Cholesterol Metabolism and Cholesterol Metabolism and the Concept of Dual Inhibitionthe Concept of Dual Inhibition
David E. Cohen, MD, PhDDavid E. Cohen, MD, PhD
OverviewOverview
Digestive lipid metabolism
Cholesterol balance
Inhibitors of cholesterol synthesis and absorption
Dual inhibition
Digestive Lipid MetabolismDigestive Lipid Metabolism
Reverse Cholesterol TransportReverse Cholesterol Transport
BloodBloodPeripheralPeripheralTissuesTissues
LiverLiver
BileBile
ExcessExcessCholesterolCholesterol
Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile Salts
CholateCholateCholesterolCholesterol
CholesterolCholesterol77-hydroxylase-hydroxylase
HOHO HOHO
OHOH
COO -COO -
OHOH
Bile SaltsBile Salts
Breakdown products of cholesterol
Amphipathic molecules
Function to transport cholesterol in the digestive system
Structure of Biliary and Intestinal MicellesStructure of Biliary and Intestinal Micelles
CholesterolCholesterol
Bile SaltBile Salt
PhospholipidPhospholipid
Functions of MicellesFunctions of Micelles
Transport cholesterol from the liver into the intestine via the biliary tree
Participate in fat digestion and absorption
Biliary Lipid SecretionBiliary Lipid Secretion
Sinusoidal Membrane
BloodBlood HepatocyteHepatocyte
Canalicular Membrane
Bile SaltBile Salt
ABCG5/G8Cholesterol
ABCB4Phospholipid
ABCB11
BileBile
Biliary LipidsBiliary Lipids
Daily Secretion (g)Daily Secretion (g)Lipid ClassLipid Class
Bile salts
Phospholipids
Cholesterol
24
11
2
Biliary Lipid TransportBiliary Lipid Transport
DuodenumDuodenum
JejunumJejunum
IleumIleum
ColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
Liver
Fat DigestionFat Digestion
DuodenumDuodenum
JejunumJejunum
IleumIleum
ColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
Liver
Fat DigestionFat Digestion
TriglyceridesTriglyceridesDietaryDietaryCholesterolCholesterol
Fatty Acids +Fatty Acids +MonoglyceridesMonoglycerides
Fat AbsorptionFat Absorption
DuodenumDuodenum
JejunumJejunum
IleumIleum
BiliaryBiliaryTransportTransport
and and StorageStorage
ColonColon
Liver
LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Cholesterol AbsorptionCholesterol Absorption
Cholesterol
NPC1L1
CholesterylEster ABCG5/G8
ACAT
LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Triglyceride AbsorptionTriglyceride Absorption
2 Fatty Acid+
Monoglyceride
DGAT
Triglyceride
LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Chylomicron FormationChylomicron Formation
CholesterylEster
CMapoB48
Triglyceride
Cholesterol BalanceCholesterol Balance
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
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
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
Inhibitors of Cholesterol Synthesis Inhibitors of Cholesterol Synthesis and Absorptionand Absorption
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
LDLLDLReceptorReceptor
StatinsStatins
Acetate
LDLLDL
HMG-CoAReductase
Cholesterol
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
Plant Sterols and StanolsPlant Sterols and Stanols
Sterol/StanolSterol/StanolDietaryDietaryCholesterolCholesterol
LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Plant Sterols and StanolsPlant Sterols and Stanols
Cholesterol
CholesterylEster ABCG5/G8
ACAT NPC1L1
LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
EzetimibeEzetimibe
Cholesterol
NPC1L1
CholesterylEster ABCG5/G8
ACAT
Ezetimibe
XX
LymphLymph EnterocyteEnterocyte IntestinalIntestinalLumenLumen
Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
CholesterylEster
CMapoB48
Triglyceride
Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
DuodenumDuodenum
JejunumJejunum
IleumIleum
CMapoB48
Liver
CM RemnantapoB48
VLDLapoB100
EzetimibeXX
LDLapoB100
ColonColon
Dual InhibitionDual Inhibition
Assembly and Secretion of VLDLAssembly and Secretion of VLDL
Presence of Triglycerides
ApoBMTPMTP
Cholesteryl Esters
Cholesterol
Dietary/Biliary Synthesis
Effect of Cholesterol Absorption InhibitorEffect of Cholesterol Absorption Inhibitor
Presence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary Synthesis
EzetimibeXX
MTPMTPCholesteryl Esters
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
Dual InhibitionDual Inhibition
DuodenumDuodenum
JejunumJejunum
IleumIleum
CMapoB48
Liver
CM RemnantapoB48
VLDLapoB100
EzetimibeXX
LDLapoB100
XXStatinStatin
ColonColon
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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