lipogenesis to reform TAG and cholesterol. |
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What is SCAD, MCAD, and LCAD?
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Short, medium and long chain acyl CoA dehydrogenase deficiencies.
These enzymes are used to convert fatty acid CoA into Acetyl CoA in beta oxidation in the mitochondria. (fatty acid metabolism). |
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Which Acyl CoA dehydrogenase deficiency is most common?
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Medium chain acyl CoA dehyrogenase deficiency (MCAD).
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Why is it VERY important to identify patients with medium chain acyl CoA dehydrogenase deficiency (MCAD)?
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With this enzyme deficiency, the patient is unable to adequately mobilize fatty acids and convert into Acetyl CoA for ketone synthesis in times of fasting or physiological stress.
This leads to continuous consumption of glucose without appropriate ketonemia. Patients become hypoglycemic, hypoketonemic and hyperammonemic leading to coma, cerebral edema and death. |
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How do you determine if someone has MCAD? What test do you perform?
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In an attempt to save CoA, the body will substitute carnitine as a coupling agent resulting in elevated acyl-cartinine levles.
Elevated C8:C10 acyl carnitine ratio is indicative of MCAD disease. |
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How do you treat someone with MCAD deficiency?
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Avoid fasting - can't produce ketones
In times of obligatory fast provide with IV glucose. |
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What enzyme is responsible for turning unsaturated and polyunsaturated fatty acids into trans alpha, beta Acyl CoA so that they can be beta oxidized?
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Isomerases - may take several steps.
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Which fatty acids must be metabolized slightly different then just beta oxidation in the mitochondria?
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Odd numbered fatty acids and very long chain fatty acids.
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Where are very long chain fatty acids metabolized?
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First by the peroxisome and then by the mitochondria.
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How can a peroxisome disorder arise?
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Due to failure of biogenesis of the peroxisome organelle, deficiency in transport proteins or deficiency in peroxisome enzyme.
These deficiencies prevent long chain fatty acids from being metabolised and become built up. |
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What causes X-linked adrenoleukodystrophy (ALD)?
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Mutation in a gene that encodes for a peroxisomal transporter membrane protein.
This transporter is necessary to transport and enzyme that degrades long chain fatty acids. Without it, it causes a build-up of long chain fatty acids in the perixosome leading eventually to CNS dyemylination, brain damage and adrenal failure. |
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Who should have their lipids checked?
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1) Women >50yo
2) Men >40 yo 3) Anyone with symptoms of CVD 4) Anyone with a first degree relative with CVD or high cholesterol 5) Anyone with DM 6) Anyone with kidney disease or SLE 7) Clinical evidence of dyslipidemia (ie: xanothoma or corneal arcus) 8) Obese 9) Smoker 10) Physically inactive 11) Excessive drinker 12) HTN 13) Erectile dysfunction (indication of CVD). |
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How is total cholesterol tested?
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Step 1 - add cholesterol esterase to break ester bonds
Step 2 - add oxidase to produce peroxide Step 3 - measure peroxide levels with chromogenic reaction. |
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What methods are used to measure HDL levels? Which method is most commonly used.
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Ultracentrifugation
Direct Precipitation Direct is most commonly used |
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How is the HDL level determined using the direct method?
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VLDL, LDL and chylomicrons are coated with selective detergents and polyanions to prevent digestion.
HLD cholesterol level is determined the same way as total cholesterol - esterases, oxidases - peroxide. |
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How do you determine the LDL cholesterol concentration?
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Friedewald equation.
LDL = Total cholesterol - (HDL-C + TAG/2.2) TAG/2.2 is an estimation of the VLDL-C Can not be used if the TAG >4.5mmol/L |
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What are some of the problems associated with abdominal obesity (visceral fat)?
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1) Small dense LDL particles which are more atherogenic
2) Increased Apo B100 3) Decreased HDL 4) Increased Triglycerides 5) Insulin resistance 6) HTN |
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Which biochemical markers are the strongest predictors for CAD?
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TC/HDL ratio
C reactive protein (chronic inflammation) |
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What foods should you eat and avoid for healthy eating habits?
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1) Avoid saturated fats, trans fats, simple sugars and refined CHO
2) Eat lots of fruits and veggies, whole-grain cereals and poly/monounsaturated oils, including omega 3 fatty acids. |
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What is the ideal, healthy waist circumference? BMI?
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Males <94cm, females <80cm
Minimum BMI goal is <27, optimal is <25 |
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How much exercise should we be getting a week?
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60 minutes of mild, 30-60minutes of moderate and 20-30 of vigorous activity 4-7x per week.
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What are some guidelines to REDUCE LDL-cholesterol?
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- Total fat should be 25-30% of total calories
- Saturated fats should be <7% of total calories, minimize trans fats - Dietary cholesterol <200mg per day - Total fiber 20-30g per day. |
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What are some guidelines to LOWER LDL-cholesterol?
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Plant stanols/sterols (2g per day)
Vicsous (soluble) fiber (10-25g per day) |
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What foods are high in saturated fats?
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Red meats
Cheeses Butter Whipping cream Chocolate bar |
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What foods are high in trans fats (trans unsaturated fatty acids)?
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Deep fried foods
French fries Crisco |
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To increase our omega-3 fatty acid intake, how much fish should we be eating?
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2-3x per week.
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What types of foods have monounsaturated fats?
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Olive oil
Canola oil Avocado Nuts (watch portions) |
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What type of foods have polyunsaturated fats?
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Liquid at room temperature
Sunflower, Safflower, corn, soybean Nuts Linoelic and linolenic acids |
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Where do we intake daily cholesterol from?
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Animal products only
Meat, eggs, cheese |
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4g of sugar is equal to how many calories? 4g of fat is equal to how many calories?
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4g of sugar = 1tsp = 16 calories
4g of fat = 36 calories |
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We are suppose to intake 10-25g of soluble (viscous) fiber per day - what foods does this include?
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Beans, oats, barley, some fruits and veggies
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What foods encompass insoluble fibers?
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Wheat bran, whole grain foods, nuts, fruits and veggies.
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How does total fat intake alter the lipid profile?
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Increases in total fat cause an increase in serum cholesterol and triglycerides due to increased chylomicron and VLDL production.
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How do increased saturated fat intake affect the lipid profile?
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Increases LDL-cholesterol levels by down regulating LDL receptors.
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What effect does excess trans fats have on lipids?
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Increases total cholestrol and LDL cholesterol.
It may decrease HDL Lesser extent then saturated fats. |
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What effects do mono and polyunsaturated fats if replacing saturated fats, have on lipids?
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It will decrease LDL-cholesterol by increasing LDL receptors.
Decreases ApoB production |
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What affect does dietary cholesterol have on LDL levels?
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Increases LDL levels by down regulating the LDL receptor however not to the same extent that saturated fats do.
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What affect does small amounts of alcohol(<2 glasses per day) have on lipids?
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Alcohol can increase HDL
However be careful because alcohol can increase TAG. |
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What positive effect does soluble (viscous) fiber have on lipids?
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Decreases cholesterol absorption, increases bile acid secretion and upregulates LDL receptors.
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What foods are main sources of flavonoids?
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Tea, onions, chocolate, wine and soy.
Also present in fruits, veggies, nuts and seeds. |
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What possible mechanism as to have flavonoids decrease your risk of CAD?
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- prevent oxidation of LDL particles
- prevent platelet aggregation |
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What medications may be a cause of secondary dyslipidemia?
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1) Antipsychotics
2) Beta blockers 3) Protease inhibitors 4) Isotretinoin |
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What can happen if you combine thiazolidinedione (TZD oral hypoglycemic) and fenofibrate (lipid lowering meds)?
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Can decrease HDL-C causing really low HDL-C levels.
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Alcoholic binging can cause a huge effect on what lipid?
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Can cause large increases in Triglycerides. Will decrease when alcohol is stopped.
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