Lipoprotein Physiology and Atherosclerosis Flashcards
How are cholesterol and TGs transported through lymph and blood?
By lipoproteins
Outer envelope of lipoprotein?
Phospholipid bilayer interspersed with apolipoproteins and un-esterified cholesterol
Inner portion of lipoprotein?
Cholesterol esters and TGs
Routes for lipid transport through the body? (3)
- Exogenous pathway
- Endogenous pathway
- Reverse cholesterol transport
Exogenous pathway?
Gathers lipids from the digestive tract and distributes them throughout the body after a meal
Endogenous pathway?
Liver builds apolipoproteins and secretes them into the bloodstream
Reverse cholesterol transport?
Scavenges cholesterol from peripheral tissues and returns it to the liver
Initial lipoprotein of the exogenous pathway? Where is it synthesized?
Chylomicron - synthesized by enterocyte
What do chylomicrons contain? (4)
- Rich in TGs
- Retinyl esters
- Phospholipids
- Vitmain E
What is inserted as a structural protein for the chylomicron?
ApoB-48
Where are chylomicrons secreted to be transported to the bloodstream?
Into the lymph => travel to thoracic duct
What does HDL transfer to chylomicrons? Why?
- ApoC-II and ApoA-V
- Allows them to interact with lipoprotein lipase (LPL)
What does LPL do?
Cleaves TGs in chylomicrons to FFAs, which are taken up by peripheral tissues
What is the chylomicron after the TGs are lost?
Chylomicron remnant
What does HDL transfer to chylomicron so it can be cleared by the liver?
ApoE
Initial lipoprotein of endogenous pathway? Where is it synthesized?
VLDL - synthesized in the liver
What does VLDL contain? (4)
- Mostly TGs
- Phospholipids
- Cholesteryl esters
- Vitamin E
Why are ApoC-II and ApoA-V important for LPL activity in peripheral tissues?
As LPL drains TGs from VLDL, it becomes IDL and LDL
What is the significance of ApoB-100 in VLDL?
Major structural protein that allows clearance by the liver
How does the liver clear IDL and LDL?
Via the LDL receptor on hepatocytes
What happens if LDL is not cleared?
Becomes oxidized => major risk factor for atherosclerosis
Initial lipoprotein of reverse cholesterol transport? Where is it synthesized?
HDL - synthesized in both hepatocyte and enterocyte
What are the major structural proteins of HDL?
Apo-A1 and Apo-A2
What additional function does Apo-A1 have?
Allow HDL to receive cholesterol from the liver or peripheral tissues
What does the enzyme LCAT do?
Converts free cholesterol into cholesterol esters
What is the cholesterol-to-ApoA1 transporter?
ATP-binding cassette (ABC) protein
How can the liver remove cholesterol esters from HDL?
Scavenger receptor B1
Can the unloaded HDL recirculate?
Yes
How can HDL exchange cholesterol between other lipoproteins (VLDL and LDL)?
Via cholesterol ester transfer protein (CETP)
What happens when the hepatocytes accumulate excess cholesterol? (3)
- Reduces LDL clearance
- Secrete more cholesterol in bile
- Produce less VLDL
What does reducing liver cholesterol content result in?
Improved clearance of IDL and LDL
What protein degrades/removes the LDL-R from the hepatocyte membrane?
PCSK9
Development of atheromas in a wide range of large and medium-sized arteries?
Atherosclerosis
What causes endothelial injury in atherosclerosis? (4)
- Inflammation
- HTN
- Toxins
- Hyperlipidemia
What does endothelial injury cause in atherosclerosis? (3)
- Increased vascular permeability
- Leukocyte adhesion
- Thrombosis
What does accumulation of lipoproteins in the vessel wall cause? (2)
- Increase free radical production
- Activates macrophages
Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into _______and _______
Macrophages and foam cells
What happens while the LDL is bound weakly to the ECM of the intima for a variable period of time?
They become oxidized (ox-LDL) and are hidden from antioxidants in the plasma
What may increase the binding of LDL to the matrix?
AGEs
As the plaque grows and the overlying endothelium becomes more dysfunctional → ___________
Platelet adhesion
Lipid-filled macrophages + smooth muscle cells = ________
Foam cells
Emerging risk factors for atherosclerosis?
- Lipoprotein (a)
- Pro-thrombotic factors
- Pro-inflammatory factors
Primary care lipid measurements?
TC, LDL, HDL, TGs
When do you screen with full fasting profile q1-3 year?
- Males > 40 yo
- Females > 50 yo in menopause
- any age for adults with additional RF
________ is linked to the development, enlargement, and rupture of atheromas
Inflammation
What are the best markers for systemic inflammation pertaining to atherosclerosis?
- hsCRP (best)
- CRP
What is hsCRP?
Independent risk factor for development of MI and stroke
What does CRP do with regards to atherosclerosis?
Increased adhesion of leukocytes to atherosclerotic endothelium
What is metabolic syndrome?
A combination of physical exam and lab findings conferring a higher risk for coronary heart disease, diabetes, fatty liver, and cancer
Is metabolic syndrome common?
Common in NA - prev ranges from 20-30%
How do you recognize metabolic syndrome?
Must have 3/5:
- Elevated fasting glucose
- BP > 130/85
- Hypertriglyceridemia
- Lowered HDL-C
- Increased waist circumferance
Cardiac consequences of atherosclerosis?
- Myocardial infarction (heart attack)
- Heart failure
Neurologic consequences of atherosclerosis?
- Ischemic strokes
Peripheral vascular disease consequences of atherosclerosis?
- Impaired circulation to the extremities (esp. lower)
- Impaired circulation to the kidneys due to renal artery stenosis
Aneurysm formation as a consequence of atherosclerosis?
- Usually in abdominal aorta
Acute plaque changes fall under 3 categories…?
- Rupture/fissuring = exposure of highly thrombogenic plaque constituents
- Erosion/ulceration = exposure of the thrombogenic subendothelial basement membrane to blood
- Hemorrhage into the atheroma = enlargement of atheroma
What is plaque stability strongly affected by? (3)
- Hemodynamic disturbances
- Increased inflammation
- Factors that increase clot formation
Plaque rupture can discharge atherosclerotic debris into the bloodstream, producing microemboli?
Atheroembolism
What can an atheroembolism cause?
Stroke or MI
Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue → weakness resulting in aneurysmal dilation and potential rupture?
Aneurysm formation
Often the thrombosis migrates “downstream” to cause more complete occlusion of a smaller vessel when this happens?
Rupture, ulceration, or erosion
What will ruptures, ulcerations, or erosions cause?
Stroke or MI
Rupture of the overlying fibrous cap, or of the thin walled vessels in the areas of neovascularization, can cause?
Hemorrhage into a plaque
What might a hemorrhage into a plaque cause? (2)
- Make aneurysm worse
- Cause acute ischemic insult
Abnormal stretching (dilation or dilatation) in the wall of an artery, a vein, or the heart with a diameter that is at least 50% greater than normal?
Aneurysm
True aneurysm?
An “intact” attenuated arterial wall or thinned ventricular wall of the heart
False aneurysm?
Defect in the vascular wall → extravascular hematoma
Blood exits the lumen and enters the wall of the vessel?
Dissection
