cholesterol metabolism and homeostasis. 2 basic lipoprotein structure phospholipid...
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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
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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
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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
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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
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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
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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
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Atheroma
LiverIntestine Peripheral Tissues
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
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Atheroma
LiverIntestine Peripheral Tissues
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
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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
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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
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Atheroma
Liver Peripheral Tissues
NPC1L1 Is Involved in the Intestinal Uptake of Cholesterol From Diet and Bile
CholesterolPool (Micelles)
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
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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
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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
CholesterolPool (Micelles)
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)
CholesterolPool (Micelles)
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
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Atheroma
Liver
Some Absorbed Cholesterol May Be Delivered Directly to Extrahepatic Tissues
Including the Arterial Wall
CholesterolPool (Micelles)
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
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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
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Atheroma
LiverIntestine
CholesterolPool (Micelles)
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
CholesterolPool (Micelles)
25%Dietary chol
Fecalsterols
Cholesterol Pool
FreeChol
Plosch et al. J Biol Chem. 2002;277:33870.
Bile Acids
75% Biliarychol
Peripheral Tissues
Blood
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Atheroma
LiverIntestine
Due to Biliary Cholesterol Being Reabsorbed, Some Cholesterol Is Returned to the Liver and the
Circulation
CholesterolPool (Micelles)
25%Dietary chol
NPC1L1
FreeChol
Fecalsterols
Cholesterol Pool
Bile Acids
Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884.
75% Biliarychol
VLDL
lDL
LDL
CMR
CMBlood
Peripheral Tissues
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Atheroma
LiverIntestine
Some Cholesterol Can Recycle Between the Liver and Intestine
CholesterolPool (Micelles)
NPC1L1
FreeChol
Cholesterol Pool
Bile Acids
Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884.
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
CholesterolPool (Micelles)
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