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Multiple SREBPs regulate expression of numerous lipid-metabolizing proteins
Fatty acid metabolism
Chosterol metabolism
SREBP also
regulated
NADPH activity
Chapter 18
Part II
Low cholesterol→ cell → SREBPs activation → turn on gene
A.
Normal/High cellular free cholesterol
Protease is inhibited
B.
ER
ER
Sterol Regulatory Element Binding Protein trapped in ER as precursor
X
Low cellular free cholesterol
protease is active to cleave pre-SREBP-1
ER
NUCLEUS
Repressed
Genes
Repressed Genes:
1. HMG CoA
reductase
2. LDL receptor
Transcriptional
Activation
Nucleus
Induced Genes:
1. HMG CoA
reductase
2. LDL receptor
Promoter Region
Promoter Region
pre-SREBP-1
SREBP-1
protease
pre-SREBP-1
Figure 3. Regulation of HMG CoA
reductase by repression
SREBP-1
Figure 3. Regulation of HMG CoA
reductase by induction
protease
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Member of the nuclear receptor superfamily contribute to cellular
an whole body lipid regulation
ABC proteins mediate cellular export of phospholipids and cholesterol
SREBP regulated cholesterol and lipid metab
Other hydrphobic molecular (steroid hormone) enter cytosol → nuclear receptor →
regulated related gene expression
In liver:
Cholesterol ↑↑ → produce oxysterol → activated LXR (liver X receptor) →
cholesterol 7α-hydroxylase → (cholesterol convent to) bile acid → secret excessive
cholesterol
LXR → stimulated ABC expression (ABCG5/8; ABCA1) → cholesterol release
LXR → SREBP activation → lipid synthesis related enzyme expression
LXR sense massive cholesterol
Bile acid bind to FXR (nuclear receptor) → activation of FXR → I-BABP, ABCB11,
NTCP expression ; inhibited cholesterol 7α-hydroxylase
Na-linked
symporter (NTCP)
95%
Binding protein
IBAT: ileal bile acid transporter (IBAT)
I-BABP: intenstinal bile acid-binding protein
Fig 18-11 Major transport proteins in the liver and intestine taking
part in the enterohepatic circulation of biliary lipids
Role of LXR and FXR
When cholesterol accumulates
in cells, cholesterol is oxidized
to create oxysterols
2
Role of LXR and FXR
Oxysterols activate LXR
through LXR/RXR
heterodimers to activate genes
such as the CYP7A1 enzyme
that catalyzes the rate-limiting
step in bile acid biosynthesis
Role of LXR and FXR
Role of LXR and FXR
In the intestine, LXR also
activates ABC-1 to remove
cholesterol
18.5 The cell biology of atherosclerosis, heart attacks, and strokes
In the intestine, FXR
activates expression of IBABP, a protein that
increases the transport of
bile acids back to the liver
from the intestine, reducing
their excretion.
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Endothelial Dysfunction
Increased endothelial permeability
to lipoproteins and plasma
constituents mediated by NO,
PDGF, AG-II, endothelin.
Up-regulation of leukocyte
adhesion molecules (L-selectin,
integrins, etc).
Up-regulation of endothelial
adhesion molecules (E-selectin,
P-selectin, ICAM-1, VCAM-1).
Migration of leukocytes into artery
wall mediated by oxLDL, MCP1, IL-8, PDGF, M-CSF.
Formation of Fatty Streak
SMC migration stimulated by PDGF,
FGF-2, TGF-B
T-Cell activation mediated by TNF-a,
IL-2, GM-CSF.
Foam-cell formation mediated by
oxLDL, TNF-a, IL-1,and M-CSF.
Platelet adherence and aggregation
stimulated by integrins, P-selectin,
fibrin, TXA2, and TF.
Ross, NEJM; 1999
Formation of Advanced, Complicated Lesion
Fibrous cap forms in response
to injury to wall off lesion
from lumen.
Fibrous cap covers a mixture of
leukocytes, lipid and debris
which may form a necrotic
core.
Lesions expand at shoulders by
means of continued
leukocyte adhesion and
entry.
Necrotic core results from
apoptosis and necrosis,
increased proteolytic activity
and lipid accumulation.
Ross, NEJM; 1999
Development of Unstable Fibrous Plaque
Rupture or ulceration of fibrous
cap rapidly leads to
thrombosis.
Occurs primarily at sites of
thinning of the fibrous cap.
Thinning is a result of
continuing influx of and
activation of macrophages
which release
metalloproteinases and other
proteolytic enzymes.
These enzymes degrade the
matrix which can lead to
hemorrhage and thrombus
formation
Ross, NEJM; 1999
Ross, NEJM; 1999
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Plaque Rupture with Thrombus
Thrombus
Cholesteryl esters in lipoproteins can be selectively taken up
by the receptor SR-BI (scavenger receptor, class B type I)
Can bind HDL, LDL, VLDL
Fibrous cap
Still unclear
Binds HDL, LDL, VLDL
SR-BI:
1 mm
Lipid core
1.
2.
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
Lipids Online
cluster on microvilli and in the cell surface lipid raft, not in coated pits
as does the LDL receptor
Mediate the transfer of lipid across the membrane, not endocytosis of
entire LDL particles
LDL Cellular Metabolism
LDL Cellular Metabolism
LDL are taken up by the LDL Receptor into clathrin-coated pits
LDL dissociates from the receptor; the receptor recycles to the membrane
Cholesterol and
Atherosaclerosis, Grundy)
Cholesterol and
Atherosaclerosis, Grundy)
5
LDL Cellular Metabolism
In the lysosome, lipids are deseterified; proteins are hydrolyzed
LDL Cellular Metabolism
Increase in free cholesterol regulates decrease cholesterol synthesis
and uptake; increase cholesterol esterification
Cholesterol and
Atherosaclerosis, Grundy)
Cholesterol and
Atherosaclerosis, Grundy)
Arterial inflammation and cellular import of cholesterol mark the
early stage of atherosclerosis
Arterial inflammation and cellular import of cholesterol mark the
early stage of atherosclerosis (LDLR-independent mechanism)
LDLR-independent uptake of LDL (bad cholesterol) leads to
formation of foam cell (LDLR play an important role of
atherosclerosis??????? No no no no這不是LDLR的錯 )
Plasma LDL→ LDL in artery high → LDLR-mediated endocytosis ↑→rapidly
foam cell develop ??????
However, LDL-mediated endocytosis is not a factor for the development of
atherosclerosis:
Two reasons, still atherosclerosis
1. Intracellular regulation: LDLR gene activity is cholesterol-dependent; High
intracellular cholesterol →insig/SCAP/SREBP pathway ↓→ LDLR gene
regulation ↓→ low LDLR gene expression
2. In familial hypercholesterolemic patient: LDLR activity is lower, but still has
atherosclerosis
Generation of macrophage foam cells in an artery wall
A site infection or damage →
activated endothelial cell → cell
adhesion molecular expression
→ monocyte adhesion →
migration → differentiation to
macrophage
High LDL →oxidized to oxLDL
→ bind to scavenger receptor
(macrophage) → degraded
→lipid droplets cytosol →
formed foam cell →ABCA1 or
SR-B1→ transport HDL out
via ABCA1
and/or SR-BI
Scavenger receptor
6
Atherosclerosis narrows and blocks blood flow through coronay arteries
A coronary artery with an
atherosclerotic plaque
FC: macrophage
contain cholesteryl
ester and lipid droplets
intima
Smooth muscle
Reverse cholesterol transport by HDL protect against atherosclerosis
Cholesterol →ABC → blood
→SR-BI uptake→ liver →
LCAT cholesteryl ester
HDL: decrease foam cell,
macrophage
HDL Function
Cholesteryl
estertransfer
protein
indirectly
Directly
possibility of contracting
atherosclerosis!
LDL/HDL < 3.5 (healthy status)
decrease LDL, increase HDL
•
•
•
•
Removal of CE from LDL
Reverse Cholesterol transport
Apo A-1 prevent seeding of LDL
Apo A-1 prevent oxidized LDL
formation
LCAT
Lecithin:cholesterol
acyl transferase; in plasma
Fig 18-22 HDL-mediated reverse cholesterol transport
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Reverse Cholesterol Transport
Delivery of peripheral tissue cholesterol to the liver for catabolism
Requires HDL, apoA-I and LCAT
sorting endosome:
ligand/receptor
dissociation
LDL
receptor
Recycling
Recyclingofofreceptor
receptor
clathrincoated pit
Peripheral
Cell
UC
diffusion
Macrophage/ Foam cell
ABCA1
o
o
o
HDL
UC
HDL
UC
vesicle
LDL
CE
HDL
CE
CE
CE
apoA-I
UC = unesterified cholesterol
CE = esterified cholesterol
PL = phospholipid
LDLr = LDL receptor
VLDL
or LDL apoB
CE
Liver
LDLr
Chol
CERP; cholesterol
efflux regulatory
protein
Membrane
Cholesterol
Bile acids
Bile to gut
CE in nascent HDL
ACAT (stimulated
by cholesterol)
CE stored in
Cholesterol droplets
CE CE
Esterase
Cholesterol metabolism to
bile acids or steroids
Apo A1 receptor
L
C
A
T
Cellular cholesterol
uptake, metabolism and
release.
Golgi
free pool of
cholesterol
Cholesterol release for
transport to liver
SR-B1
TG
NPC-1
mediated
transfer
ACEH
CE Æ cholesterol
B100 Æ amino acids
LCAT
Nascent
HDL
lysosome
oand clathrin
o
late endosome
o
endocytosis
LCAT
PL
transport vesiclelysosome fuse forming
late endosome
A1
CII
E
Reverse
Cholesterol
Transport
Apo A1 binds to receptor, activates
CERP to pump out cholesterol, and
LCAT to esterify cholesterol
A1
E
CII
Mature HDL:
Cleared by liver
Two treatments for atherosclerosis are based on SREBPregulated cellular cholesterol metabolism
1. Bile acid-binding resins (“sequestrants”)
- bind tightly to bile acid → inhibits IBAT absorption into int.
epith. cell. → increased LDLR expression (Fig 18-23b)
Feedback repression by bile acids on 7α-hydroxylase lost; cholesterol to
bile acids greatly enhanced to maintain pool of bile acids
2. Statin (inhibitor of HMG-CoA reductase)
- less cholesterol synthesized
- increased LDLR expression (Fig 18-23b)
IBAT : ileal bile acid transporter
I-BABP : intestinal bile acid transporter
NTCP : Na+-linked symporter
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CONSEQUENCES OF BILE SALT
SEQUESTERING RESINS
(e.g., Cholestyramine)
1) Feedback repression by bile acids on 7α-hydroxylase; cholesterol to
bile acids greatly enhanced to maintain pool of bile acids.
2) Lowered liver cholesterol up-regulates LDL receptors via SREBP
induction of transcription in the liver
3) More LDL receptors increases the hepatic uptake of LDL with
consequent lowering of plasma cholesterol
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