Cholesterol Flashcards
Iniation of Artherosclerosis
Transport of plasma LDL-cholesterol through the endothelial cell layer into the extracellular matrix of the subendothelial space
At low levels, this may NOT be problematic. LDL is a naturally occurring lipoprotein
An artherosclerotic plague can be present for… without any….
Decades
Symptoms
How can an artherosclerotic plague cause MI?
Rupture
The exposed “core” of an atherosclerotic plaque is highly stimulating to circulating platelets
Platlets cause a blockage
What are the two most common plasma lipids?
Cholesterol
Triglycerides (TG)
Cholesterol Facts
A “sterol” or modified steroid molecule
A type of lipid molecule synthesized by all animal cells
Essential structural component of all animal cell membranes
Allows cells to function without a cell wall
Cholesterol is the building block for these molecules….
Bile acids
Vitamin D
Steroid hormones*
- “Steroid hormones” include corticosteroids (glucocorticoids, mineralocorticoids) and sex steroids (androgens, estrogens, and progestogens)
Triglycerides are….
3 fatty acids connected by a glycerol backbone
Fatty acids can be oxidized for energy by many tissues (except brain)
The glycerol backbone can be used for gluconeogenesis
Cholesterol and TG Transport
NOT water soluble so must have specialized “vehicles” to circulate in the blood
These “vehicles” are made from “apolipoproteins”
Apolipoproteins are proteins that bind lipids (to form lipoproteins)
Lipoproteins have varying density based on the relative amount of protein vs lipid
Plasma lioproteins contain….
protein and lipid
The protein component of lipoproteins function… What does it define?
Provide structural stability and also may function as ligands in receptor interactions or as cofactors in enzymatic processes that regulate lipoprotein metabolism.
The type of protein typically defines the use of the particle
Lipid componnetsof lipoproteins
Free cholesterol
Esterified cholesterol (>1 cholesterol molecule linked together to improve storage efficiency)
Triglycerides
Phospholipids.
Apoplipoproteins on surface of lipoprotein do what?
Facilitates dissolution in blood
Facilitates receptor interactio
The more…. are found in the middle. Examples?
More insoluble molecules in middle
TGs
Cholesterol ester
Chylomicrons
Large lipoproteins containing +++ triglyceride (80-95%)
Major vehicle to carry dietary fat
(and cholesterol) immediately after
absorption from gut
How long are chlyomicrons present in blood for? When?
Present in plasma for
3–6 h after a fat-containing meal
has been ingested
What are the roles of chlyomicrons?
Source of TG for adipose tissue and muscle (cardiac and skeletal)
Capillaries in these tissues contain LPL that liberates free fatty acids for a cellular energy source
Source of TG and cholesterol for liver to produce VLDL (another TG delivering vehicle)
What increases LDL?
Diets high in fat and cholesterol
Describe the process of Chylomicron to increased serum LDL
Chylomicron remnants (i.e., remainder of molecule after TG has been donated in tissues) contain cholesterol
When taken up by liver cells, increases intra-cellular cholesterol levels
Liver responds by downregulation of LDL-receptors (to prevent further uptake of LDL (cholesterol) from blood
LDL levels accumulate in blood
VLDL is….
Very similar to a chylomicron molecule
Synthesized in liver
Main source of FFA in the fasting state (i.e., chylo’s are low)
Provides FFA to tissues similar to
Chylomicrons (LPL in capillary bed
steal the TG from VLDL)
What do blood tests measure?
Blood tests measure “triglycerides” rather than VLDL and chylomicrons separately
TG blood tests measure all TG levels in the blood.
VLDL’s transform into….
Eventually VLDL’s are stripped of most of TG in the tissues and transform into IDL’s (intermediate density lipoproteins)
High TG on blood tests is indicative of….
high levels of VLDL and chylomicrons
IDl transforms into…. Where does this occur?
Additional loss of TG by lipoprotein lipase (LPL) will change IDL to LDL (often after interacting with HDL molecules)
This process can occur in the liver (frequently) or in peripheral tissues that use TG (fatty acids)
LDL is the main carrier of what molecule….
Main carrier of cholesterol in blood (60-70%)
Most LDL is derived from….
VLDL metabolism
Can tissues synthesize cholesterol?
YES
LDL contains which apolipoprotein?
Contains apolipoprotein B-100 (or apo B)
If cholsetrol is needed, cells….. How does binding occur and what molecule?
Upregulate LDL receptor
Affinity for LDL receptor is based on apo-B on the LDL particle
LDL Receptors in liver cells. WHat is the liver mainly responsible for?
Liver cells express the LDL receptor constantly (to eliminate excess LDL from the circulation). The liver disposes of ¾ of circulating LDL
Familial Hypercholesterolemia
is a genetic trait that is associated with no LDL receptors
LDL is not cleared from the circulation AND intracellular production is increased. People with FH have very high LDLs from a young age and experience ACVD at very young ages.
High levels of intracellular cholsesterol cause….
Inhibits intracellular production
Decreases synthesis of LDL receptors
Increased chol storage within cells
In liver, LDL can be excreted in bile
NOn-HDL Liporproteins
chylomicrons, VLDL, IDL, and LDL
Non-HDL useful measure when….
Non-HDL is a useful measure when TG levels are high. represents the full burden of cholesterol.
When TG are high, LDL level may go down. So LDL would not tell you the total cholesterol burden.
Non-Hdl is the target of
Cholesterol tx
HDl is derived in which organs…
Derived in the periphery (mainly gut) and in the liver
HDL formation
HDL can be formed by remodeling of chylomicrons or by VLDL catabolism
HDL main role….
Main role “reverse cholesterol transport”
In reverse chol transport, excess cholesterol is acquired from cells and transferred to the liver for excretion.
A full HDL can donate a cholesterol to….
donate cholesterol to LDL, and VLDL too!
HDL benfit to health
Allowing tissues (such as coronary arteries) to eliminate excessive cholesterol may be a reason why HDL is considered protective (good cholesterol)
What can lower the risks for ACVD events (molecules)?
Apo A-I (the major HDL apolipoprotein) and HDL levels
- No pharm target here
Pharm Management focuses on….
Currently, pharmacologic management of dyslipidemia focuses on levels of LDL
When does LDL become problematic?
LDL may not be that dangerous on its ownIf it is chemically modified by oxidation, it becomes problematic
Oxidaized LDL causes
Oxidized LDL appears to elicit an immune response
Mildly oxidized LDL in the subendothelial space triggers signals to recruit monocytes into the artery wall (monocytes are a type of WBC)
- Stimulate T-cells to seceret inflammatory cytokines
- Cytokine strigger conversion of mnocyte to macrophages
- Cytokines cause migration of smooth muscle to the intimal layer of vessel wall
- Increase oxidation of LDL
Oxidized LDL triggers the LDL-receptor to change to a “scavenger receptor” (SR) in macrophages and migrated muscle cells
SR’s are not governed by the level of intracellular LDL
As a result, macrophages and migrated muscle cells consume enormous volumes of oxidized LDL and become “foam cells”
Monocytes are attracted to the tissue and are activated into macrophages.
What triggers the artherosclerotic process?
Oxidization of LDL appears to be a key trigger of the atherosclerotic process
Provokes an inflammatory response mediated by several chemo-attractants and cytokines
HDL role in oxidization of LDL
HDL may serve to reduce oxidation of LDL
Anti-oxidants in Oxidized LDL
- Theory there
- Not clinically useful
Over time, changes of artherosclerosis….
Vascular SM cells proliferate and lay down collagen and other matrix molecules, and contribute to the bulk of the lesion.
Repeated injury and repair eventually leads to a fibrous cap protecting the plaque (lipids, collagen, calcium, and inflammatory cells such as T-lymphocytes).
Endothelial dysfunction appears to occur
frequently (e.g., impaired N.0. synthesis)
- The endothelial cells become dysfunctional, and endothelial cells are the major source of NO that is responsible for vasodilation
Artherosclerosis presentation and what time in life?
Low levels of atherosclerosis appear as “fatty streaks” in blood vessels that can be seen in the first 10 years of life
factors that increase progression artherosclerosis….
Extent of oxidation of LDL and extent of inflammatory response to oxidized LDL
Level of plasma lipids (dietary factors, genetic factors, demand for cholesterol)
Metabolic factors / classic risk factors / endothelial damage (HTN, sugar, smoking, etc)
Non-modfiable risk factors for artherosclerosis
Age ≥55 years
Male
Family history of premature
cardiovascular disease
(age <55 in men and
<65 in women)
Modifiable risk factors of artherosclerosis
Sedentary lifestyle (low LDL receptors on cells so it hangs around)
Poor dietary habits
Abdominal obesity
Dysglycemia (or diabetes)
Smoking (even 2nd hand)
Dyslipidemia
Stress
Hypertension
