The Role of CETP in Reverse Cholesterol Transport: Will Its Inhibition Reverse Atherosclerosis?
Cholesterol Metabolism and the Concept of Dual Inhibition David E. Cohen, MD, PhD.
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Transcript of Cholesterol Metabolism and the Concept of Dual Inhibition David E. Cohen, MD, PhD.
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Cholesterol Metabolism and Cholesterol Metabolism and the Concept of Dual Inhibitionthe Concept of Dual Inhibition
David E. Cohen, MD, PhDDavid E. Cohen, MD, PhD
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OverviewOverview
Digestive lipid metabolism
Cholesterol balance
Inhibitors of cholesterol synthesis and absorption
Dual inhibition
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Digestive Lipid MetabolismDigestive Lipid Metabolism
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Reverse Cholesterol TransportReverse Cholesterol Transport
BloodBloodPeripheralPeripheralTissuesTissues
LiverLiver
BileBile
ExcessExcessCholesterolCholesterol
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Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile Salts
CholateCholateCholesterolCholesterol
CholesterolCholesterol77-hydroxylase-hydroxylase
HOHO HOHO
OHOH
COO -COO -
OHOH
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Bile SaltsBile Salts
Breakdown products of cholesterol
Amphipathic molecules
Function to transport cholesterol in the digestive system
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Structure of Biliary and Intestinal MicellesStructure of Biliary and Intestinal Micelles
CholesterolCholesterol
Bile SaltBile Salt
PhospholipidPhospholipid
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Functions of MicellesFunctions of Micelles
Transport cholesterol from the liver into the intestine via the biliary tree
Participate in fat digestion and absorption
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Biliary Lipid SecretionBiliary Lipid Secretion
Sinusoidal Membrane
BloodBlood HepatocyteHepatocyte
Canalicular Membrane
Bile SaltBile Salt
ABCG5/G8Cholesterol
ABCB4Phospholipid
ABCB11
BileBile
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Biliary LipidsBiliary Lipids
Daily Secretion (g)Daily Secretion (g)Lipid ClassLipid Class
Bile salts
Phospholipids
Cholesterol
24
11
2
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Biliary Lipid TransportBiliary Lipid Transport
DuodenumDuodenum
JejunumJejunum
IleumIleum
ColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
Liver
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Fat DigestionFat Digestion
DuodenumDuodenum
JejunumJejunum
IleumIleum
ColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
Liver
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Fat DigestionFat Digestion
TriglyceridesTriglyceridesDietaryDietaryCholesterolCholesterol
Fatty Acids +Fatty Acids +MonoglyceridesMonoglycerides
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Fat AbsorptionFat Absorption
DuodenumDuodenum
JejunumJejunum
IleumIleum
BiliaryBiliaryTransportTransport
and and StorageStorage
ColonColon
Liver
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LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Cholesterol AbsorptionCholesterol Absorption
Cholesterol
NPC1L1
CholesterylEster ABCG5/G8
ACAT
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LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Triglyceride AbsorptionTriglyceride Absorption
2 Fatty Acid+
Monoglyceride
DGAT
Triglyceride
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LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Chylomicron FormationChylomicron Formation
CholesterylEster
CMapoB48
Triglyceride
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Cholesterol BalanceCholesterol Balance
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DuodenumDuodenum
JejunumJejunum
IleumIleum
ColonColon
Portal Venous Return (>95% of Biliary
Secretion) FecalFecalexcretionexcretion(0.4 g/d)(0.4 g/d)
BiliaryBiliaryTransportTransport
and and StorageStorage
LiverSynthesisSynthesis
0.4 g/d0.4 g/d
SecretionSecretion24 g/d24 g/d
Enterohepatic Circulation of Bile SaltsEnterohepatic Circulation of Bile Salts
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DuodenumDuodenum
JejunumJejunum
IleumIleum
ColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
FecalFecalexcretionexcretion(1.2 g/d)(1.2 g/d)
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
AbsorptionAbsorption~50%~50%
CMapoB48
LiverBiliary Biliary
Cholesterol Cholesterol (2 g/d)(2 g/d)
Biliary and Dietary CholesterolBiliary and Dietary Cholesterol
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Cholesterol BalanceCholesterol Balance
DuodenumDuodenum
JejunumJejunum
IleumIleum
ColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
CholesterolCholesterol
CholesterolCholesterol(1.2 g/d)(1.2 g/d)
++Bile SaltsBile Salts(0.4 g/d)(0.4 g/d)
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
LossLoss(1.6 g/d)(1.6 g/d)
Bile saltsBile saltsLossLoss
(1.6 g/d)(1.6 g/d)——
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
SynthesisSynthesis(1.2 g/d)(1.2 g/d)
Liver
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Inhibitors of Cholesterol Synthesis Inhibitors of Cholesterol Synthesis and Absorptionand Absorption
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Inhibitors of Cholesterol Synthesis: StatinsInhibitors of Cholesterol Synthesis: Statins
Inhibit synthesis of cholesterol by cells
Lower LDL cholesterol
Mechanism: Mechanism: Promote LDL ClearancePromote LDL Clearance
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LDLLDLReceptorReceptor
StatinsStatins
Acetate
LDLLDL
HMG-CoAReductase
Cholesterol
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Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
Inhibit absorption of dietary cholesterol
Inhibit reabsorption of biliary cholesterol
Lower LDL cholesterol
Mechanism: Mechanism: Inhibit LDL FormationInhibit LDL Formation
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Plant Sterols and StanolsPlant Sterols and Stanols
Sterol/StanolSterol/StanolDietaryDietaryCholesterolCholesterol
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LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Plant Sterols and StanolsPlant Sterols and Stanols
Cholesterol
CholesterylEster ABCG5/G8
ACAT NPC1L1
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LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
EzetimibeEzetimibe
Cholesterol
NPC1L1
CholesterylEster ABCG5/G8
ACAT
Ezetimibe
XX
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LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
CholesterylEster
CMapoB48
Triglyceride
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Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
DuodenumDuodenum
JejunumJejunum
IleumIleum
CMapoB48
Liver
CM RemnantapoB48
VLDLapoB100
EzetimibeXX
LDLapoB100
ColonColon
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Dual InhibitionDual Inhibition
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Assembly and Secretion of VLDLAssembly and Secretion of VLDL
Presence of Triglycerides
ApoBMTPMTP
Cholesteryl Esters
Cholesterol
Dietary/Biliary Synthesis
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Effect of Cholesterol Absorption InhibitorEffect of Cholesterol Absorption Inhibitor
Presence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary Synthesis
EzetimibeXX
MTPMTPCholesteryl Esters
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Adding a Statin Blocks Compensatory Increase in Adding a Statin Blocks Compensatory Increase in SynthesisSynthesis
Presence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary Synthesis
EzetimibeXX XX Statin
MTPMTPCholesteryl Esters
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Dual InhibitionDual Inhibition
DuodenumDuodenum
JejunumJejunum
IleumIleum
CMapoB48
Liver
CM RemnantapoB48
VLDLapoB100
EzetimibeXX
LDLapoB100
XXStatinStatin
ColonColon
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ConclusionsConclusions
Cholesterol balance is regulated by both synthesis and absorption
Inhibition of cholesterol absorption may be compensated by increases in synthesis
Optimal LDL lowering may best be achieved by inhibiting both pathways
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