肠道胆固醇吸收的心血管病风险

肠道胆固醇吸收的心血管病风险,提纲,1 胆固醇代谢（肝脏和肠道）2 胆固醇吸收与心血管病风险3怎样区分患者的胆固醇代谢类型,2,胆固醇代谢（肝脏和肠道）,3,4,肝脏与肠道是胆固醇平衡最主要的两个器官,胆固醇体内平衡是由一系列因素决定的: 胆固醇合成 食物摄入 胆固醇吸收 胆固醇排泄,Dietschy JM et al. J Lipid Res. 1993;34:1637.,肝脏在胆固醇体内平衡中的作用,6,Peripheral Tissues,Atheroma,Liver,Intestine,胆固醇在肝脏内合成,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,Atheroma,Liver,Intestine,肝脏向循环系统中分泌 Apo B100 Lipoproteins (VLDL),VLDL,Cholesterol Pool,VLDL = very low-density lipoprotein.Goldstein JL, Brown MS. Science. 2001;292:1310.,Peripheral Tissues,Hepatic Apo B100,Blood,8,Liver,Intestine,Apo B100 Lipoproteins 向循环系统中运输甘油三酯，胆固醇，胆固醇,TGLipoproteinLipase,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 B100,Blood,9,Liver,Intestine,Peripheral Tissues,肝脏可以通过LDL 受体清除Apo B100 Lipoproteins,LDL,lDL,Hepatic Apo B100,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,Atheroma,Liver,Intestine,LDL-C 占循环中胆固醇的2/3,LDL-C可以穿透动脉内皮,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,Liver,Intestine,Peripheral Tissues,肝脏可以清除乳糜微滴残留物,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,Liver,Intestine,Peripheral Tissues,胆固醇通过高密度脂蛋白胆固醇和 CETP从动脉壁和周边组织清除LDL-C和乳糜微粒,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,CMR,LDL/VLDL,HDL,CETP,TG,CE,Blood,肠道在胆固醇体内平衡中的作用,14,Atheroma,Liver,Intestine,Cholesterol Pool,Peripheral Tissues,肝脏向肠道分泌游离胆固醇和胆汁酸,FreeChol,Bile Acids,CholesterolPool (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,胆汁中的胆固醇（75%）与膳食中的胆固醇（25%）在肠道混合形成聚集体,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 决定肠道吸收的胆固醇,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,17,Atheroma,Liver,Intestine,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 决定肠道吸收的胆固醇,Peripheral Tissues,Blood,18,Intestinal Lumen,Enterocyte (Jejunum),Lymph,吸收的胆固醇和甘油三酯被包装成乳糜微粒进入淋巴液,NPC1L1,Cholesterol,Cholesterol Ester,ACAT,2 Fatty Acid,Monoglyceride,+,DGAT,Triglyceride,ChylomicronApo B48,ACAT = acyl co-A:cholesterol acyltransferase; DGAT = diacylglycerol acyltransferase; MPT = microsomal triglyceride transfer protein,MTP,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,Atheroma,Liver,Intestine,吸收的胆固醇和固醇类物质可以通过ABCG5/8 反向转运回肠道,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,20,Atheroma,Liver,大部分肠道吸收的胆固醇通过Apo B48 Lipoproteins 转运到肝脏,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,21,Atheroma,Liver,一些胆固醇可以直接透过动脉壁,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,22,Atheroma,Liver,Intestine,Cholesterol Pool,当乳糜微滴胆固醇转运到肝脏可以通过LDL-C或胆汁外排分布到肝外组织,Bile Acids,CholesterolPool (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,Liver,Intestine,CholesterolPool (Micelles),25%Dietary chol,95% 的胆汁在回肠重吸收回肝脏,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,24,Atheroma,Liver,Intestine,肠道内剩余胆固醇将排出,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,25,Atheroma,Liver,Intestine,由于胆汁胆固醇被重吸收一部分胆固醇返回到肝脏和循环,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,CM,Blood,Peripheral Tissues,26,Atheroma,Liver,Intestine,一部分胆固醇可以在肝脏和肠道之间反复循环,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,CM,Blood,Peripheral Tissues,27,Atheroma,Liver,Intestine,LDL 和 其他循环中的脂蛋白和肝脏与肠道胆固醇池密切相关,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,28,Summary,肝脏和肠道在胆固醇动态平衡中扮演重要的角色肝脏是通过合成胆固醇，吸收循环中的胆固醇，以及胆汁排泄到肠，调节肝脏胆固醇池大小。肠道吸收来自饮食和胆汁的胆固醇，并通过肠道排泄清除胆固醇。胆固醇可以在肝脏，肠道和循环系统中反复循环,胆固醇吸收与心血管病风险,血液中胆固醇水平和心血管事件正相关,30,the Framingham study. Am J Med 1984;76:412.,降低血液中胆固醇水平的药物,抑制合成的药物 他汀类 贝特类抑制吸收的药物 树脂类 植物固醇 依折麦布,31,抑制胆固醇合成与心血管病风险,32,Lancet Neurol 2009; 8: 45363,抑制胆固醇合成与心血管病风险,33,Finnish 4S Investigators. BMJ 1998;316:112730,抑制胆固醇吸收与心血管病风险,POSCH-study,34,(POSCH). N Engl J Med 1990;323:94655.,抑制胆固醇吸收与心血管病风险,35,0,1,2,3,4,5,0,5,10,15,20,安慰剂,依折麦布/辛伐他汀,随访年,出现事件的比例（%）,17%,Baigent et al. Lancet 2011 June 9; online,高胆固醇血症机制,血胆固醇水平,胆固醇平衡与心血管风险,Framingham 后代研究：危险因素与CVD的相关性,37,Odds Ratios Univariant Analysis,Matthen, N et al Poster-AHA Scientific Sessions, 2005,传统危险因素,合成标志物,吸收标志物,合成/吸收比值,Framingham Offspring Study: Association Between Risk Factors and CVD Status,胆固醇平衡与心血管风险,38,Silbernagel G. etc. J. Lipid Res. 2009. 50: 334341,502,553,793,592,Friesinger Score(4 categories）),N,高胆甾烷醇（吸收）/胆固醇比值对应高FS,LURIC study：胆固醇平衡与冠心病严重性,新的认识,胆固醇代谢在冠心病中的作用已经超越了我们以往的认识。有关胆固醇吸收和合成的标志物可能成为反映冠心病进展新的血浆标志物。,39,怎样区分患者的胆固醇代谢类型,正常人群中胆固醇吸收率,41,由于个体差异，胆固醇吸收效率在人群高度变异，这种高吸收或低吸收现象具有遗传性。,Bosner MS et al. J Lipid Res 1999;40:302-308.,55%,评价胆固醇代谢的指标,42,LIVER,Acetyl-CoA,Cholesterol,GUT,吸收,合成,Lathosterol,植物固醇,高吸收个体,高合成个体,植物固醇,HIGH,LOW,HIGH,LOW,胆固醇前体,胆固醇,常见胆固醇代谢血清标志物,43,胆固醇合成角鲨烯 （Squalene） 2,4去氢胆固醇 （Desmosterol ）7脱氢胆固醇 7-dehydrocholesterol7-烯胆脘醇 Lathosterol,胆固醇吸收-谷固醇 （-Sitosterol ）菜油固醇 （Campesterol ）豆固醇 （Stigmasterol ）胆甾烷醇 （ Cholestanol ）,胆固醇代谢标志物的检测方法,44,临床常用TC、LDL-C等指标只能说明患者血中胆固醇水平的高低，不能反映胆固醇代谢的状态。以往标志物检测同位素示踪法 静脉注射或口服同位素标记物3H-胆固醇，先入肝，后到肠，在粪便中，如按一定的间隔取血和粪便，费时费力，不利于推广。,传统方法,胆固醇代谢标志物的检测方法,气相色谱-氢火焰离子化检测器可测定人血清中角鲨烯及2,4-脱氢胆甾烷醇、7-烯胆甾烷醇、菜油固醇、豆固醇和-谷固醇等5种非胆固醇类固醇。重现性好、精密性高，可为个体化治疗中临床诊断提供依据。,45,各种检测方法都存在临床简便性的问题是否能丛病人特点判定高吸收的风险？,46,高胆固醇吸收病人的特点,代谢综合征2型糖尿病正在使用抑制吸收药物治疗,47,代谢综合征,依折麦布对代谢综合征患者内脏脂肪影响的研究,49,依折麦布10mg,计算机断层扫描内脏脂肪变化,安慰剂,6个月,门诊代谢综合征患者63.7 10.4 岁78例,Eur J Clin Invest. 2012 Dec;42(12):1287-94.,依折麦布对代谢综合征患者内脏脂肪影响的研究,50,Eur J Clin Invest. 2012 Dec;42(12):1287-94.,依折麦布对代谢综合征患者内脏脂肪影响的研究,51,Eur J Clin Invest. 2012 Dec;42(12):1287-94.,依折麦布对代谢综合征患者内皮影响（PANACEA study）,52,100例肥胖并伴有代谢综合征患者,80mg,80mg,10mg/10mg,10mg/10mg,Atherosclerosis. 2012 Dec 6,依折麦布对代谢综合征患者内皮影响（PANACEA study）,53,Atherosclerosis. 2012 Dec 6,依折麦布10mg+辛伐他汀10mg组与辛伐他汀80mg组降脂疗效相同的情况下能更多改善FMD值，改善血管内皮病变程度,依折麦布可以改善代谢综合征患者病变情况,54,在人类数据中，依折麦布改善 :, 接受减重饮食的胰岛素抵抗的肥胖患者的肝脏脂肪变性、炎症和LDL-apoB-100代谢,Chan et al. Diabetes Care 2010; 33: 1134-9,2型糖尿病,IN-CROSS研究: 有和没有T2DM患者的主要终点,-27.7%,-17.0%,亚组交互治疗 p-值 = 0.015,LDL-C较基线的平均变化%,-30.3%,-11.5%,-26.5%,-18.0%,较基线平均变化% （SE）,Vaverkova et al. Cardiovasc Ther 2010, Jul 7,n 305 296 94 80 211 216,p 135 mg/dL的T2D患者随机接受依折麦布10 mg或者安慰剂 2个月,依折麦布组 - 30.9%安慰剂组 NS,p 0.0001,LDL-C,Ruggeneuti et al. Diabetes Care, online, June 21, 2010,27项试验荟萃分析在糖尿病和非糖尿病比较疗效,LDL-C,非HDL-C,ApoB/ApoA1,有糖尿病,无糖尿病,有糖尿病,无糖尿病,有糖尿病,无糖尿病,较基线变化%,Leiter et al. Diab Obes Metab 2011; online Feb 18, -17.4