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Lipoprotein Formation, Structure and Metabolism:
Cholesterol Balance and the Regulation of Plasma Lipid LevelsDavid E. Cohen, MD, PhD
Director of Hepatology, Gastroenterology Division, Brigham and Women’s Hospital
Director, Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology
Associate Professor of Medicine and Health Sciences and Technology, Harvard Medical School
Multiple Studies Showed a Relationship BetweenLDL-C Reduction and CHD Relative Risk
15 20 25 30 35 40
Š20
0
20
40
60
80
100
LDL-C Reduction, %
Non
fata
l MI a
nd C
HD
Dea
thR
elat
ive
Ris
k R
educ
tion,
%
4S CARDSPOSCH ASCOT-LLANHLBI PROSPERLRC ALERTUpjohn HPSLos Angeles AF/TexCAPSMRC LIPIDOslo CARELondon WOSCOPS
ATP 2004 Update: LDL-C Therapy by Risk Categories Based on Recent Clinical Trial Evidence
Adapted from Grundy SM et al. Circulation. 2004;110:227–239; http://lww.com.
≥190 mg/dL (consider drug options if LDL-C160–189 mg/dL)
≥160 mg/dL<160 mg/dLLow risk: ≤1 risk factor
>160 mg/dL≥130 mg/dL<130 mg/dLModerate risk:≥2 risk factors(10-year risk <10%)
≥130 mg/dL (consider drug options if LDL-C100–129 mg/dL)
≥130 mg/dL<130 mg/dL Moderately high risk:≥2 risk factors(10-year risk10%–20%)
≥100 mg/dL ≥100 mg/dL<100 mg/dLHigh risk: CHD or CHD risk equivalents (10-year risk >20%)
Consider Drug Therapy
Initiate TherapeuticLifestyle Changes (TLC)
LDL-C GoalRisk Category
Very high risk Optional goal of <70 mg/dL
(optional goal<100 mg/dL)
Overview
• Digestive lipid metabolism
• Cholesterol balance
• Inhibitors of cholesterol synthesis and absorption
• Dual inhibition
Overview
• Digestive lipid metabolism
• Cholesterol balance
• Inhibitors of cholesterol synthesis and absorption
• Dual inhibition
Cholesterol
• Critical for membrane function
• Substrate for steroid hormone synthesis
• Synthesized by all cells in the body
• Toxic to cells when present in excess
• Broken down and eliminated by the liver only
Cholesterol - membranes
Cholesteryl ester - transport/storage
HO
O
O
Cholesterol
PERIPHERALTISSUES BLOOD LIVER
BILE
Reverse Cholesterol Transport
ExcessCholesterol
Liver Cell ONLY
Cholesterol Catabolism Into Bile Salts
HO
Cholesterol
HO
COO _
OH
OH
Cholate
Cholesterol7α-hydroxylase
Cholesterol Catabolism into Bile Salts
Bile Salts
• Breakdown products of cholesterol
• Amphipathic molecules
• Function to transport cholesterol in the digestive system
Structure of Biliary and Intestinal Micelles
Phospholipid
Cholesterol
Bile Salt
Functions of Micelles
• Transport cholesterol from the liver into the intestine via the biliary tree
• Participate in fat digestion and absorption
Biliary Lipid Secretion
BLOOD HEPATOCYTE BILE
Sinusoidal Membrane
Canalicular Membrane
ABCB4Phospholipid
CholesterolABCG5/G8
Bile SaltABCB11
Biliary Lipids
Lipid Class Daily secretion (g)
Bile salts 24
Phospholipids 11
Cholesterol 2
Biliary Lipid Transport
Duodenum
Jejunum
Ileum
Biliary Transport
and Storage
Colon
Liver
Fat Digestion
Duodenum
Jejunum
Ileum
Biliary Transport
and Storage
Colon
Liver
Fat DigestionDietary
Cholesterol
Fat DigestionDietary
Cholesterol
Fat DigestionTriglycerides
Fatty Acids + Monoglycerides
Lipase
Fat Digestion
Lipase
Triglycerides
Fatty Acids + Monoglycerides
Lipid Absorption
Duodenum
Jejunum
Ileum
Biliary Transport
and Storage
Colon
Liver
Cholesterol AbsorptionLYMPH INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT?
ENTEROCYTE
Cholesterol AbsorptionLYMPH INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
ENTEROCYTE
Triglyceride AbsorptionLYMPH ENTEROCYTE INTESTINAL
LUMEN
2 Fatty Acid
Monoglyceride+
Triglyceride
DGAT
Chylomicron FormationLYMPH ENTEROCYTE INTESTINAL
LUMEN
CholesterylEster
TriglycerideCMapoB48
Overview
• Digestive lipid metabolism
• Cholesterol balance
• Inhibitors of cholesterol synthesis and absorption
• Dual inhibition
Enterohepatic Circulationof Bile Salts
Duodenum
Jejunum
IleumPortalVenousReturn
(>95% of Biliary Secretion)
FecalExcretion(0.4g/d)
Synthesis0.4 g/d
Biliary Transport
and Storage
Secretion24 g/d
Colon
Biliary Cholesterol Secretion
Duodenum
Jejunum
Ileum
Biliary Transport
and Storage
Colon
BiliaryCholesterol
(2 g/d)
Biliary and Dietary CholesterolDietary
Cholesterol(0.4 g/d)
BiliaryCholesterol
(2 g/d) Duodenum
Jejunum
Ileum
Biliary Transport
and Storage
Colon
Cholesterol Absorption
10 20 30 40 50 60 70 80
Low Fat/Low Cholesterol
High Fat/Low Cholesterol
High Fat/High Cholesterol
Diet
Cholesterol Absorption, %Modified from Sehayek et al. 1998.
Cholesterol Absorption
Duodenum
Jejunum
Ileum
Biliary Transport
and Storage
Colon
DietaryCholesterol
(0.4 g/d)
Absorption~50%CM
apoB48
BiliaryCholesterol
(2 g/d)
Jejunum
Ileum
Biliary Transport
and Storage
Colon
DietaryCholesterol
(0.4 g/d)
Absorption~50%CM
apoB48
BiliaryCholesterol
(2 g/d)
Fecal Cholesterol Excretion
FecalExcretion(1.2 g/d)
Cholesterol Balance
Cholesterol(1.2 g/d)
+Bile Salts(0.4 g/d)
DietaryCholesterol
(0.4 g/d)Loss
(1.6 g/d)-
DietaryCholesterol
(0.4 g/d)
Loss(1.6 g/d)
Synthesis(1.2 g/d)
CholesterolCholesterol
Bile salts
Overview
• Digestive lipid metabolism
• Cholesterol balance
• Inhibitors of cholesterol synthesis and absorption
• Dual inhibition
• Inhibit synthesis of cholesterol by cells
• Lower LDL cholesterol
Mechanism: Promote LDL clearance
Inhibitors of Cholesterol Synthesis: Statins
LDLReceptor
Cholesterol
Acetate
HMG-CoA Reductase
Statins
LDLReceptor
Cholesterol
Acetate
HMG-CoA Reductase
LDL
Statins
• Inhibit absorption of dietary cholesterol
• Inhibit reabsorption of biliary cholesterol
• Lower LDL cholesterol
Mechanism : Inhibit LDL formation
Cholesterol Absorption Inhibitors
• Inhibit absorption of dietary cholesterol
• Inhibit reabsorption of biliary cholesterol
• Lower LDL cholesterol
Mechanism : Inhibit LDL formation
Cholesterol Absorption Inhibitors
Cholesterol AbsorptionLYMPH ENTEROCYTE INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
• Plant sterols and stanols
• Ezetimibe
Agents That Interfere With Cholesterol Absorption
Agents That Interfere With Cholesterol Absorption
• Plant sterols and stanols
• Ezetimibe
Cholesterol AbsorptionLYMPH ENTEROCYTE INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Plant Sterols and StanolsDietary
Cholesterol Sterol/Stanol
Plant Sterols and StanolsDietary
Cholesterol Sterol/Stanol
Plant Sterols and StanolsLYMPH ENTEROCYTE INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Plant Sterols and StanolsLYMPH ENTEROCYTE INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Plant Sterols and StanolsLYMPH ENTEROCYTE INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Cholesterol Absorption Inhibitors
• Plant sterols and stanols
• Ezetimibe
EzetimibeLYMPH ENTEROCYTE INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Ezetimibe
X
EzetimibeLYMPH ENTEROCYTE INTESTINAL
LUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Ezetimibe
X
Mechanism of Ezetimibe Action: Role of NPC1L1
Cholesterol Absorption in NPC1L1 Knockout Mice
50
40
30
20
10
0
% C
hole
ster
ol
abso
rptio
n
+/+ Wild type +/- Heterozygous-/- Homozygous
-/-EZE
+/+EZE
*
+/+ -/-
* *
†P<0.001 compared with wild-type mice (+/+) and heterozygous (+/-) mice.Altmann et al. Science. 2004;303:1201.
Cholesterol Absorption InhibitorsLYMPH ENTEROCYTE INTESTINAL
LUMEN
CholesterylEster
TriglycerideCMapoB48
Cholesterol Absorption InhibitorsLYMPH ENTEROCYTE INTESTINAL
LUMEN
CholesterylEster
TriglycerideCMapoB48
Cholesterol Absorption InhibitorsLYMPH ENTEROCYTE INTESTINAL
LUMEN
CholesterylEster
TriglycerideCMapoB48
Duodenum
Jejunum
Ileum
Colon
CMapoB48
CM RemnantapoB48
VLDLapoB100
LDLapoB100
Liver
XEzetimibe
Cholesterol Absorption Inhibitors
Overview
• Digestive lipid metabolism
• Cholesterol balance
• Inhibitors of cholesterol synthesis and absorption
• Dual inhibition
Assembly and Secretion of VLDL
MTP MTP
ApoB
Presence of Triglycerides
EndoplasmicReticulum
MTP MTP
ApoB
Presence of Triglycerides
Cholesteryl Esters
Cholesterol
Dietary/Biliary Synthesis
Assembly and Secretion of VLDL
Effect of Ezetimibe
MTP MTP
ApoB
Presence of Triglycerides
Cholesteryl Esters
Cholesterol
Dietary/Biliary SynthesisXEzetimibe
Effect of Ezetimibe
MTP MTP
ApoB
Presence of Triglycerides
Cholesteryl Esters
Cholesterol
Dietary/Biliary SynthesisXEzetimibe
Compensatory Upregulation of Cholesterol Synthesis
MTP MTP
ApoB
Presence of Triglycerides
Cholesteryl Esters
Cholesterol
Dietary/Biliary SynthesisXEzetimibe
Compensatory Upregulation of Cholesterol Synthesis
MTP MTP
ApoB
Presence of Triglycerides
Cholesteryl Esters
Cholesterol
Dietary/Biliary SynthesisXEzetimibe
Addition of Statin Therapy Blocks the Compensatory Response
MTP MTP
ApoB
Presence of Triglycerides
Cholesteryl Esters
Cholesterol
Dietary/Biliary SynthesisXXEzetimibe Statin
Addition of Statin Therapy Blocks the Compensatory Response
MTP MTP
ApoB
Presence of Triglycerides
Cholesteryl Esters
Cholesterol
Dietary/Biliary SynthesisXXEzetimibe Statin
Duodenum
Jejunum
Ileum
Colon
CMapoB48
CM RemnantapoB48
VLDLapoB100
LDLapoB100
Liver
XEzetimibe
Cholesterol Absorption Inhibitors
Duodenum
Jejunum
Ileum
Colon
CMapoB48
CM RemnantapoB48
VLDLapoB100
LDLapoB100
Liver
XEzetimibe
Dual Inhibition
StatinX
Duodenum
Jejunum
Ileum
Colon
CMapoB48
CM RemnantapoB48
VLDLapoB100
LDLapoB100
Liver
XEzetimibe
Dual Inhibition
StatinX
Benefits of Managing Dual Pathways
• Cholesterol balance is regulated by both synthesis and absorption
• Each pathway may compensate for changes in the other
• Optimal LDL lowering may best be achieved by inhibiting both pathways