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

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Presentation on theme: "Cholesterol Metabolism and Homeostasis. 2 Basic Lipoprotein Structure Phospholipid (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine,"— Presentation transcript:

1 Cholesterol Metabolism and Homeostasis

2 2 Basic Lipoprotein Structure Phospholipid (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, sphingomyelin) Free cholesterol Cholesterol ester Triglyceride Apolipoprotein Reproduced with permission from Meisenberg G. Principles of Medical Biochemistry. St. Louis, MO: Mosby; 1998.

3 3 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. 2007. Golan et al, eds. Philadelphia: Lippincott, Williams and Wilkins; 2007.

4 4 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.

5 The Role of the Liver in Cholesterol Homeostasis

6 6 Peripheral Tissues Atheroma Liver Intestine The Liver Endogenously Synthesizes Cholesterol Synthesis Acetyl CoA Shepherd J. Eur Heart J Suppl. 2001;3:E2.; Buhaescu I, Izzedine H. Clin Biochem. 2007;40(9-10):575. Cholesterol Pool Blood

7 7 Atheroma Liver Intestine The Liver Secretes Apo B 100 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 B 100 Blood

8 8 Liver Intestine Apo B 100 Lipoproteins Carry Triglycerides, Cholesterol, and Cholesterol Esters Into the Circulation TG Lipoprotein Lipase LDL lDL TG VLDL Atheroma Peripheral Tissues Goldstein JL, Brown MS. Science. 2001;292:1310.; Shepherd J. Eur Heart J Suppl. 2001;3:E2. Cholesterol Pool Hepatic Apo B 100 Blood

9 9 Liver Intestine Peripheral Tissues The Liver Clears Apo B 100 Lipoproteins via the LDL Receptor LDL lDL Hepatic Apo B 100 VLDL LDLR 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. Cholesterol Pool Blood

10 10 Atheroma Liver Intestine LDL-C Accounts for About 2/3 of the Cholesterol in Circulating Lipoproteins and Can Penetrate the Arterial Subendothelium Peripheral Tissues Hepatic Apo B 100 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 11 Atheroma Liver Intestine Peripheral Tissues The Liver Clears Chylomicron Remnants After Release of Triglycerides to Peripheral Tissues CMR Absorption Remnant receptors Intestinal Apo B 48 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 Lipoprotein Lipase TG CM Blood

12 12 Atheroma Liver Intestine 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 Remnant receptors 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 CETP TG CE CMR LDL/VLDL HDL CETP TG CE Blood

13 The Role of the Intestine in Cholesterol Homeostasis

14 14 Atheroma Liver Intestine Cholesterol Pool Peripheral Tissues The Liver Excretes Cholesterol Into the Intestine as Free Cholesterol or Bile Acids Free Chol Bile Acids Cholesterol Pool (Micelles) 75% Biliary chol 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 15 Atheroma LiverPeripheral Tissues Biliary Cholesterol Is Mixed With Dietary Cholesterol in the Intestine to Form Micelles Cholesterol Pool (Micelles) Cholesterol Pool Free Chol Bile Acids 75% Biliary chol 25% Dietary chol Intestine Hui, Howles. Sem Cell Develop Biol. 2005;16:183.; Turley, Dietschy. Prev Cardiol. 2003;6(1):29. Blood

16 16 Atheroma LiverPeripheral Tissues NPC1L1 Is Involved in the Intestinal Uptake of Cholesterol From Diet and Bile Cholesterol Pool (Micelles) NPC1L1 Altmann et al. Science. 2004;303:1201.; Davis et al. J Biol Chem. 2004;279:33586. Cholesterol Pool Free Chol Bile Acids 75% Biliary chol 25% Dietary chol Intestine Blood

17 17 Atheroma Liver Intestine NPC1L1 Cholesterol Pool Free Chol Bile Acids 75% Biliary chol 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 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 + DGAT Triglyceride Chylomicron Apo B 48 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

19 19 Atheroma Liver Intestine Absorbed Cholesterol and Other Sterols Can Be Diverted Back Into the Intestinal Lumen via ABCG5/8 Transporters Cholesterol Pool (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 B 48 Cholesterol Pool CM Peripheral Tissues Blood

20 20 Atheroma Liver Most Absorbed Cholesterol Is Delivered to the Liver via Intestinally Derived Apo B 48 Lipoproteins (Chylomicron Remnants) Cholesterol Pool (Micelles) NPC1L1 Intestinal Apo B 48 Cholesterol Pool Free Chol 75% Biliary chol 25% Dietary chol Intestine Lipoprotein Lipase 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 21 Atheroma Liver Some Absorbed Cholesterol May Be Delivered Directly to Extrahepatic Tissues Including the Arterial Wall Cholesterol Pool (Micelles) NPC1L1 Cholesterol Pool Free Chol 75% Biliary chol 25% Dietary chol Intestine Intestinal Apo B 48 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 22 Atheroma Liver Intestine 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 Acids Cholesterol Pool (Micelles) 25% Dietary chol NPC1L1 Hepatic Apo B 100 Intestinal Apo B 48 Free Chol Goldstein, Brown. Science. 2001;292:1310.; Quintao et al. J Lipid Res. 1971;12:233. 75% Biliary chol CMR CM VLDL lDL LDL Peripheral Tissues Blood

23 23 Atheroma Liver Intestine Cholesterol Pool (Micelles) 25% Dietary chol 95% of Bile Acids Are Reabsorbed in the Ileum and Returned to the Liver ASBT Cholesterol Pool Free Chol 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% Biliary chol Peripheral Tissues Blood

24 24 Atheroma Liver Intestine Cholesterol Remaining in the Intestinal Lumen Is Eliminated From the Body Cholesterol Pool (Micelles) 25% Dietary chol Fecal sterols Cholesterol Pool Free Chol Plosch et al. J Biol Chem. 2002;277:33870. Bile Acids 75% Biliary chol Peripheral Tissues Blood

25 25 Atheroma Liver Intestine Due to Biliary Cholesterol Being Reabsorbed, Some Cholesterol Is Returned to the Liver and the Circulation Cholesterol Pool (Micelles) 25% Dietary chol NPC1L1 Free Chol Fecal sterols Cholesterol Pool Bile Acids Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884. 75% Biliary chol VLDL lDL LDL CMR CM Blood Peripheral Tissues

26 26 Atheroma Liver Intestine Some Cholesterol Can Recycle Between the Liver and Intestine Cholesterol Pool (Micelles) NPC1L1 Free Chol Cholesterol Pool Bile Acids Alrefai, Gill. Pharm Res. 2007;24(10):1803.; Huff et al. Arterio Thromb Vasc Biol. 2002;22:1884. 75% Biliary chol ASBT CMR CM Blood Peripheral Tissues

27 27 Atheroma Liver Intestine LDL and Other Circulating Plasma Lipoproteins Are Interrelated With the Hepatic and Intestinal Cholesterol Pools Cholesterol Pool (Micelles) 25% Dietary chol NPC1L1 Bile Acids Free Chol Fecal sterols Chol Acetyl CoA Remnant receptors Hepatic Apo B 100 Intestinal Apo B 48 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% Biliary chol Cholesterol Pool CMR CM VLDL lDL LDL Blood Peripheral Tissues

28 28 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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