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