Cholesterol Metabolism and Homeostasis. 2 Basic Lipoprotein Structure Phospholipid (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine,

Cholesterol Metabolism and Homeostasis

2

Basic Lipoprotein Structure

Phospholipid (phosphatidylethanolamine,phosphatidylcholine, phosphatidylserine,sphingomyelin)

Free cholesterol

Cholesterol ester

Triglyceride

Ap

olip

op

rote

in

Reproduced with permission from Meisenberg G. Principles of Medical Biochemistry. St. Louis, MO: Mosby; 1998.

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Function of Apo B–ContainingLipoproteins

• Primary - To deliver triglycerides

–Muscle cells for fuel

–Fat cells for storage

• Secondary - To assist with reverse cholesterol transport

Cohen, Armstrong. Pharmacology of Cholesterol and Lipoprotein Metabolism. In: Principles of Pharmacology. Second Edition. 2007. Golan et al, eds. Philadelphia: Lippincott, Williams and Wilkins; 2007.

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The Liver and the Intestine Are Key Organs Involved in Cholesterol Homeostasis

Cholesterol homeostasis is maintained by a complex balance between:

Cholesterol synthesis

Dietary intake

Cholesterol absorption

Excretion of cholesterol

Dietschy JM et al. J Lipid Res. 1993;34:1637.

The Role of the Liver in Cholesterol Homeostasis

6

Peripheral Tissues

Atheroma

LiverIntestine

The Liver Endogenously Synthesizes Cholesterol

Synthesis

Acetyl CoA

3 CH3 COO Acetate3 CH3 COO Acetate

CH3

OOC CH2 C CH2 CH2 OH

OH

CH3

Mevalonate

CH3

OOC CH2 C CH2 CH2 OH

OH

CH3

Mevalonate

CH2 C CH2 CH2 O P O P O

CH3 O

O O

O

Isoprene

CH2 C CH2 CH2 O P O P O

CH3 O

O O

O

Isoprene

Activated isoprene Squalene

2

Squalene

2

CholesterolHO

CholesterolHO

Shepherd J. Eur Heart J Suppl. 2001;3:E2.; Buhaescu I, Izzedine H. Clin Biochem. 2007;40(9-10):575.

Cholesterol Pool

Blood

7

Atheroma

LiverIntestine

The Liver Secretes Apo B100 Lipoproteins (VLDL) Into the Circulation

VLDL

Cholesterol Pool

VLDL = very low-density lipoprotein.Goldstein JL, Brown MS. Science. 2001;292:1310.

Peripheral Tissues

Hepatic Apo B100

Blood

8

LiverIntestine

Apo B100 Lipoproteins Carry Triglycerides, Cholesterol, and Cholesterol Esters Into the

Circulation

TGLipoprotein

Lipase

LDL

lDL

TGVLDL

Atheroma

Peripheral Tissues

Goldstein JL, Brown MS. Science. 2001;292:1310.; Shepherd J. Eur Heart J Suppl. 2001;3:E2.

Cholesterol Pool

Hepatic Apo B100

Blood

9

LiverIntestine Peripheral Tissues

The Liver Clears Apo B100 Lipoproteins via the LDL Receptor

LDL

lDL

Hepatic Apo B100

VLDL

LDLR

AtheromaKesanami et al. J Clin Invest. 1983;71:950.; Goldstein JL, Brown MS. J Biol Chem. 1974;249(16):5153.; Brown MS, Goldstein JL. Proc Natl Acad Sci. 1974;71:788.; Goldstein JL, Brown MS. Science. 2001;292:1310.; Rudling et al. Proc Natl Acad Sci. 1990;87:3469.

Cholesterol Pool

Blood

10

Atheroma

LiverIntestine

LDL-C Accounts for About 2/3 of the Cholesterol in Circulating Lipoproteins and Can Penetrate the

Arterial Subendothelium

Peripheral Tissues

Hepatic Apo B100

VLDL

NCEP ATP III. Circulation. 2002;106:3143.; Brown et al. J Lipid Res. 2004;45:1155.; Rudling et al. Proc Natl Acad Sci. 1990;87:3469.; Simionescu et al. Ann NY Acad Sci. 1990;598:1.; Yu, Cooper. Front Biosci. 2001;6:d332.

Cholesterol Pool

lDL

LDL

Blood

11

Atheroma


The Liver Clears Chylomicron Remnants After Release of Triglycerides to Peripheral Tissues

CMR

Absorption

Remnantreceptors

Intestinal Apo B48

Rohlman et al. J Clin Invest. 1998;101:689.; Yu, Cooper. Front Biosci. 2001;6:332.; Shepherd. Eur Heart J. 2001;3:E2.

Cholesterol Pool

LipoproteinLipase

TG

TG

CM

Blood

12

Atheroma


Cholesterol Is Cleared From the Arterial Wall and Peripheral Tissues via HDL and CETP Transfer to

LDL-C and Chylomicrons

LDLR

SR-BI

Free Cholesterol

Remnantreceptors

Barter et al. Biochim Biophys Acta. 1982;713:136.; Lewis, Rader. Circ Res. 2005;96:1221.; NCEP ATP III. Circulation. 2002;106:3143.; Rader. J Clin Invest. 2006;116(12):3090.; Singh et al. J Amer Med Assoc. 2007;298(7):786.

Cholesterol Pool

LCAT

Nascent HDL

CETPTG

CE

CMR LDL/VLDLHDL

CETPTG

CE

Blood

The Role of the Intestine in Cholesterol Homeostasis

14

Atheroma

LiverIntestine

Cholesterol Pool

Peripheral Tissues

The Liver Excretes Cholesterol Into the Intestine as Free Cholesterol or Bile Acids

FreeChol

Bile AcidsCholesterolPool (Micelles)

75% Biliarychol

Hui, Howles. Sem Cell Develop Biol. 2005;16:183.; Shepherd. Eur Heart J. 2001;3(suppl E):E2.; Turley, Dietschy. Prev Cardiol. 2003;6(1):29.

Blood

15

Atheroma

Liver Peripheral Tissues

Biliary Cholesterol Is Mixed With Dietary Cholesterol in the Intestine to Form Micelles

CholesterolPool (Micelles)

Cholesterol Pool

FreeChol

Bile Acids

75% Biliarychol

25%Dietary chol

Intestine

Hui, Howles. Sem Cell Develop Biol. 2005;16:183.; Turley, Dietschy. Prev Cardiol. 2003;6(1):29.

Blood

16

Atheroma

Liver Peripheral Tissues

NPC1L1 Is Involved in the Intestinal Uptake of Cholesterol From Diet and Bile


NPC1L1

Altmann et al. Science. 2004;303:1201.; Davis et al. J Biol Chem. 2004;279:33586.

Cholesterol Pool

FreeChol

Bile Acids

75% Biliarychol

25%Dietary chol

Intestine

Blood

17

Atheroma

LiverIntestine

NPC1L1

Cholesterol Pool

FreeChol

Bile Acids

75% Biliarychol

25%Dietary chol

Altmann et al. Science. 2004;303:1201.; Davis et al. J Biol Chem. 2004;279:33586.

NPC1L1 Is Involved in the Intestinal Uptake of Cholesterol From Diet and Bile

Peripheral Tissues

Blood

18

Intestinal Lumen

Enterocyte (Jejunum)

Lymph

Absorbed Cholesterol and Triglycerides Are Packaged Into Chylomicrons and Secreted Into

the Lymph

NPC1L1

Cholesterol Cholesterol Ester

ACAT

2 Fatty Acid

Monoglyceride+

DGATTriglyceride

Chylomicron

Apo B48

ACAT = acyl co-A:cholesterol acyltransferase; DGAT = diacylglycerol acyltransferase; MPT = microsomal triglyceride transfer protein

MTP

ABCG5/8

Cohen DE, Armstrong EJ. In: Principles of Pharmacology Second Edition, Golan et al, eds. Philadelphia: Lippincott, Williams and Wilkins; 2007.; Wang. Ann Rev Physiol. 2007;69:221.; Berge et al. Science. 2000;290:1771.; Lee et al. Nat Genet. 2001;27:79.; Yu et al. J Clin Invest. 2002; 110:671.

Free Cholesterol

Triglyceride

Lipase

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Atheroma

LiverIntestine

Absorbed Cholesterol and Other Sterols Can Be Diverted Back Into the Intestinal Lumen via ABCG5/8

Transporters


NPC1L1

ABCG5/8

Berge et al. Science. 2000;290:1771.; Lee et al. Nat Genet. 2001;27:79.; Yu et al. J Clin Invest. 2002;110:671.

Intestinal Apo B48

Cholesterol Pool

CM

Peripheral Tissues

Blood

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Atheroma

Liver

Most Absorbed Cholesterol Is Delivered to the Liver via Intestinally Derived Apo B48 Lipoproteins

(Chylomicron Remnants)


NPC1L1

Intestinal Apo B48

Cholesterol Pool

FreeChol

75% Biliarychol

25%Dietary chol

Intestine

LipoproteinLipase

TG

TG

Bile Acids

Rohlman et al. J Clin Invest. 1998;101:689.; Yu, Cooper. Front Biosci. 2001;6:332.; Shepherd. Eur Heart J. 2001;3:E2.

CMR

CM

Peripheral Tissues

Blood

21

Atheroma

Liver

Some Absorbed Cholesterol May Be Delivered Directly to Extrahepatic Tissues

Including the Arterial Wall


NPC1L1

Cholesterol Pool

FreeChol

75% Biliarychol

25%Dietary chol

Intestine

Intestinal Apo B48

Bile Acids

Mamo JC, Wheeler JR. Coron Artery Dis.1994;5(8):695.; Pal et al. Clin Chem Lab Med. 2003;41(6):792.; NCEP ATP. Circulation. 2002;106:3143.

CMR

CM

Peripheral Tissues

Blood

22

Atheroma

LiverIntestine

Cholesterol Pool

Once Chylomicron Cholesterol Is Delivered to the Liver It Can Be Distributed to Extrahepatic Tissues via LDL or

Excreted in the Bile

Bile AcidsCholesterolPool (Micelles)

25%Dietary chol

NPC1L1

Hepatic Apo B100

Intestinal Apo B48

FreeChol

Goldstein, Brown. Science. 2001;292:1310.; Quintao et al. J Lipid Res. 1971;12:233.

75% Biliarychol

CMR

CM

VLDL

lDL

LDL

Peripheral Tissues

Blood

23

Atheroma

LiverIntestine


25%Dietary chol

95% of Bile Acids Are Reabsorbed in the Ileum and Returned to the Liver

ASBT

Cholesterol Pool

FreeChol

ASBT = apical sodium bile acid transporter.

Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884.

Bile Acids

75% Biliarychol

Peripheral Tissues

Blood

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Atheroma

LiverIntestine

Cholesterol Remaining in the Intestinal Lumen Is Eliminated From the Body


25%Dietary chol

Fecalsterols

Cholesterol Pool

FreeChol

Plosch et al. J Biol Chem. 2002;277:33870.

Bile Acids

75% Biliarychol

Peripheral Tissues

Blood

25

Atheroma

LiverIntestine

Due to Biliary Cholesterol Being Reabsorbed, Some Cholesterol Is Returned to the Liver and the

Circulation


25%Dietary chol

NPC1L1

FreeChol

Fecalsterols

Cholesterol Pool

Bile Acids


75% Biliarychol

VLDL

lDL

LDL

CMR

CMBlood

Peripheral Tissues

26

Atheroma

LiverIntestine

Some Cholesterol Can Recycle Between the Liver and Intestine


NPC1L1

FreeChol

Cholesterol Pool

Bile Acids


75% Biliarychol

ASBT

CMR

CMBlood

Peripheral Tissues

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Atheroma

LiverIntestine

LDL and Other Circulating Plasma Lipoproteins Are Interrelated With the Hepatic and Intestinal

Cholesterol Pools


25%Dietary chol

NPC1L1

Bile Acids

FreeChol

Fecalsterols

Chol

Acetyl CoA

Remnantreceptors

Hepatic Apo B100

Intestinal Apo B48

Goldstein JL, Brown MS. Science. 2001;292:1310.; Shepherd. Eur Heart J. 2001;3(suppl E):E2.; Turley, Dietschy. Prev Cardiol. 2003;6(1):29.

LDLR

75% Biliarychol

Cholesterol Pool

CMR

CM

VLDL

lDL

LDL

Blood

Peripheral Tissues

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Summary

The liver and the intestine both contribute to the circulating cholesterol pool

– The liver regulates its own cholesterol pool size through synthesis of cholesterol, uptake from the circulation, and biliary excretion into the intestine

– The intestine absorbs both dietary and biliary cholesterol and eliminates cholesterol from the body

– Cholesterol can recycle between the liver, the intestine, and the circulation

Cholesterol Metabolism and Homeostasis. 2 Basic Lipoprotein Structure Phospholipid (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine,

Documents

dietary cholesterol

cholesterol homeostasis

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