Presentation is loading. Please wait.

Presentation is loading. Please wait.

Lipoprotein metabolism

Similar presentations


Presentation on theme: "Lipoprotein metabolism"— Presentation transcript:

1 Lipoprotein metabolism
Patarabutr Masaratana

2 Outline Structure & Function Classification Metabolism Atherosclerosis
Abnormalities

3 Blood protein Plasma Erythrocytes Plasma protein Lipoprotein
Hemoglobin

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

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

6 Components of lipoprotein particles

7 Structure of lipoproteins
most lipoprotein particles: spherical shape core: hydrophobic molecules surface (shell): hydrophilic/amphipathic molecules triglyceride (TG) CE 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
highest lowest TG content 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:

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

14 Classification of lipoproteins
chylomicron VLDL LDL HDL Main components Main apo % Lipid - TG - cholesterol % Protein TG (from diet) B48 98 84 7 2 TG (endogenous) B100 89-96 44-60 16-22 4-11 CE 77 11 62 23 Protein AI 50 3 19 Agarose

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

16 Overview of lipoprotein metabolism
Exogenous pathway Endogenous pathway Reverse cholesterol transport

17 Overview of lipoprotein metabolism
Exogenous pathway 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 chylomicron apo B-48 direction of major lipid transport

18 Overview of lipoprotein metabolism
Endogenous pathway ขนส่ง endogenous TG จากตับไปยัง 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 ถูกส่งกลับไปที่ตับ VLDL-IDL-LDL apo B-100 direction of major lipid transport

19 Overview of lipoprotein metabolism
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 ซึ่งจะย้ายไปอยู่ใน core ของ HDL HDL มีขนาดใหญ่ขึ้น และเปลี่ยนรูปร่างเป็น spherical shape (mature HDL) HDL apo A-I direction of major lipid transport

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

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 เข้าสู่เซลล์กล้ามเนื้อและ adipocyte chylomicron และ VLDL สูญเสีย TG ที่ core ของอณู ทำให้มีขนาดเล็กลง กลายเป็น chylomicron remnant, IDL ตามลำดับ chylomicron remnant และ IDL ถูกนำเข้าสู่ตับ TG ใน IDL บางส่วน จะถูกสลายเพิ่มเติมอีก ทำให้ IDL มีขนาดเล็กลงอีก 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 LDL receptor-related protein (LRP)
Exogenous pathway Lipolysis of core TG apo C-II LPL chylomicron chylomicron remnant apo C apo E FFA apo C apo E β-oxidation lipogenesis HDL LDL receptor LDL receptor-related protein (LRP)

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 chylomicron apo C-II LPL apo E chylomicron remnant

27 Endogenous pathway Sources of endogenous TG
de novo lipogenesis (e.g. from excess dietary carbohydrate) cytosolic TG storage in hepatocytes fatty acids acquired from lipoproteins delivered to the liver 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 HDL VLDL IDL apo C apo E apo C phospholipid
endogenous TG CE phospholipid apo B-100 VLDL apo C phospholipid Lipolysis of core TG apo C-II LPL FFA IDL β-oxidation lipogenesis

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

32 Receptor-mediated endocytosis of LDL

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

34 Reverse cholesterol transport
apo A-I nascent HDL ABCA1 SR-BI aqueous diffusion apo C, apo E phospholipid cholesterol CE chylomicron, VLDL, IDL (through lipolysis) LCAT apo A-I mature HDL (HDL3) TG VLDL CETP chylomicron CE apo C, apo E mature HDL (HDL2) LCAT: lecithin-cholesterol acyltransferase CETP: cholesteryl ester transfer protein ABCA1: ATP-binding cassette transporter A1

35 Reverse cholesterol transport
mature HDL (HDL2) lipolysis by hepatic TG lipase (HTGL) SR-BI (liver) LDL receptor (apo E) LRP (apo E) other unknown receptors FFA nascent HDL CE another cycle of reverse cholesterol transport

36 Reverse cholesterol transport

37 HDL

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

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

40 Cholesterol & Atherosclerosis

41 Cholesterol & Atherosclerosis

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

43 Adult reference ranges for lipids
Reference range (mg/dL) Total cholesterol HDL cholesterol 40-75 LDL cholesterol 50-130 TG 60-150 LDL + HDL + VLDL LDL cholesterol calculation (Friedewald formula) LDL-C = Total cholesterol – HDL-C – (TG/5) not valid if TG > 400 The National Cholesterol Education Program (NCEP) NCEP Adult Treatment Panel (ATP) ATP III, ATP IV (due 2012)

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

45 Hyperlipoproteinemia
Monogenic disorders Polygenic disorders Multifactorial: Genetics + Environment

46 Hypercholesterolemia
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

47 Familial hypercholesterolemia
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

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

49 Hypertriglyceridemia
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

50 Hypertriglyceridemia
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

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

52 Fig. 1: Clinical manifestations of primary hypertriglyceridemia.
Fig. 1: Clinical manifestations of primary hypertriglyceridemia. A: Eruptive cutaneous xanthomas (here on a patient's knee) are filled with foam cells that appear as yellow morbiliform eruptions 2–5 mm in diameter, often with erythematous areolae. Most often associated with markedly elevated plasma chylomicrons in cases of familial chylomicronemia (hyperlipoproteinemia type 1) or primary mixed dyslipidemia (hyperlipoproteinemia type 5), they usually occur in clusters on the skin of the trunk, buttocks or extremities. B: Lipemic plasma. Whole blood has been allowed to stand at 4°C overnight. The sample on the left comes from a patient whose fasting total cholesterol result was 14.2 mmol/L and triglyceride concentration was 41.8 mmol/L. The sample on the right comes from a normolipidemic subject. C: Lipemia retinalis. A milky appearance of the retinal vessels and pink retina can be seen when plasma triglyceride concentration exceeds 35 mmol/L. D: Tuberous xanthomas, filled with foam cells, appear as reddish or orange, often shiny nodules, up to 3 cm in diameter. They are usually moveable and nontender. In patients with familial dysbetalipoproteinemia (hyperlipoproteinemia type 3), they usually appear on extensor surfaces; these are on a patient's elbows. E: Palmar crease xanthomas are filled with foam cells and appear as yellowish deposits within palmar creases. These skin lesions are pathognomonic for familial dysbetalipoproteinemia (hyperlipoproteinemia type 3). Photo by: Panels A, B and D are courtesy of Robert A. Hegele; panel C is courtesy of Ted M. Montgomery; and panel E is courtesy of Jean Davignon. Yuan G et al. CMAJ 2007;176: ©2007 by Canadian Medical Association

53 Combined hyperlipidemia
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

54 Combined hyperlipidemia
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

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

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

57 Fredrickson classification for Primary hyperlipoproteinemia
Type I Type II A Type II B Type III Type IV Type V Prevalence very rare most common very common rare Serum analysis Cholesterol Triglyceride N or N LP pattern Chylomicron VLDL LDL chylomicron remnant IDL Serum appearance Cream layer Turbidity ++++ 0 or + + ++ +++ Cause LPL defect no or abn. LDL receptor LDL cat. VLDL syn. abn. apo E CHO intake severe degree of type V

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

59 Standing plasma test

60 Secondary hypertriglyceridemia
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

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

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

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

64 Metabolism in the fed (postprandial) state

65 Metabolism in postabsorptive state

66 Metabolism in prolonged fasting state

67 Hypolipoproteinaemia
decreased lipoprotien concentrations 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 hypobetalipoproteinaemia isolated low levels of LDL (apo B-100 mutations) - no accompanying lipoprotein disorders abetalipoproteinaemia: very rare, caused by defective VLDL assembly

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


Download ppt "Lipoprotein metabolism"

Similar presentations


Ads by Google