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Cholesterol Metabolism and Homeostasis
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Basic Lipoprotein Structure
Phospholipid (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, sphingomyelin) Apolipoprotein Free cholesterol Cholesterol ester Triglyceride Reproduced with permission from Meisenberg G. Principles of Medical Biochemistry. St. Louis, MO: Mosby; 1998.
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Function of Apo B–Containing Lipoproteins
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 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.
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The Role of the Liver in Cholesterol Homeostasis
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The Liver Endogenously Synthesizes Cholesterol
Intestine Liver Peripheral Tissues Acetyl CoA Synthesis Cholesterol Pool Blood Atheroma Shepherd J. Eur Heart J Suppl. 2001;3:E2.; Buhaescu I, Izzedine H. Clin Biochem. 2007;40(9-10):575.
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The Liver Secretes Apo B100 Lipoproteins (VLDL) Into the Circulation
Intestine Liver Peripheral Tissues Cholesterol Pool Hepatic Apo B100 VLDL Blood Atheroma VLDL = very low-density lipoprotein. Goldstein JL, Brown MS. Science. 2001;292:1310.
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Apo B100 Lipoproteins Carry Triglycerides, Cholesterol, and Cholesterol Esters Into the Circulation
Intestine Liver Peripheral Tissues Cholesterol Pool Hepatic Apo B100 VLDL TG TG Lipoprotein Lipase lDL LDL Blood Atheroma Goldstein JL, Brown MS. Science. 2001;292:1310.; Shepherd J. Eur Heart J Suppl. 2001;3:E2.
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The Liver Clears Apo B100 Lipoproteins via the LDL Receptor
Intestine Liver Peripheral Tissues Cholesterol Pool Hepatic Apo B100 LDLR VLDL lDL LDL Blood Atheroma Kesanami 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.
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LDL-C Accounts for About 2/3 of the Cholesterol in Circulating Lipoproteins and Can Penetrate the Arterial Subendothelium Intestine Liver Peripheral Tissues Cholesterol Pool Hepatic Apo B100 VLDL lDL LDL Blood Atheroma 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.
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The Liver Clears Chylomicron Remnants After Release of Triglycerides to Peripheral Tissues
Intestine Liver Peripheral Tissues Cholesterol Pool Remnant receptors Absorption TG Lipoprotein Lipase CMR TG CM Intestinal Apo B48 Blood Atheroma Rohlman et al. J Clin Invest. 1998;101:689.; Yu, Cooper. Front Biosci. 2001;6:332.; Shepherd. Eur Heart J. 2001;3:E2.
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Cholesterol Is Cleared From the Arterial Wall and Peripheral Tissues via HDL and CETP Transfer to LDL-C and Chylomicrons Intestine Liver Peripheral Tissues Cholesterol Pool LDLR SR-BI Remnant receptors CETP TG CE CE CETP Nascent HDL CMR Free Cholesterol HDL TG LDL/VLDL LCAT Blood Atheroma 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.
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The Role of the Intestine in Cholesterol Homeostasis
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The Liver Excretes Cholesterol Into the Intestine as Free Cholesterol or Bile Acids
Peripheral Tissues 75% Biliary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool Blood Atheroma 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.
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Biliary Cholesterol Is Mixed With Dietary Cholesterol in the Intestine to Form Micelles
Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool Blood Atheroma Hui, Howles. Sem Cell Develop Biol. 2005;16:183.; Turley, Dietschy. Prev Cardiol. 2003;6(1):29.
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NPC1L1 Is Involved in the Intestinal Uptake of Cholesterol From Diet and Bile
Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool NPC1L1 Blood Atheroma Altmann et al. Science. 2004;303:1201.; Davis et al. J Biol Chem. 2004;279:33586.
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NPC1L1 Is Involved in the Intestinal Uptake of Cholesterol From Diet and Bile
Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Bile Acids Free Chol Cholesterol Pool NPC1L1 Blood Atheroma Altmann et al. Science. 2004;303:1201.; Davis et al. J Biol Chem. 2004;279:33586.
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Absorbed Cholesterol and Triglycerides Are Packaged Into Chylomicrons and Secreted Into the Lymph
Intestinal Lumen Enterocyte (Jejunum) Lymph NPC1L1 ACAT Cholesterol Ester Free Cholesterol Cholesterol ABCG5/8 MTP Triglyceride Chylomicron Apo B48 Lipase 2 Fatty Acid DGAT + Triglyceride Monoglyceride ACAT = acyl co-A:cholesterol acyltransferase; DGAT = diacylglycerol acyltransferase; MPT = microsomal triglyceride transfer protein 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.
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Absorbed Cholesterol and Other Sterols Can Be Diverted Back Into the Intestinal Lumen via ABCG5/8 Transporters Intestine Liver Peripheral Tissues Cholesterol Pool (Micelles) Cholesterol Pool NPC1L1 ABCG5/8 CM Intestinal Apo B48 Blood Atheroma Berge et al. Science. 2000;290:1771.; Lee et al. Nat Genet. 2001;27:79.; Yu et al. J Clin Invest. 2002;110:671.
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Most Absorbed Cholesterol Is Delivered to the Liver via Intestinally Derived Apo B48 Lipoproteins (Chylomicron Remnants) Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool NPC1L1 TG Lipoprotein Lipase CMR TG CM Intestinal Apo B48 Blood Atheroma Rohlman et al. J Clin Invest. 1998;101:689.; Yu, Cooper. Front Biosci. 2001;6:332.; Shepherd. Eur Heart J. 2001;3:E2.
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Some Absorbed Cholesterol May Be Delivered Directly to Extrahepatic Tissues Including the Arterial Wall Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool NPC1L1 CMR CM Intestinal Apo B48 Blood Atheroma 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.
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Once Chylomicron Cholesterol Is Delivered to the Liver It Can Be Distributed to Extrahepatic Tissues via LDL or Excreted in the Bile Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool Hepatic Apo B100 VLDL NPC1L1 lDL CMR LDL CM Intestinal Apo B48 Blood Atheroma Goldstein, Brown. Science. 2001;292:1310.; Quintao et al. J Lipid Res. 1971;12:233.
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ASBT = apical sodium bile acid transporter.
95% of Bile Acids Are Reabsorbed in the Ileum and Returned to the Liver Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool ASBT Blood Atheroma ASBT = apical sodium bile acid transporter. Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884.
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Plosch et al. J Biol Chem. 2002;277:33870.
Cholesterol Remaining in the Intestinal Lumen Is Eliminated From the Body Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool Fecal sterols Blood Atheroma Plosch et al. J Biol Chem. 2002;277:33870.
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Due to Biliary Cholesterol Being Reabsorbed, Some Cholesterol Is Returned to the Liver and the Circulation Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool NPC1L1 VLDL lDL CMR Fecal sterols LDL CM Blood Atheroma Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884.
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Some Cholesterol Can Recycle Between the Liver and Intestine
Peripheral Tissues 75% Biliary chol Cholesterol Pool (Micelles) Bile Acids Free Chol Cholesterol Pool NPC1L1 ASBT CMR CM Blood Atheroma Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884.
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LDL and Other Circulating Plasma Lipoproteins Are Interrelated With the Hepatic and Intestinal Cholesterol Pools Intestine Liver Peripheral Tissues 75% Biliary chol 25% Dietary chol Acetyl CoA Bile Acids Cholesterol Pool (Micelles) Chol Free Chol Cholesterol Pool Hepatic Apo B100 LDLR NPC1L1 Remnant receptors VLDL lDL CMR Fecal sterols LDL CM Intestinal Apo B48 Blood Atheroma 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.
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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
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