Lecture 17+18 Flashcards
Cholesterol ABC transporters
release free cholesterol into the blood from membranes undergoing turnover and from dying cells
macrophages and reverse cholesterol transport
- they uptake LDL with the LDL-R and uptake oxLDL by the SRs
- release free cholesterol by the ABCA1 transporter for HDL
what does LCAT do?
an enzyme synthesized in the liver and released into the blood.
needs to be activated by apo A-1
binds to HDL and uses a fatty acid from phosphatidylcholine (PC) of the HDL membrane to form cholesteryl esters (CE) in the blood.
CE move immediately inside the HDL.
The two fates of mature HDL?
HDL can bind to the SR-B1 receptor and allow cholesteryl esters to flow into the liver, then can be filled up again by LCAT
HDL can interact with VLDL via the CETP (a hydrophobic channel is formed). Nonpolar lipids are exchanged
Functions of HDL
- transport excess cholesterol from tissues/ macrophages to the liver
this can be done by SR-B1 or CETP - prevent or reduce fatty streak formation caused by foam cells
- act as a circulating “reservoir” of apo C and apo E which are transferred to nascent chylomicrons and VLDL.
Tangier disease (hypolipidemia)
this occurs due to extremely low HDL levels caused by a defect of the ABAC1 transporter, thus less free cholesterol
features: orange colored tonsils in nearly all children (due to cholesterol) peripheral neuropathy premature MI enlargement of liver and spleen
Abetalipoproteinemia and Hypobetalipoproteinemia (hypolipidemias)
both show low CM, VLDL, and LDL levels
abetalipoproteinemia = MTP deficiency
TAG = below 19mg/dL
total cholesterol = below 50mg/dL
hypobetalipoproteinemia = apo B-48 and 100 deficiency
features: failure to thrive TAG accumulation retinitis pigmentosa peripheral neuropathy Acanthocytosis (RBC with spicules)
normal ranges for cholesterol in the blood?
normal LDL = 100-130mg/dL
normal HDL =
males: 50
females: 70
normal VLDL = 20-30
primary and secondary causes of dyslipidemia
primary:
genetic disorders
secondary: smoking lifestyle diet diabetes obesity etc.
Friedewald equation
LDL-C = total C – [(HDL-C) + (TAG / 5)]
Type 1: Familial Hyperchylomicronemia (rare)
seen to have abnormally high TAG levels due to high CM levels
normally CM are not present in a fasting serum, however they are present in those who have this disease. can be seen by creamy layer on top of serum
this can result from a LPL deficiency and/or a apo C-II deficiency (impacts CM clearance)
clinical features:
- onset is childhood
- lipemia retinalis
- heptosplenomegaly
- recurrent epigastric pain
- eruptive xanthomas
Type IIa: Familial Hypercholesterolemia (common)
seen to have high HDL, normal VLDL, and clear serum
higher risk of CVD and MI. Treatment is holistically and statins
heterozygous: adult onset
homozygous: childhood onset; chance of MI
this is due to a defective LDLr (AD)
clinical:
seen to have tendon xanthomas and xanthomas near eyelids
diminished clearance of LDL
Type IIb: Familial Combined Hyperlipidemia (common)
seen to have high LDL, VLDL, and lipemic serum
risk of CVD and MI. treated holistically along with statins
heterozygous show puberty onset
result from: overproduction of apo B-100, VLDL, or defective clearance of LDL
xanthomas are rare
Type III: Dysbetalipoproteinemia (rare)
high CM remnants and IDL, abnormal beta-VLDL
adult onset is seen with accelerated atherosclerosis
results from apo E deficiency
clinical:
seen to have palmar and tubereruptive xanthomas on elbows and knees
Type IV: Familial Hyperprebetalipoproteinemia (common)
High VLDL, normal LDL, and low HDL
plasma is lipemic
High VLDL level may result from LPL deficiency or VLDL overproduction. High VLDL lead to low HDL
high serum TAG’s lead to the risk of pancreatitis and CVD
Type V: Familial Mixed Hypertriacylglyerolemia
High CM and high VLDL
patients blood will be lipemic and a creamy layer will be seen on top.
How to treat hypercholesterolemia?
- to stimulate LDL-R synthesis
2. increase LDL-R recycling
PCSK9 inhibitor
PCSK9 inhibitors lead to increased recycling of the hepatic LDL receptors. This increases the amount of LDL receptors by reducing LDL-R degradation in
hepatocytes
LDL-B
smaller and more dense than LDL-A
is oxidized to ox-LDL
LDL pattern B can result from saturated fatty acids, tans fats, and cleavage of TAG’s
higher risk of CVD
Lp(a)
very similar to LDL, but it has a apo-A linked to apo B-100 by a disulfide bond.
competes for the binding of fibrin, thus may reduce the removal of clots and trigger stroke or MI
How are prostanoids formed?
They are formed from arachidonic acid by COX
arachidonic acid comes from the membrane phospholipid; converted by phospholipase A2
What are the prostanoids and what do they do?
PGE-2 = mediator of inflammation
PGF2 = induction of labor in pregnant uterus
PGI2 (prostacyclin) = inhibits platelet aggregation and vasodilation
TXA2 (thromboxane A2) = facilitates platelet aggregation and vasoconstriction (antagonist of PGI2)
inhibitors of eicosanoid synthesis
cortisol inhibits phospholipase A2 and COX-2 (anti-inflammatory)
aspirin and NSAIDs inhibit COX 1 and 2; again anti-inflammatory
How are leukotrienes synthesized
membrane phospholipid is converted to AA by phospholipase A2
AA is converted to leukotriene by lipoxygenase
synthesized in mast cells
Effects of leukotrienes
mediate allergic and anaphylactic response
bronchoconstriction and airway obstruction (asthma)
inhibited by cortisol and lipoxygenase inhibitors
What are the steps of hemostasis
- vascular spasm / vasoconstriction
- platelet plug formation / primary hemostasis
- blood coagulation / secondary hemostasis
- clot stabilization and resorption
what occurs during vascular spasm
trauma to the vessel results in SM contraction due to the release of endothelin
transient effect
platelet plug formation
- Exposure of subendothelial collagen
- Platelet adhesion via GPIA and GPIB (via vWF) to subendothelial collagen
- Platelet activation, shape change and degranulation (ADP release)
- ADP binds to neighboring platelets to increase intracellular calcium and decrease intracellular cAMP;
Increased TXA2 - Platelets recruited to the site of injury
- Platelet aggregation via fibrinogen linking adjacent platelets via GPIIB/IIIA
Bernard- Soulier syndrome
A defect in the GP-IB
defective platelet adhesion and aggregation
What is vWF deficiency associated with
defect in primary and secondary hemostasis
defective formation of platelet plug and coagulation
Thromboxane A2 formation
- membrane phospholipids to AA due to phospholipase A
- AA to PGG2
- PGG2 to PGH2
- PGH2 to TXA2 by thromboxane synthesis
Glanzmann Thrombasthenia
a defect in gp-IIB and gp-IIIA
impaired aggregation of the platelets
Bleeding test
increase in bleeding time / defective platelet aggregation may point to a defect in hemostasis
extrinsic pathway to the formation of thrombin?
- Tissue injury leads to the release of tissue factor or factor III
- Factor VII is activated by tissue factor to Vlla
- Factor VIIa and tissue factor, with Ca and phospholipids, activate factor X
intrinsic pathway of thrombin formation
- exposure of collagen leads to the activation of factor XII
- XIIa acts on XI to activate it
- XIa acts on IX to activate it
- thrombin activates factor VIII to VIIIa
- IXa and VIIIa and Ca and phospholipids activate X to Xa
common pathway of thrombin formation
- thrombin acts on factor V to Va
- Xa combines with Va, phospholipids, and Ca to form the prothrombin to form thrombin
- Prothrombin complex splits prothrombin to form thrombin
- thrombin acts on fibrinogen to form fibrin
- thrombin activates factor XIII to XIIIa
- Fibrin monomers are covalently crosslinked by factor XIIIa to form cross-linked fibrin (Hard clot)
Lab tests for the coagulation cascade?
prothrombin time (INR): tests the extrinsic pathway
aPTT: tests the intrinsic pathway
