????? www.sinoas.com - PowerPoint PPT Presentation

Title: ????? www.sinoas.com


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????? www.sinoas.com
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??????????????????????????????????(???)???????????
????, ?????????, ?????????????????????????
5
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6
??????????
????????????????????????, ????????????????,
?????????????????????????????(Apo),
?????20??????? ??????????????????????????????????
?????????????, ????????????, ?????????(LPL)???????
(HTGL)?
7
??????
8
??????
9
??????
10
????????
??? ????(nm) ????() ????() ????() ????() ????()
??? ????(nm) FC PL Apo TG CE
CM 80-500 2 5 2 88 3
VLDL 30-80 7 18 9 54 12
IDL 25-30 9 19 17 22 33
LDL 20-25 9 22 22 6 41
Lp(a) 26 9 18 34 3 36
HDL2 10 6 28 44 4 18
HDL3 8 3 25 55 3 14
11
????????
?? (g/ml)
?? ??
0.95
CM
VLDL
1.006
IDL
CM??
1.02
LDL
Lp(a)
1.10
HDL2
1.15
?? (nm)
HDL3
1.20
500
20
40
5
10
60
80
12
????????
HDL
LDL
CM,VLDL, IDL
gt 30 nm
2022 nm
915 nm
Potentially anti- inflammatory
Potentially proinflammatory
Doi H et al. Circulation 2000102670-676 Colome
C et al. Atherosclerosis 2000149295-302
Cockerill GW et al. Arterioscler Thromb Vasc Biol
1995151987-1994.
13
???TG?????
VLDL
CM
TG
9095
5065
CE
24
814
PL
26
1216
FC
1
47
Apo
610
12
801000nm
3080nm
14
???????????
LDL
HDL
TG
56
7
CE
3545
1020
PL
2226
25
FC
615
5
Apo
2225
45
2025nm
813nm
15
? LDL????
??PL?FC?????
ApoB
TG?CE?????
Murphy HC et al. Biochemistry 2000399763-970.
16
? HDL????
??PL?FC?????
ApoA-I
TG?CE?????
ApoA-II
Rye KA et al. Atherosclerosis 1999145227-238.
17
? HDL?????
????
????
??
??
A-I HDL
A-I/A-II HDL
A-II HDL
????
HDL2b
HDL2a
HDL3a
HDL3b
HDL3c
Rye KA et al. Atherosclerosis 1999145227-238.
18
?????
19
?????
20
?????????????
? ?
??
??
LP
FFA
????
?? ??
CM
GLU
????
LP
????
21
?TG??????
O
fatty acid (1)
CH2-O-C-(CH2)14-CH3
fatty acid (2)
O
CH3-(CH2)7-CHCH-(CH2)7-C-O-CH
O
fatty acid (3)
CH2-O-C-(CH2)16-CH3
glycerol
22
?TG????
R1COOH R2COOHR3COOH
LPL
3H2O
LPL
????
????
LPL
LPL
????
??
FFA
FFA
FFA
23
????????
??????
??????
ß-?????
24
????????
???????????????CoA?????CoA????
ATP
AMPPPi
O
O
R-C-OH CoA-SH
R-C-SCoA
COSCoA???
25
????????
??????
?????
???
?????
??
??
??????
???????I
???????II
H-SCoA
H-SCoA
26
?ß-??????
???
????
???
FAD
ß-?????
FADH2
CoASH
H2O
NAD
NADH
27
????????
28
????????
??CoA??????
??CoA???
???????
29
???CoA???????
???b-??
??
???????
?????
??????????????,?????????????,???????CoA??????????
??CoA???????????,?????????????????????????
30
???CoA???????
31
???CoA???????
?????
?????
???
???
???
CoA
CoA
ATP
??CoA
??CoA
ADPPi
????
????
NADHH
NADHH
ADPPi
ADPPi
NAD
NAD
???
???
ATP
ATP
CO2
CO2
???
???
32
???CoA ????
??????????,??????????????????????CoA,????CoA?????
?????CoA?
ATP
ADPPi
O
O
CH3-C-SCoA HCO3- H
HOOC-CH2-C-SCoA
??CoA???
??CoA
??CoA
33
?????????
???????(FAS)????????,????????????? ?
??CoA-ACP??? ? ?????CoA-ACP??? ? b -???-ACP?? ? b
-???-ACP??? ? b -???-ACP??? ? ???-ACP??? ???????(A
CP) ????ACP?? ????b-???-ACP????
????
????
?
?
ACP
?
?
?
?
34
?ACP??????
??
? ?
????
Ser??
???
4-????????
35
?ACP????
?
?
ACP???????????,????????????????????????,?????????
?
ACP
?
?
?
36
?????????
???
NADPH
NADP
?
b-????
b-????
?
?
CO2
???
H2O
ACP
???
??-D2-????
HSCoA
?
?
??CoA
NADPH
???
???
NADP
HSCoA
?
HSCoA
???
HSCoA
??CoA
??CoA
FFA
37
?????????
38
????????
??CoA
??CoA
??CoA
???
CO2
??CoA
CO2
C2
C2
C2
C2
C2
C2
C2
C2
C16
C4
C6
C8
C10
C12
C14
39
????????
??CoA
????CoA
HMG-CoA
HMG-CoA???
MVA
????5-???
??????
?????
?????
??
40
???????
41
??????????
CM?????????????????
1
STEP
2
CM???????
STEP
CM????????
3
STEP
42
?CM???
TG,FC,PL,FFA
FC
TG,CE
????
ApoE-R
FFA
CM??
CM
LPL
HDL
??
43
?VLDL?IDL?LDL???
HDL
CETP
CM??GLU????????
??
CM??LDL??????
??
LPL
FFA
VLDL
B-RE-R
???????
LDL-R
VLDL-R
LPL
IDL
LDL
FFA
????
SR-A
LDL-R
44
?????????(RCT)?
????????(SMC? M? )???
HDL??????????CE???
?????????
45
?FC??????????
Fibrates, TZDs
PPARs
oxysterols
A-I
FC
LXR/RXR
FC
ABCA1
New agents
n-HDL
46
?????????(RCT)?
Cell
Membrane
SR-BI
Liver
LDL
receptor
CE
CE
FC
LCAT
CETP
HDL
TG
HDL
Free cholesterol (FC)
VLDL, IDL, LDL
TG
Triglycerides
Peripheral
tissues
CE
Cholesterol esters
LCAT
Lecithin cholesterol
acyltransferase
CETP
Cholesteryl ester transfer protein
47
?????????(RCT)?
Bile
A-I
A-I
FC
CE
LCAT
CE
FC
FC
FC
CE
ABCA1
SR-BI
Nascent HDL
Macrophage
Liver
Mature HDL
48
?HDL????RCT?
????
HDL2b
HDL2a
HDL3a
HDL3b
HDL3c
49
?????????(RCT)?
???
??????
??
FC
LCAT
ABC1
SMC M?
ACAT
??
??
FC
HDL
nHDL
CE
CETP
Foam Cell
BA
ACAT
CEH
??
CE
HDL-R
CM??
FC
IDL
VLDL
ACAT
CEH
SR-A
????
LDL-R
E-R
CE
???????
LDL
LDL-R
50
???????
????
LDL-R
?
TG??
SR-A
?
LPLHTGL
CE
???????
?
HDL-R
?
LCAT
FC
VLDL-R
B-R,E-R
E-R
? ?
?
HDL
?
?
CE
LPL
TG
TG??
?
?
CE
CE
LCAT
?
?
FC
?
??
?
LPL
TG??
??
?
??
51
???????
???????????,????,?TG???TG????????,???????????????T
G(???TG),????Ch?PL?ApoA??B48??????CM,?????????????
?(???)???????CM,?HDL??ApoC??E?CE(???),????????????
??LPL?ApoC?????CM(???),???????ApoB48?ApoE???CM??,?
????ApoB?E???????????(???)?CM????????5-15??,???,??
???CM???
?
52
???????
?????????????TG(???TG),??Ch?ApoB100?ApoC??ApoE????
?VLDL?????(???),??VLDL???HDL????ApoC??E?CE(???)???
????????LPL???,?????TG????(???),?????LDL??VLDL??,?
??????,????????????????VLDL????,?????TG???????,?10
?????LDL????TG??VLDL????,40???VLDL????????LDL??
??(???),?????LPL?HL????TG????,???????,???????,???A
poB100???LDL?LDL????????LDL?????????(???)????????
???????????????????(???)?
?
53
???????
HDL??(???)???(???)????????,????????Ch???????????LC
AT?????FFA???Ch????????????,HDL?????????????HDL???
HDL,???,?ApoE?,?LCAT???????HDL3????????HDL2(???)??
????????????HDL(???),HDL???ApoC??ApoE?CE???CM
(???)?VLDL (???) ?
?
54
??????????
CM ?????TG????????
LDL ????????????
HDL ??????????????
VLDL ?????TG????????
55
??????????
CM???AS???
VLDL?????CHD??????
IDL????????AS???
LDL?????AS????????????????LDL, ??????AS???
HDL???????????????????,??????????
56
??????????
57
??????
LP Apo Apo Apo Apo Apo Apo Apo Apo Apo Apo
LP AI AII AIV B100 B48 CII CIII E CETP (a)
CM v v v v v v
VLDL v v v v
IDL v v
LDL v v
HDL v v v v v v v
LP(a) v
58
???????????
Apo?? ? ? ? ?
AI ??LCAT, ?FC????RCT
AII ??LCAT????HTGL(?)
AIV ??LCAT??RCT??HDL??????(?)??CII??LPL????
B100 ??LDL?LDL-R?????
B48 ?CM????????, ????????
CII ??LPL??LCAT??HTGL??(?)
CIII ??LPL??????????????, ?????HDL???
E ?????LDL???Apo E????
CETP ??RCT,??HDL??CE?VLDL??TG???,???HDL????????
59
? ? ?
60
?????????
?????????????/??????????????????????????????????,
?????????????? ???, ???????????????-???(HDL-C)????
???????????, ????????????, ???????????????????????
???
61
???????????
NCEP ATP III (2001),USA
?? ??TC?? ??TC?? ??TG?? ??TG??
?? mmol/L mg/d mmol/L mg/d
???? lt5.2 lt200 lt1.7 lt150
???? 5.26.2 200240 1.72.2 150199
???? gt6.2 gt240 gt2.3 gt200
?HDL-C?? lt1.0 lt40
Cleeman J I. JAMA,20012852486-2497
62
???????????
????????(1997),??
?? ??TC?? ??TC?? ??TG?? ??TG??
?? mmol/L mg/d mmol/L mg/d
???? lt5.20 lt200 lt1.70 lt150
???? 5.23-5.69 201-219
? ? gt5.72 gt220 gt1.70 gt150
?HDL-C?? lt0.91 lt35
???????????????? 1997
63
??????????
????????(1970),WHO
?? ??4????? TC TG CM VLDL LDL ??
I ??????? ?? ?? ?? ?? ?? ?????
IIa ?? ?? ? ? ? ?? ?????
IIb ?? ?? ?? ? ? ? ?????
III ???????? ?? ?? ? ? ? ?????
IV ?? ?? ?? ? ?? ? ?????
V ???????? ? ?? ?? ? ?? ?????
64
??????????

• ???????????????
• ?????????????AS, ??CHD???????
• ????????????????
• TG?????????????????????????
• ????????????????????????
• ???????????????

65
?????????
??????????????????????,???????????????????????????
?????, ???????????????????????????????????? ??????
????????????????????????????????????????,
??????????????????????????????????? LDL????, Apo
B100??, Apo E??, LPL?Apo CII????
66
?????????
???????????????????????????? ?????????????????????
??????????????????????????????????????????????????
?????, ?????????ß????????????????????????
67
?????????
??? ???? ???? ????
????????? LDL-R?? ?TC????,???TG??, LDL-C????,???????,??CHD???????? IIIIb
???ApoB100??? ApoB100?? ?? IIIIb
?????????? ??? TC?TG???, VLDL?LDL???, ????, ???????????????, ??????? IIb
?????ß-????? ApoE?? TC?TG???, CM?VLDL????IDL????, ??????,??ApoE2?? III
????TG?? LPL?? ?????????, ?????????, VLDL???? IV
68
????????????
69
??????????
?????????200mg/d??? 400mg/d,???????5mg/dL
TC
??
??????????????, LDL????????
??
??FA
??FA?????????7???14,TC????20mg/dL, ?????LDL-C

• ??CE?????
• ?????????TC?????
• ????????????
• ??????LDL????
• ??LDL?LDL???????

??
??TG??
70
?????????????
??????????????LDL-C?HDL-C?????????6???????,???????
??,??????????????????????,??5055?????????,
?????????, ?????????????????????????????????LDL???
???, LDL???????, ?????????????LDL?????????????,
????????????, ???????, ??????????,
?????LDL????????????, ??????, ?????????????0.78mmo
l/L(30mg/dL)??? ?4550??, ???????????,
?????????????????????????????????????????????,????
??LDL????????????????????0.52mmol/L(20mg/dL)?
71
?????CHD???????????
72
?????CHD????????????
????(Seven Countries Study)
?????????????????????????,?????????????,?????1958?
???????????Aucel Keys??????, ????
????????????????????????16????12763?4059????????1
0????, ??????????????????????????????
Verschuren W M M,et al. JAMA,1995,274131
73
?????CHD????????????
??????????(Framingham Heart Study, FHS)
FHS???????28000????3060??5209?????,?2????????????
??????????????????????????????????????30????????,?
???????7.8mmol/L(300mg/dL)??,90?????????,????????
??????????6.3mmol/L(244mg/dL),?????????????5.27.0
mmol/L( 200 270mg/dL)?
Kannel W B, et al. Ann Intern Med, 1979,9085
74
?????CHD????????????
?????????(MRFIT)
(MRFIT)?356222???????6????, ??????????????????????
???????????????????????????????????????????????5.2
mmol/L(200mg/dL)?,???????????????????????????????
5.2mmol/L(200mg/dL) ??,??????????????????????
Stamler J D, et al. JAMA, 1986,2562823
75
???????????????
76
???????????????

• ???????????????????????
• ???????????????????????
• ??????????????????????
• ?????????????????
• ???????????????????????
• ?????????????????
• ????????????????????????
• ?????????????????????
• ?????(a)?????
• ??????????????

77
????????CHD???????????????
??????????(4S)
?????????,?????????????????????,??????????????????
??????????????4444????3570??????,????????????????
????????(20mg/d)????????,????5.4?(???4.96.3?)????
?????????????LDL-C???????????25?35?10,HDL-C??8
???, ????????????????30, ???????????42?
The Scandinavian Simvastatin Survival Study
Group. Lancet, 1994,3441383
78
????????CHD???????????????
???????????(WOSCOPS)
????????????????????????????????????????????,
?????????????????????????????????40mg,??1??????4.9
???????????????????20,LDL-C??26, HDL-C??5,
??????12?????????(??????????????)????????31,????
????????28,??????????????????,????????????22?
Shepherd J, et al. N Engl J Med, 1995,3331301
79
????????CHD???????????????
?????????????(CARE)
??????????????????????????????????????????????????
???????????4159?(??3583?, ??576?)?????(???????),??
??599?, ????lt6.2mmol/L(240mg/dL),
?LDL-C?3.04.5mmol/L(115170mg/dL),
??????????????????????5?(???4.62?)????????????LDL-
C????????28, ??????20, ?HDL-C???5,??????14
???????????????????????24, ?????????31,
?????????????????????????
Sacks F M,et al. N Engl J Med,1996,3351001
80
????????CHD???????????????
????????????????(LIPID)
????????????????????????????????????????????9014?(
??7458?, ??1556?)?????(???????????????),
??3175?, ????lt4.07.0mmol/L(155271mg/dL),
????lt5.0mmol/L(445mg/dL)???????????????????????(4
512?)??????40mg/?, ????????6.1?????????????LDL-C??
??????25, ?????? 18, ?HDL-C???5,
??????11?????????????????24(Plt0.001),
????????????22, ?????????19?????????????????????
??????
The Long-Term Intervention with Pravastatin in
ischaemic disease(LIPID)study group. N Engl J
Med,1998,3391349
81
????????CHD???????????????
??/??????????????(AFCAPS/TexCAPS)
?????????,????????????????????????????????????????
???????????????????(??LDL-C3.9mmol/L,
HDL-C0.9mmol/L, TC5.8mmol/L)?6605???????20
mg/dLDL-C?????,????40 mg/d, ?LDL-Clt2.8mmol/L,??5.
2?????????LDL-C??25,HDL-C??6,??????15,?????????
???????????????????????37,????????????,??????????
?????40?32????????????25?
Doans J R. et al. JAMA, 19982791615
82
????????????????
??????,????????????(TC)?????????(CHD)?????????????
????,?????????CHD???,??????????????,??CHD?????????
??????????
?????????CHD?????? (Lipid Research Clinics
Coronary Primary Prevention Trial) (LRC-CPPT)
????????? (Los Angeles Veterans Study, LAVS)
????????? (Oslo Primary Prevention Trial)
????????? (MRFIT)
?????? (The European Collaborative Trial)
???????? (DART)
?????????? (POSCH)
??????? (Coronary InterventionsStudy, CIS)
????????????????? (Cholesterol-Lowering
Atherosclerosis Study, CLAS-I)
????????????????? (Cholesterol-Lowering
Atherosclerosis Study, CLAS-II)
???????????? (St Thomas' Atherosclerosis
Regression Study, STARS)
????????? (coronary Drug Project, CDP)
????????????? (FATS)
???????????? (MARS)
??????????? (ACAPS)
????????? (CRISP)
??????????????? (CCAIT)
??????????????????? (AFCAPS/TexCAPS)
?????????? (4S)
??????????? (MAAS)
????????????????????????? (REGRESS)
Kuopio?????????? (KAPS)
??????????? (WOSCOPS)
??????????????I (PLAC I)
??????????????II (PLAC-II)
????????????? (CARE)
???????????????? (LIPID)
?????????? (WHO Cooperative Trial)
???????? (Helsinki Heart Study, HHS)
????????????? (LOCAT)
??????????????????????? (BECAIT)
83
?????????????
?????
????????
??????
??????
????
?????
84
???????????????
Daniel Steinberg
Russell Ross
Peter Libby
85
?????????????

• ??????????????????
• ????????-??????
• ???????????????????????????????????
• ????????????????,????????????,??Ox-LDL?Ox-Lp(a)
• ????????????????????????????????????
• ?????????????????LDL??????
• ??????????????,PDGF??????????????????????????????
  ???
• ??????????????????????????????????????,??????????
  ????
• ???????????Ox-LDL???????????

86
???????????
87
????????
????
????
????
??
T??
?? ??
?????
88
?ICAM-1?VCAM-1?
??????????????,????????-1(ICAM-1)???????-1(VCAM-1)
?ICAM-1??????ß2?????,????????EC????,?VCAM-1???????
??EC????? ?????????????,???????????????VCAM-1?????
????
Li H et al. Arterioscler Thromb 199313197-204.
89
?VCAM-1???????????
3 weeks on atherogenic diet
Li H et al. Arterioscler Thromb 199313197-204.
90
??????????????
Mono
T
PMN
B
91
?Monocyte?EC???
Monocyte
Endothelium
MCP-1
SMC
92
?????????-1(MCP-1)?
?????T??????????????????(EC)????AS???????,????????
????,???????????????-1(MCP-1)????-8(IL-8),????????
??T????????????? MCP-1???????????????????,????????
????(cyclic stretchCS)??????LDL(Ox-LDL)????????
Navab M et al. J Clin Invest 1991882039-2046.
93
? MCP-1??????LDL-R????AS????
LDL-R /MCP-1 /
LDL-R /MCP-1 /
Gu L et al. Mol Cell 19982275-281.
94
? MCP-1??????LDL-R????AS????
30
25
20
Oil Red Staining Aortic Surface Stained
15

10

5
0
/
-/-
/
-/-
Time on Diet
12 14 weeks
20 25 weeks
P 0.001 compared to /p 0.005 compared
to /
Gu L et al. Mol Cell 19982275-281.
95
????????????
VCAM-1
MCP-1
M-CSF
96
???????????(M-CSF)?
?AS?????,EC?SMC??????T??????????PDGF?FGF?M-CSF?EF-
1?AngII???????,??????????????????,?????SS?CS??????
???????M-CSF????????????????????????
97
?M-CSF???????????????
M-CSF
Smith JD et al. Proc Natl Acad Sci U S A
1995928264-8268.Qiao JH et al. Am J Pathol
19971501687-1699.
98
? M-CSF??????LDL-R????AS????
/
op/
op/op
Rajavashisth T et al. J Clin Invest
19981012702-2710.
99
?????????????
Fibrous cap
Lumen
Shoulder
Lipid Core
Intima
Internal
Elastic laminæ
Media
External
100
?????????????
Intima
Lipidcore
Fibrouscap
Lumen
Media
T lymphocyte
Macrophagefoam cell (tissue factor)
Activated intimal SMC
Normal medial SMC
Libby P. Lancet. 1996348S4-S7.
101
?????????????

• ???
• ????

102
???????SMC?M????????? ?
Galis ZS et al. J Clin Invest 1994942493-2503.
103
??????????? ?
104
??????????? ?
105
??????????? ?
106
????? (Weigert ??10) ?
???
???
???
?
?
?
107
????? ?
108
????? ?
Lipid
Thin Cap
Macrophages
Fibrotic
Thick Cap
No Macrophages
Moreno PR, et al. Circulation 2002105923-927
109
?ox-LDL????????????? ?
????
??
LDL
??
??
VCAM-1 ICAM-1
????
MCP-1
LDL
??
PDGFFGFM-CSFEF-1
????LDL
???????
SR-A
????
????
Ross R. N Engl J Med 1999340115-126.
110
(No Transcript)
111
?ox-LDL????????????? ?
112
(No Transcript)
113
???????????
114
(No Transcript)
115
(No Transcript)
116
(No Transcript)
117
(No Transcript)
118
?ox-LDL????????????

• ??????????????????????????(LDL)??????????????????
  ??????? ????????(??????????)???????????????
  ??????????????, ??????????
• ?????????????????????????LDL, ?????LDL(Ox-LDL)???
  , ???????????, ?????LDL??????????????
• ?????LDL??????LDL(mmLDL)?????????????????????????
  ?
• ??????????Ox-LDL?????????,????????????????,
  ??????, ???????????, ???????????????????,??????,??
  ???????????

119
??????

• ?????????????????
• ???????????????

120
?LDL?????
???? Ox-LDL Gly-LDL Gly-ox-LDL LDL-CIC
LDL
??????
121
???????????LDL????
122
?????LDL???????????
123
????ox-LDL? ?
O2-O2-
??
???????????
??
????
ApoB
LDL???LDL-R?????SR-AI????
??LDL????
Witztum, J.L. et al. J. Clin. Invest. 1991. 88,
1785-1792
124
???LDL?ox-LDL???????????
????
?????
????
??
????????
Cu2,Fe2,?????
Native LDL
ox-LDL
??????????
???
???
LDL-R
????????
SR-A
????????
????
Daniel S, et al. Nature Medicine. 2002 Nov
8(11)1211-7
125
?OX-LDL?????????????
OX-LDL?? ? ?
??????????????? Watson, A.D. et al.J.Biol. Chem. 272, 13597-13607 (1997)
????????(PAF)?? Marathe, G.K. et al.J.Biol. Chem. 274, 28395-28404 (1999)
??????(TF)?? Marathe, G.K. et al.J.Biol. Chem. 274, 28395-28404 (1999)
????????????(M-SCF)???? Navab, M. et al. J. Clin. Invest. 88, 2039-2046 (1991)
??????????-1(MCP-1)???? Navab, M. et al. J. Clin. Invest. 88, 2039-2046 (1991)
????????-1(VCSM-1)???? Cybulsky, M.I. et al.Science 251, 788-791(1991)
???????(FAS)??????? Sata, M. et al.J. Clin. Invest. 102, 1682-1689 (1998)
??IL-1,IL-8?? Terkeltaub, R. et al.Arterioscler Thromb. 14, 47-53 (1994)
??????NO?????????? Murohara, T. et al.Am. J. Physiol. 267, H2441-H2449 (1994)
??????????????? Jimi, S. et al.Atherosclerosis 116, 15-26 (1995)
??Ca???? Thorin, E. et al.Atherosclerosis 114, 185-195 (1995)
???????(NF-?B) Brand, K. et al.Arterioscler. Thromb. Vasc. Biol. 17, 1901-1909 (1997)
?????????-1(MMP-1)?? Rajavashisth, T.B. et al.J. Biol. Chem. 274, 11924-11929 (1999)
126
?MM-LDL?OX-LDL??????
? ? MM-LDL OX-LDL
??????? No Yes
?ApoB???????? No Yes
???????? No Yes
?LDL-R?? Yes No
?????? Yes No
??????????(EDRF) No Yes
????? No Yes
????? No Yes
???????? No Yes
?????? No Yes
127
? MM-LDL?OX-LDL??????
??????????
?????
??LDL
MM-LDL
OX-LDL
LDL??????
Judith A. et al. Circulation. 1995912488-2496
128
?HDL????????????? ?
Vessel Lumen
Monocyte
LDL
AdhesionMolecules
Endothelium
MCP-1
LDL
Modified LDL
Cytokines
Foam Cell
Macrophage
Intima
HDL ????????
Miyazaki A et al. Biochim Biophys Acta
1992112673-80.
129
?LDL-C?HDL-C?CHD?????????
Risk of CHD
25
45
65
85
HDL-C(mg/dL)
100
160
220
LDL-C (mg/dL)
Gordon T et al. Am J Med 197762707-714.
130
?HDL-C?CHD?????????
Framingham Study
Total-C/HDL-C ratio
Kannel WB. Am J Cardiol 1983529B12B. Kannel
WB. Am J Cardiol 19875980A90A
131
?????HDL-C????????
??????a-??????????????
????????????????
???????2.25Kg, ??HDL-C????5
????????LDL-C???, ?????HDL-C??
???????????HDL-C?35mg/dL
???????HDL-C???????
132
?????????????
133
?????????????

• ????AS???????????, ?????????
• ??????
• ?
• ??????(???????)
• ?
• OX-LDL?????????(????)
• ?
• ????????????? ??????????
• ?
• ???????

134
?????????????
???????AS????? ??????AS????? LDL?????????????????
135
?????????????

• ????
• ?????
• ????
• ????
• ???

136
?HDL???????????

• HDL???????????,??????????????????????????,
  ?????????????????????, HDL????????????????????????
  ??????, HDL??????LDL???????LDL???????????LDL??????
  ??
• HDL?????LDL??????, ????HDL???????????????????????
  ??
• HDL????????????HDL??ApoAI??????????????
• HDL????????????????, ?????????????????,HDL???????
  ?????????????
• HDL??????????????????????, ?????????Apo AI?Apo
  AII???????HDL????????????????????????????
• HDL???????

137
?????????????
???????????
Pt???????
?????????
????
???????????
?????????
????
????
?????
HDL??
????????
?????
??????????
???????
138
????????????????
139
?AS?CHD?????
140
????????
141
????????
142
????????
143
????CHD?????

• ???????(causal risk factors)??,???,TC??,LDL-C??,
  HDL-C?,????
• ???????(conditional risk factors)TG?Lp(a)?sLDL??
  ????????PAI-1???????C??????
• ???????(predisposing risk factors)??????????????
  ????????????????????????
• ??????????(plaque burden as a risk
  factor)???????????,??????????????????
• ???????(susceptibility risk factor)?????

Smith S C, et al. Circulation, 2000101207
144
?LDL-C????????????
???? ????(mg/dl) ????(mg/dl) LDL-C??(mg/dl)
???? ???? ???? LDL-C??(mg/dl)
?CHD lt2??????? 160 190 lt 160
?CHD 2??????? 130 160 lt 130
CHD ???AS?? 100 130 lt 100
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 1993269 3015-3023
145
?CHD?????????
?????????????(ATP III)
???? ??LDL-C???? ??LDL-C????
???? mmol/L mg/dL
CHD?CHD?????? 2.6 100
???(2???)???? 3.4 130
?0?1????? 4.1 160
CHD?????????????????????10???CHD??20
146
?CHD?????????
?????????????
???? ???? ???????? ???????? ???????? ???????? ???????? ???????? ???????? ???????? ????? ????? ????? ?????
???? ???? TC TC LDL-C LDL-C TC TC LDL-C LDL-C TC TC LDL-C LDL-C
CHD ???? mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL
- - gt5.72 gt220 gt3.64 gt140 gt6.24 gt240 gt4.16 gt160 lt5.72 lt220 lt3.64 lt140
- gt5.20 gt200 gt3.12 gt120 gt5.72 gt220 gt3.64 gt140 lt5.20 lt200 lt3.12 lt120
gt4.68 gt180 gt2.60 gt100 gt5.20 gt200 gt3.12 gt120 lt4.68 lt180 lt2.60 lt100
147
?CHD?????????
??????????????????????? ?????TC??lt5mmol/L(LDL-Clt3.
0mmol/L) 1. ???????????????????? 2.
??????,10??????????gt20 3. II???????
?????,????????????, 1998
148
?????????????

• ??????????????
• ???????46????TC??20(LDL-C??25)??, ?????TG???
  HDL-C???
• ??????, ??????, ???????????
• ????????????????????,???????????
• ???????????

149
? ? ?
150
????????????????
151
?????
? ? ? ?
? ? ? ?? ? ? ? ?
????(Cholestyramine) ??? 4-5g/?,1-6?/d,???????24g???????????,l-3??????????
????(Cholestipol) ??? 10-20g/?,1-2?/d
????(Divistyramine) 612g/d
152
?????

• ?????????????????,?????????????,?????????
• ?????????????????????,??????????????,????????????
  ?,?????????????,?????????????????????????????,????
  ??,?????????????,?????????????,??????,??????????LD
  L??,?????LDL??????,????,?????????LDL??,???????????
  ,??????LDL??LDL???45??????,????LDL-C?TC?????
• ????????????,????????,???????????????,???????????
  ?????

153
?????
LDL-R
LDL
E-R
???
CMR
??
154
?????
??????LDL-C???, HDL-C?,TG?(?) ?????FH
(?????????),FCH (??????????) ?????????????????????
?????? ???????????????????????????????
??????????????????????? ?????????,???,
???,??? ??????LRC-CPPT NHLBI Type II CLAS
FATS STARS
155
?????
? ? ? ?
? ? ? ?? ? ? ? ?
??(Niacin) l-2g/?,3?/d????????,?????37??,??0.1-0.5g/?,4?/d,???????1-2g/?,3?/d?
????(Acipimox) ??????? 0.25g/?,3?/d
?????(lnositolHexanicotinate) 0.2g0.6g/?,3?/d
156
?????

• ??????????????,?????VLDL?????,?????????
• ????????cAMP??????????HTGL???,
  ?????????????????, ??????????????, ????VLDL???
• ???CoA??????????????,????????????CoA??????
• ??LPL???, ?????????????, ????TG????????????????
• ???????HDL?Apo-AI???,?????CE???,??????????HDL?

157
?????
cAMP
NIACIN
LPL
??
??
HTGL
VLDL
SR-B1
??
HDL
A-I
NIACIN
158
?????
??????TG?VLDL-C?IDL-C??? LDL-C?(?),HDL-C?(?) ????
???????????????? I ????????? ???????,??,????,?????
?,?????,??, ????,????,??????,
ALT/AST??? ???????? ß-???,NSAID,
???,??? ?????????,??? ??????CDP, CLAS, FATS
159
?????
? ? ? ?
? ? ? ?? ? ? ? ?
???(Clofibrate) ?????????? 0.25-0.5g/?,3?/d
????(Bezafibrate) ?????? 0.2g/?,3?/d
????(Fenofibrate) ??? 0.1g/?,3?/d
???(Etofylline Clofibrate) ?????? 0.25g/?,2-3?/d
????(Gemfibrozil) ??????? 0.6g/?,2?/d,????0.6g,???0.3g
???(Lifibrate) ???? 50mg/?,3?/d
?????(Alufibrate) 0.5g/?,3?/d
???(Simfibrate) 0.5g/?,3?/d
160
?????
O
CH3
CH3
CH
O
C
COO
C
Cl
Fenofibrate
CH3
CH3
CH3
Cl
Clofibrate
O
C
COOC2H5
CH3
CH3
CH3
C
COOH
O
CH2
CH2
CH2
CH2
Gemfibrozil
CH3
CH3
161
?????

• ???????????, ??????,???VLDL??/??,????????
• ??????????,??????cAMP????,????????cAMP??????????H
  TGL???, ?????????????????, ??????????????,
  ????VLDL???
• ????????????????????(PPAR),??Apo AI?Apo
  AII??????(LPL)?????,??Apo CIII?????,???????ApoAI?A
  poAII?HDL?LPL???,????Apo CIII???,????CM?VLDL?????,
  ????TG??,?????????????????TG?LDL???
• ????????????????????(PPAR),??LXL/RXR?????,????FC?
  ???????,??RCT?
• ?HMG-CoA???????CoA????????(ACAT)???????

162
?????
Fibrates
??????
cAMP
ATP
? ?
VLDL
??
LPL
HTGL
LPL
HMG-CoA???
LDL-R
Fibrates
LDL
IDL
CETP
LCAT
LXL/RXR
HDL
ACAT
163
?????
?????? TG?VLDL-C?IDL-C??? HDL-C ????,
LDL-C ?(?) ?????III ?, ??????????(IV ?),
FCH (??????????) ??????????,????,??
,???,??,CK??? ???????????,?????,??? ????????,??,??
?(Betteridge?) ??????CDP, WHO, HHS, BECAIT
164
?????
? ? ? ?
? ? ? ?? ? ? ? ?
????(lovastatin) ?????????????? 10-80mg/d, ????
????(simvastatin) ??? 5-80mg/d , ????
????(pravastatin) ??????? 10-40mg/d, ?????
????(fluvastatin) ??? 20-80mg/d, ????
?????(atorvastatin) ??? 10-80mg/d, ????
165
?????
HO
Pravastatin
HO
Simvastatin
HO
Lovastatin
O
O
COONa
OH
O
O
O
O
O
H
H
O
H3C
H
O
H3C
H3C
H
H3C
H
H
H3C
H
H3C
H
H
CH3
H
CH3
CH3
CH3
HO
H3C
H3C
CH3
N
ONa
CH3OCH2
Cerivastatin
N
NHC
O Ca
ONa
CH3
N
Atorvastatin
Fluvastatin
CH3
Lennernas H et al. Clin Pharmacokinet
199732403423.
166
?????

• ???????????, ??????,???VLDL??/??,????????
• HMG-CoA????HMG-CoA???MCV,???????????????????HMG-C
  oA?????????????????,?HMG-CoA????,???????????HMG-C
  oA??????????????????????????
• ????????LDL??,???????VLDL???LDL?????????LDL??????
  ??LDL????????????????????????????,
  HMG-CoA??????????????????,????????LDL????,????LDL?
  ??????????,????VLDL???LDL??????

167
?????
HMG-CoA
Lovastatin
168
?????
??CoA
????CoA
HMG-CoA
STATINS
MVA
??
???
169
?????
B
C-II
TG
LPL
CM/VLDL
B
LDLR
STATINS
CMR/IDL
A-I
A-I
STATINS
CE
LCAT
FC
FC
CE
ABC1
Nascent HDL
?
HL
Macrophage
Mature HDL
STATINS
170
??????????
171
?????
?????? LDL-C???,TG ?? HDL-C ? (?)
???????????(FH, FCH) ????????,??,??,??,??,CK??,AL
T??, AST?? ????????????,???,??,???
????????,???,(????),(???) ??????FATS, MARS,
CCAIT, PLAC II, PLAC I, MAAS,
REGRESS,4S, KAPS, WOSCOPS, CARE, LCAS
172
?????
? ? ? ?
? ? ? ?? ? ? ? ?
????? 1.8g/?,3?/d
??? 0.45g0.9g/?,3?/d
???? 4?/?,3?/d
??,???-3?????????,?????????(EPA)????????(DHA),????
????????
173
?????
? ? ? ? ? ?
?????(SFA,saturated fatty acid) ??????? ???????
????????(MUFA,mono unsaturated fatty acid) ??? ???
????????(PUFA,poly unsaturated fatty acid) ?-3?? ???????????
????????(PUFA,poly unsaturated fatty acid) ?-6?? ?????????????
EPA
DHA
174
???????-?????
????????(Probucol)
?????4,4-(1-?????)?(?)-?2,6-?(1,1-?????)??
?????
?????C31H48O2S2
?????516.85
175
????????????????
??
??
??
???
LDL??
???????
OLeary VJ et al.Atherosclerosis,1996119169-173
176
????????????????
??PL?FC????????
TG?CE????????
ApoB
????
Murphy HC et al. Biochemistry 2000399763-970.
177
???????????????
??????
178
??????
??????
Probucol
????
??
LDL
??
??
VCAM-1
????
MCP-1
LDL
Probucol
??
????LDL
M-CSF
???????
SR-A
????
????
179
??????????
Probucol
HDL
LCAT
ABC1
SMC M?
FC
nHDL
CETP
Probucol
Foam Cell
ACAT
CEH
??
CE
HDL-R
FC
IDL
VLDL
ACAT
CEH
SR-A
LDL-R
CE
????
LDL
180
???????

• ??????

• PTCA?????

• ??????

• ???(??)

181
?????
????????????????????,??????????????,?????????,????
??,???????????,???????????????????????????????????
???????? ??????TG ??,VLDL??LDL-C ?(?), HDL-C ?
(?) ?????????????? ?????????????,???????????????
????????,???????????????????,???????????
182
???????
183
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