Cholesterol rich lipoproteins and Cholesterol Homeostasis Flashcards
How do CE-rich LPs modify atherclerosis risk?
Serum LDL –> arterial wall MACROPHAGE CE storage –> conversion from macrophage to foam cell –> conversion from foam cell to fatty streak
How does the liver regulate serum LDL?
hepatic intracellular [Chol]
What does hepatocyte IC [chol] regulate?
Chol input - de novo synth & LDL uptake
Chol output - CE & BA synth
Acetyl CoA
Precursor to FA, chol, & KB
chol is from cytosolic acetyl CoA
Cholesterol synth
- Glucose –> cytosolic acetyl CoA
- Synth and reduce HMG CoA
- Assemble ring structure and tail to –> Chol
HMG CoA reductase
converts HMG CoA to chol in smooth ER
ATP citrate lyase (ACLY)
Converts citrate to acetyl CoA
Hormonal regulation of HMG CoA reductase
(-) by glucagon
(+) by Insulin
Other HMG CoA Reductase regulation
intracellular [chol]
LDL-R synth
Regulated by intracellular [chol]
In RER –> processed in golgi –> secretory vesicle –> plasma membrane
LDL-R degradation
regulated by intracellular [chol] & by PCSK9 protein secreted by hepatocytes
PCSK9 regulation of LDL-R
binds LDL to LDL-R -> no LDL-R recycling –> inc LDL-R degradation –> dec LDL-R expression
Which lipoproteins can cross endothelial
HDL (normal levels)
LDL (high levels)
Intermeds (only at very high serum levels):
IDL
CMR
Cross into arterial wall connective tissue and interact w macrophages
Macrophages use ___ to take up ___ in connective tissue
LDL-R
LDL, IDL, or CMR
Macrophages use ___ to convert ___ to ___ for storage
Macrophages use ACAT to convert chol to CE for storage
Macrophages use _____ to efflux ___ onto ____
Macrophages use ABCA1 to efflux chol onto HDL
Scavenger receptors (SR)
- expressed by macrophages
- recognize various ligands so macrophages can clear shit up
- not downreg by high IC [chol]
Macrophages take up enough chol from apoptotic bodies to _____ the LDL-Rs at normal LP levels
downregulate
At normal serum LP levels, little ___ is modified and taken up by ____
LDL
SRs
How can macrophages prevent excessive CE accumulation?
By effluxing chol onto HDL
What happens to LDL that remains in arterial walls?
Oxidation, acetylation, etc.
Becomes a target for SRs
How does high serum [LDL] affect SR?
High serum LDL –> inc LDL transport –> inc modified LDL –> IC chol –> dec LDL-R
but does NOT dec SRs
What causes a macrophage to turn into a foam cell
Very high [CE] activates secretion of cytokines that convert it and also recruit more macrophages to become foam cells –> fatty streaks –> atherosclerosis
Which of the following increase early risk of atherosclerosis:
VLDL, LDL, IDL, CMR, or CM?
High LDL, IDL, and CMR; CM do not
What contributes to macrophage CE storage?
High serum LDL (major contributor), IDL, CMR
Low HDL
Key initiator of athersclerosis?
Excess macrophage CE storage
Sterol-responsive transcription factors
How IC [chol] regulates cell processes
SREBP
Inc transcription of LDL-R and HMG CoA
Is inhib by IC [chol]
LXR/RXR
Inc transcription of: ABCA1 ACAT 7alphaOHase PCSK9 secretion
Stim by IC [chol]
What is the major cause for an inc in IC [chol] in liver?
HMG CoA reductase
What is a major cause for dec in IC [chol] in liver?
7alpha-OHase (chol–> BA)
