Lecture 17: Cholesterol Homeostasis Flashcards
cholesterol (descr.)
relatively flat molecule
cholesterol play an important role in ____
determining membrane integrity and fluidity (biological properties of PM)
cholesterol vs. phospholipid amount at PM
equimolar (equal amount of cholesterol and phospholipid)
cholesterol location in PM/ER
restricted to subdomains
cholesterol synthesized where?
ER
cholesterol in membrane forms _____ which creates ______
lipid rafts
microdomain for signaling
role of cholesterol for membranes
-with sphingomyelin, it forms rafts and caveolae
-serves as precursor for sex hormones, bile acids
lipid rafts and caveolae is important for ____
cell signaling and endocytosis
lipid rafts and caveolae = cholesterol + _____
sphingomyelin
dysregulation of cholesterol leads to ____
important pathologies
cholesterol comes from ____ or _____
diet or produced by cell (de novo synthesis)
↓ cholesterol = ↑ ______
enzymes that make cholesterol
removing cholesterol induces _____
transcription of many enzymes involved in cholesterol synthesis
presence of cholesterol blocks ____
transcription of genes implicated in cholesterol synthesis and endocytosis of LDL
presence of cholesterol promotes degradation of ___
enzyme involved in cholesterol synthesis
enzyme involved in cholesterol synthesis: ___
HMG-CoA reductase
esterified cholesterol (CE) traffics between ___
organs in specialized particles
dietary cholesterol is trafficked in __
Chylomicrons
bad cholesterol is trafficked in ___
VLDL, LDL
good cholesterol is trafficked in ___
HDL
CE is highly ____
hydrophobic
organ important for cholesterol metabolism
liver
VLDL, LDL transports excess fat from ___
liver to artery
HDL transports excess fat from ___
artery to liver
drugs that control cholesterol levels target _____
-elimination of bile salts
-level of LDL receptor
-de novo synthesis
statins are drugs that ____
inhibit HMG-CoA reductase (enzyme that produces cholesterol)
statins reduces ____
level of cholesterol
PCSK9 is _____ that activates ____
a trafficking mediator for the LDLR (LDL receptor)
itself by cleavage
dominant-negative mutant of PCSK9 doesn’t act as _____
a trafficking mediator
gain-of-function mutant of PCSK9 increases ______ (2)
action of trafficking mediator
degradation of LDLR in the lysosome
PCSK9 is a protein in the ___ that interacts with ____ and then targets it for ______
ER
LDL receptor
lysosomal degradation
hypercholesterolemia (def.)
high levels of LDL
PCSK9 inhibitors prevent ____
degradation of LDLR, reducing [cholesterol] in serum
genes regulated by sterols contains ____
unique sequence (SRE - sterol regulatory element)
nucleotide important in SRE for interaction with transcription factor
cytosine
transcription factors (proteins) that recognize SRE
nSREBP
SREBP is localized where when inactive?
ER
SREBP (descr.)
transmembrane protein
large protein with two hydrophobic membrane spanning domains
SREBP activity when cholesterol is present?
SREBP interacts with SCAP protein (transmembrane) which interacts with INSIG in ER
SREBP activity when cholesterol is absent?
SREBP interacts with SCAP protein (transmembrane) in ER
SCAP-SREBP complex moves to Golgi
proteolysis of SCAP-SREBP produces transcription factor which moves to nucleus -> affects gene expression
SCAP-SREBP complex trapped in ER by ___
INSIG
SCAP binds to cholesterol and prevents ____
entry into COPII vesicle to golgi
nSREBP is in ____
nucleus
SREBPs promote synthesis of ____
1) enzymes responsible for cholesterol synthesis
2)production NADPH - needed for lipid synthesis
3) LDL receptors
↑ nSREBP in nucleus = ↑ ___
transcription of genes for HMG-CoA reductase and LDL receptor
SREBP vs nSREBP
inactive vs active
nSREBP is located where on inactive SREBP?
globular domain at N-terminus (n=nuclear or N-term) -cytoplasmic
release of nSREBP involves _____
two specific proteases
proteolysis of SREBP happens in ___
golgi
Site 1 protease (S1P) cleaves ___
lumenal loop (in golgi lumen)
Site 2 protease (S2P) cleaves ____
within the first transmembrane anchor
nSREBP acts as ____
transcriptional facot
nSREBP rapidly degraded by ____
proteasome in Ub-dependent manner
SREBP processing by S1P requires presence of _____
SCAP
mutations in SCAP that prevent binding to SREBP also prevent ___
processing
formation of complex with SCAP stabilizes ___
SREBP
____ domain of SREBP on _____ interacts with ___ domain of SCAP on ____
Regulatory
C-terminus
WD
C-terminus
SCAP (descr..)
polytopic membrane protein (8 transmembrane domains) with two important domains
Two domains of SCAP
-c-terminal WD domain
-n-terminal domain
c-terminal WD domain of SCAP located in _____
cytoplasm
c-terminal WD domain of SCAP contains multiple ____
W,D residues,
n-terminal domain of SCAP contains ____
8 trans-membrane segments
n-terminal domain of SCAP: helices 2-6 form ___
sterol sensing domain (SSD)
SSD of SCAP binds to binding partner in ER which ___
anchor complex
overexpression of SCAP with SSD causes ___
formation of golgi complex
TM1-6 (transmembrane) of SCAP binds to ___
INSIGs (1 &2)
INSIG (def.)
Insulin Induced Gene
INSIG is localized to ___
ER
INSIG binds SSD of SCAP in ____
the presence of cholesterol
SCAP dissociates from INSIG and is exported to golgi in ____
absence of cholesterol
High cholesterol: SREBP-SCAP complex
-cholesterol-binding alters SCAP structure
-SREBP-SCAP complex binds INSIG
-complex trapped in ER
Low cholesterol: SREBP-SCAP complex
-SREBP-SCAP complex released from INSIG
-become free to interact with COPII (Sec24)
-transported to golgi
SCAP is ___ (slang) while INSIG is ____ (slang)
-sensor
-anchor
