Lipoprotein Formation, Structure and Metabolism ... · PDF fileLipoprotein Formation,...

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

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% 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