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Lipoprotein metabolism Patarabutr Masaratana. Outline  Structure & Function  Classification  Metabolism  Atherosclerosis  Abnormalities  Structure.

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Presentation on theme: "Lipoprotein metabolism Patarabutr Masaratana. Outline  Structure & Function  Classification  Metabolism  Atherosclerosis  Abnormalities  Structure."— Presentation transcript:

1 Lipoprotein metabolism Patarabutr Masaratana

2 Outline  Structure & Function  Classification  Metabolism  Atherosclerosis  Abnormalities  Structure & Function  Classification  Metabolism  Atherosclerosis  Abnormalities

3 Blood protein Plasma Erythrocytes Plasma protein Lipoprotein Hemoglobin

4  conjugated protein: protein + lipid  apolipoprotein + lipid  main function: lipid transport  transport of fat-soluble vitamins Lipoproteins

5 lipid transport - lipid: triglyceride cholesterol phospholipid cholesteryl ester (CE) - protein: apolipoprotein (apo) enzymes Components of lipoprotein particles

6

7  most lipoprotein particles: spherical shape  core: hydrophobic molecules  surface (shell): hydrophilic/amphipathic molecules Structure of lipoproteins triglyceride (TG) CE triglyceride (TG) CE cholesterol phospholipid apo cholesterol phospholipid apo

8 Structure of lipoproteins

9 Classification of lipoproteins diversity in size, density, lipid & protein components and electrophoretic movement high TG content bigger particle core larger particle size increased lipid content relative to protein lower density

10 Classification of lipoproteins diversity in size, density, lipid & protein components and electrophoretic movement low TG content higher density

11 Classification of lipoproteins  high density lipoprotein (HDL)  low density lipoprotein (LDL)  intermediate density lipoprotein (IDL)  very low density lipoprotein (VLDL)  chylomicron

12 Classification of lipoproteins Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012: TG content lowest highest

13 Classification of lipoproteins Agarose gel electrophoresis chylomicron (origin) HDL LDL VLDL (pre- β )

14 Classification of lipoproteins chylomicronVLDLLDLHDL Main components Main apo % Lipid - TG - cholesterol % Protein TG (from diet) B TG (endogenous) B CE B Protein AI

15  scaffold for lipation  ligands for lipoprotein receptors  activators/inhibitors of enzymes involving in lipoprotein metabolism General functions of apolipoproteins

16 1.Exogenous pathway 2.Endogenous pathway 3.Reverse cholesterol transport Overview of lipoprotein metabolism

17 chylomicron apo B-48 chylomicron apo B-48 Exogenous pathway Overview of lipoprotein metabolism direction of major lipid transport - ขนส่ง TG ในอาหารไปยัง muscle, adipose tissue - ลำไส้เล็ก -fatty acid ถูกสังเคราะห์กลับเป็น TG อีกครั้ง -cholesterol ถูก esterify เป็น CE -TG รวมกับ CE, apo B-48 และ phospholipid เป็น chylomicron - เข้าสู่ร่างกายทาง lacteal  thoracic duct -TG ถูกสลายได้ fatty acid เข้าสู่ peripheral cells -CE, phospholipid ถูกส่งไปที่ตับ

18 VLDL-IDL-LDL apo B-100 VLDL-IDL-LDL apo B-100 Overview of lipoprotein metabolism direction of major lipid transport Endogenous pathway - ขนส่ง endogenous TG จากตับ ไปยัง muscle, adipose tissue -TG ในตับรวมกับ CE, apo B-100 และ phospholipid เป็น VLDL แล้วหลั่งเข้าสู่ circulation -TG ถูกสลายได้ fatty acid เข้าสู่ peripheral cells -CE บางส่วนอาจเข้าสู่ peripheral cells -VLDL เสีย TG จึงมีขนาดเล็กลง กลายเป็น IDL และ LDL ตามลำดับ -CE, phospholipid ถูกส่งกลับไปที่ ตับ

19 HDL apo A-I HDL apo A-I Overview of lipoprotein metabolism direction of major lipid transport Reverse cholesterol transport - ขนส่งไขมันในทิศทางตรงข้ามกับ exogenous และ endogenous pathway - ตับสังเคราะห์ apo A-I -apo A-I รวมกับ phospholipid เกิดเป็น nascent HDL (discoidal shape) -nascent HDL ได้รับ cholesterol จาก peripheral cells -cholesterol ที่ nascent HDL ได้รับ ถูก esterify เป็น CE ซึ่งจะย้ายไปอยู่ ใน core ของ HDL -HDL มีขนาดใหญ่ขึ้น และเปลี่ยน รูปร่างเป็น spherical shape (mature HDL)

20 Reverse cholesterol transport (HDL; apo A-I) apolipoprotein - nontransferable - transferable Overview of lipoprotein metabolism Endogenous pathway (VLDL-IDL-LDL; apo B-100) Exogenous pathway (chylomicron; apo B-48) apo C, apo E

21 Lipoprotein lipase (LPL) - อยู่บนผิว endothelium ของ หลอดเลือดฝอยในอวัยวะต่างๆ เช่น กล้ามเนื้อลาย, หัวใจ, เนื้อเยื่อไขมัน - ถูกกระตุ้นการทำงานโดย apo C- II -LPL สลาย TG ที่ core ของ chylomicron, VLDL ได้ free fatty acid เข้าสู่เซลล์กล้ามเนื้อ และ adipocyte -chylomicron และ VLDL สูญเสีย TG ที่ core ของอณู ทำ ให้มีขนาดเล็กลง กลายเป็น chylomicron remnant, IDL ตามลำดับ -chylomicron remnant และ IDL ถูกนำเข้าสู่ตับ -TG ใน IDL บางส่วน จะถูกสลาย เพิ่มเติมอีก ทำให้ IDL มีขนาด เล็กลงอีก กลายเป็น LDL -LDL ถูกนำเข้าสู่ตับ หรือ peripheral cells Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:

22 Lipid absorption  lipid digestion: pancreatic lipase, bile acid  medium-chain fatty acid: directly enter the blood and transported by albumin  long-chain fatty acid: resynthesised to TG  packaged into chylomicron (apo B-48) & released into lymphatic system

23 Exogenous pathway  chylomicron acquires apo C & apo E from HDL in the blood  apo C-II activates LPL  hydrolysis of TG in chylomicron  free fatty acid (FFA)  FFA enters myocyte or adipocyte  β -oxidation or lipogenesis  chylomicron loses core TG  becomes smaller (chylomicron remnant)  exposure of apo E on particle surface (release apo C back to HDL)  apo E-mediated chylomicron uptake into liver through LDL receptor or LRP (LDL receptor-related protein)

24 Exogenous pathway chylomicron HDL apo C apo E chylomicron remnant Lipolysis of core TG LPL apo C-II FFA β -oxidation lipogenesis apo C LDL receptor LDL receptor-related protein (LRP) apo E

25 Exogenous pathway  chylomicron: half life = 10 minutes  not normally found in serum after 12-hour fasting  chylomicron: large particle  light reflection  milky serum (lipemia) (also caused by VLDL in serum)  postprandial lipemia OR patients with abnormal chylomicron metabolism

26 LPL apo E apo C-II chylomicron chylomicron remnant

27 Endogenous pathway Sources of endogenous TG 1.de novo lipogenesis (e.g. from excess dietary carbohydrate) 2.cytosolic TG storage in hepatocytes 3.fatty acids acquired from lipoproteins delivered to the liver 4.FFA delivered to the liver depend on metabolic states

28 Tamura S. and Shimomura I. J Clin Invest. 2005;115(5):1139–1142.

29 Endogenous pathway  endogenous TG + CE + phospholipid + apo B-100  VLDL  released into circulation  acquires apo C & apo E from circulating HDL  apo C-II activates LPL  hydrolysis of TG in VLDL  free fatty acid (FFA)  FFA enters myocyte or adipocyte  β -oxidation or lipogenesis  VLDL loses core TG  becomes smaller (IDL)  release apo C, phospholipid to HDL

30 Endogenous pathway endogenous TG CE phospholipid apo B-100 VLDL HDL apo C apo E Lipolysis of core TG LPL apo C-II IDL FFA β -oxidation lipogenesis apo C phospholipid

31 Endogenous pathway IDL LDL receptor/LRP 50% apo E 50% Further lipolysis by hepatic TG lipase (HTGL) LDL HDL apo C apo E apo B-100 Scavenger receptor B type I (SR-BI)

32 Receptor-mediated endocytosis of LDL

33 LDL receptor LPL apo-B100 apo E apo C-II chylomicron remnant VLDL IDL LDL

34 Reverse cholesterol transport apo A-I nascent HDL chylomicron, VLDL, IDL (through lipolysis) apo C, apo E phospholipid mature HDL (HDL 3 ) cholesterol CE LCAT apo A-I mature HDL (HDL 2 ) VLDL chylomicron CETP ABCA1 SR-BI ABCA1 SR-BI aqueous diffusion CE apo C, apo E TG LCAT: lecithin-cholesterol acyltransferase CETP: cholesteryl ester transfer protein ABCA 1 : ATP-binding cassette transporter A 1

35 Reverse cholesterol transport mature HDL (HDL 2 ) lipolysis by hepatic TG lipase (HTGL) nascent HDL another cycle of reverse cholesterol transport FFA SR-BI (liver) CE LDL receptor (apo E) LRP (apo E) other unknown receptors

36 Reverse cholesterol transport

37 HDL

38 LDL receptor LPL apo-B100 apo E apo C-II chylomicron chylomicron remnant VLDL IDL LDL HDL

39 Cholesterol & Atherosclerosis endothelial dysfunction (functional  structural) increased endothelial permeability to lipoproteins lipid deposition in intima esp. small lipoproteins LDL oxidized LDL inflammatory processes  ROS foam cells macrophages scavenger receptor No feedback regulation smoking, hypertension, diabetes, etc

40 Cholesterol & Atherosclerosis

41

42 antiathergonic properties of HDL: reverse cholesterol transport antioxidant- prevent LDL oxidation

43 The National Cholesterol Education Program (NCEP) NCEP Adult Treatment Panel (ATP) ATP III, ATP IV (due 2012) Adult reference ranges for lipids Reference range (mg/dL) Total cholesterol HDL cholesterol40-75 LDL cholesterol TG LDL cholesterol calculation (Friedewald formula) LDL-C = Total cholesterol – HDL-C – (TG/5) not valid if TG > 400 LDL cholesterol calculation (Friedewald formula) LDL-C = Total cholesterol – HDL-C – (TG/5) not valid if TG > 400 LDL + HDL + VLDL

44  dyslipidemia: abnormal lipid levels  causes: defective synthesis/transport/catabolism of lipoproteins  hyperlipoproteinemia: elevated lipoprotein levels - hypercholesterolemia - hypertriglyceridemia - combined hyperlipidemia  hypolipoproteinemia: decreased lipoprotein levels Abnormalities of lipid metabolism

45  Monogenic disorders  Polygenic disorders  Multifactorial: Genetics + Environment Hyperlipoproteinemia

46  isolated high plasma cholesterol concentration  Common hypercholesterolaemia - most frequent dyslipidemia, multifactorial  Familial hypercholesterolemia (FH) - LDL receptor gene mutations  Familial defective apo B apo B-100 gene mutations  defective LDL receptor binding  Autosomal recessive hypercholesterolemia - mutations  defective LDL receptor-mediated endocytosis Hypercholesterolemia

47  monogenic disorder, autosomal dominant, rare  LDL receptor gene mutations  very high plasma cholesterol & LDL-C levels  premature CHD (teenage years)  lipid deposits at eyelids, tendon, hand, cornea  heterozygotes: also symptomatic, develop CHD at the age of 20s-50s Familial hypercholesterolemia

48 LDL receptor LPL apo-B100 apo E apo C-II chylomicron chylomicron remnant VLDL IDL LDL

49  isolated high plasma TG concentration  borderline high: mg/dL high: mg/dL very high: >500 mg/dL  genetic abnormalities or secondary causes (e.g. some hormonal abnormalities)  imbalance between VLDL synthesis vs clearance Hypertriglyceridemia

50  Familial chylomiconemia - very rare; LPL or apo C-II deficiency - chylomicron & VLDL accumulation  very high TG - fasting chylomicronaemia  Familial hypertriglyceridemia - relatively common - isolated VLDL elevation - excess VLDL production - still largely unknown molecular basis but likely polygenic & requires secondary factor for expression Hypertriglyceridemia

51 LDL receptor LPL apo-B100 apo E apo C-II chylomicron chylomicron remnant VLDL IDL LDL

52 Fig. 1: Clinical manifestations of primary hypertriglyceridemia. Yuan G et al. CMAJ 2007;176: ©2007 by Canadian Medical Association

53  elevated total cholesterol & TG levels  Familial combined hyperlipidemia (FCH) - autosomal dominant with variable penetrance - overproduction of apo B increased VLDL production & subsequent LDL generation - variable lipid profiles Combined hyperlipidemia

54  Familial dysbetaipoproteinemia - apo E gene mutations  apo E isoforms with low affinity to LDL receptor - IDL & chylomicron remnant accumulation - defective catabolism - phenotypic expression usually requires accompanying factors e.g. obesity, type 2 DM Combined hyperlipidemia

55 LDL receptor LPL apo-B100 apo E apo C-II chylomicron chylomicron remnant VLDL IDL LDL

56  Molecular basis  Clinical descriptive names  Fredrickson system (old literatures) Classification of Primary hyperlipoproteinemia

57 57 Type IType II AType II BType IIIType IVType V Prevalencevery rare most commonvery rarevery common rare Serum analysis - Cholesterol - Triglyceride N or N LP pattern -Chylomicron -VLDL -LDL chylomicron remnant IDL Serum appearance - Cream layer - Turbidity ±0± 0 or CauseLPL defect no or abn. LDL receptor LDL cat. VLDL syn. abn. apo E CHO intake severe degree of type V Fredrickson classification for Primary hyperlipoproteinemia

58 Chylomicronemia & Lipemia?  high TG  lipemia  high chylomicron or chylomicron remnant or VLDL levels  plasma protein electrophoresis  Standing plasma test (refrigeration test) chylomicron, chylomicron remnant VLDL (unchanged) cream layer Stored at 4° overnight

59 Standing plasma test

60  Obesity, metabolic syndrome, diabetes - DM: increased glucose shunt into PPP  increased fatty acid synthesis - increased VLDL concentrations - deficient LPL activity, increased CETP activity - increased FFA flux to the liver - fatty liver  Alcohol - increased VLDL concentrations - impaired lipolysis Secondary hypertriglyceridemia

61 Hormone-sensitive lipase Epinephrine Norepinephrine Growth hormone ACTH Thyrotropin increased serum TG levels triglyceride

62 LDL receptor LPL apo-B100 apo E apo C-II DM obesity alcohol FCH DM obesity alcohol FCH DM Mechanisms of dyslipidemia: General concept chylomicron chylomicron remnant VLDL IDL LDL

63 Downloaded from: StudentConsult (on 14 August :37 PM) © 2005 Elsevier Transport and storage of fat in response to feeding

64 Metabolism in the fed (postprandial) state

65 Metabolism in postabsorptive state

66 Metabolism in prolonged fasting state

67 decreased lipoprotien concentrations 1.hypoalphalipoproteinaemia - isolated decrease in HDL levels (<40 mg/dL) - without hypertriglyceridaemia - often caused by genetic defects (e.g. apo A-I or LCAT deficiency, ABCA1 mutations) - increased risk of premature CHD - severe physiological stress  acute transient change 2.hypobetalipoproteinaemia - isolated low levels of LDL (apo B-100 mutations) - no accompanying lipoprotein disorders 3.abetalipoproteinaemia: very rare, caused by defective VLDL assembly Hypolipoproteinaemia

68  Statins - HMG-Co A reductase inhibitor - suppress cholesterol synthesis - increase LDL receptor expression  Fibrates - LPL stimulation Main lipid-lowering medications


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