浙江大学医学院：调血脂药（PPT讲稿）Lipid-regulators

调血脂药 (Lipid-regulators Yun-BiLu, PhD 卢韵碧 Dept of Pharmacology, School of Medicine, Zhejiang University yunbi@zju.edu.cn 2017.67

调血脂药 （Lipid-regulators） Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University yunbi@zju.edu.cn 2017.6.7

正常动脉脂肪线样硬化化局部症状血管闭塞 O⊙②ee Types of human brain stroke Arteries become narrowed and blood flow decreases in arteriosclerosis Buid up of fatty stances n the ∠动脉粥样硬化景致动脉管腔狭窄 atherosclerosis

plas Include Triglyceride(TG):三酰甘油 Cholesterol(TC):胆固醇 Cholesterol ester(CE):胆固醇酯 Free cholesterol(FC):游离胆固醇 Others phospholipids(PL):磷脂 free fatty acid(FFA):游离脂肪酸 Y Lipids apolipoprotein(apoprotein, apo)=lipoprotein 血脂+载脂蛋白=脂蛋白(溶于血浆,可进行转运与代谢) √ApoA,B,c,D,E:结合于转运脂质

Lipids include: • Triglyceride (TG)：三酰甘油 • Cholesterol (TC)：胆固醇 Cholesterol ester (CE)：胆固醇酯 Free cholesterol (FC)：游离胆固醇 • Others phospholipids(PL)：磷脂 free fatty acid (FFA)：游离脂肪酸 ✓Lipids + apolipoprotein (apoprotein, Apo) = lipoprotein 血脂 + 载脂蛋白 = 脂蛋白 （溶于血浆，可进行转运与代谢） ✓Apo A, B, C, D, E: 结合于转运脂质

apoproteins include Chylomicron(CM):乳糜微粒 Very Low Density Lipoprotein(LDL):极低密度脂蛋白 Low Density Lipoprotein(LDL):低密度脂蛋白 High Density Lipoprotein(HDL):高密度脂蛋白 Intermediate Density Lipoprotein(DL):中间密度脂蛋白 Y Lipids apolipoprotein(apoprotein, apo)=lipoprotein 血脂+载脂蛋白=脂蛋白(溶于血浆,可进行转运与代谢) √ApoA,B,c,D,E:结合于转运脂质

Lipoproteins include: • Chylomicron (CM):乳糜微粒 • Very Low Density Lipoprotein (VLDL)：极低密度脂蛋白 • Low Density Lipoprotein (LDL)：低密度脂蛋白 • High Density Lipoprotein (HDL)：高密度脂蛋白 • Intermediate Density Lipoprotein (IDL)：中间密度脂蛋白 ✓Lipids + apolipoprotein (apoprotein, Apo) = lipoprotein 血脂 + 载脂蛋白 = 脂蛋白 （溶于血浆，可进行转运与代谢） ✓Apo A, B, C, D, E: 结合于转运脂质

LIPOPROTEINS 0.95 VLDL VLDL Remnants Chylomicron LDL 1.06 10 HDL 00 Diameter (nm)

1.20 1.10 1.06 1.02 1.006 0.95 5 10 20 40 60 80 1000 Chylomicron Remnants VLDL IDL LDL HDL2 HDL3 Diameter (nm) Density (g/ml) VLDL Remnants LIPOPROTEINS

Correlation Between Cholesterol Levels and Coronary Heart Disease Events 18 RULE 16 For every 1%increase 141 in LDL-C, there is a 1% 12 increase in CHD events Age-adjusted 6-year 10 CHd death rate per 1000 men 8 ●●● 0 140160180200220240260280300 n=325.000men Serum total cholesterol(mg/dL) Martin MJ et al. Lancet. 1986: 11: 933-936

0 2 4 6 8 10 12 14 16 18 140 160 180 200 220 240 260 280 300 Serum total cholesterol (mg/dL) Age-adjusted 6-year CHD death rate per 1000 men Correlation Between Cholesterol Levels and Coronary Heart Disease Events Martin MJ et al. Lancet. 1986;II:933-936. n=325,000 men RULE: For every 1% increase in LDL-C, there is a 1% increase in CHD events

LDL ow density lipoprotein) LDL is associated with increased heart disease lousy cholesterol”“ bad cholesterol The major carrier of cholesterol in the blood Role: transport cholesterol to peripheral tissues Half-life: 24 hrs(every day about half of the circulating LDL is removed via receptor mediated endocytosis) Lp(a lipoprotein (a)l Lp(a is extracted from LDL Lp(a)is a independent risk factor of atherosclerosis

• LDL is associated with increased heart disease “lousy cholesterol” “bad cholesterol” • The major carrier of cholesterol in the blood LDL (low density lipoprotein) • Role: transport cholesterol to peripheral tissues • Half-life: ~ 24 hrs (every day about half of the circulating LDL is removed via receptor mediated endocytosis) Lp(a) [lipoprotein (a)] • Lp(a) is extracted from LDL • Lp(a) is a independent risk factor of atherosclerosis

Low-Density Lipoprotein (LDL) Unesterified Apo B-100O cholesterol Phospholipid Cholesterol ester Triglyceride Diameter 225-275A

Low-Density Lipoprotein (LDL) Apo B-100 Diameter 225-275 Å Phospholipid Unesterified cholesterol Cholesterol ester Triglyceride

DIETARY FAT LNVER To endocrine AND CHOLESTERO glands for steroid hormone synthesis Bile salt Biosynthesis Pickup of cholesterol Fecal of fats and cholesterol cholestero Intestine LDL ◎○ LDL receptor Lymph o88 protein Remnant FERIFHERAL Chylomicrons chylomicrons VLDL (Remnants) TISSUES and cholesteric muscles TG ald TC various organs) Capillaries Capillaries Apo B-100 Hydrolysis of chole sterol triacylglycerols TG in capillaries Plasma LCAT ○ Hydrophilic layer Lipoprotein lipase (protein, phospholipids O Triacylglycerols Glycerol Fatty acids B-Oxidation in peripheral tissues Cholesterol Transpon by serum albumin Returned to liver Resynthesis and storag for glucose synthesis mainly in adipose tissue

LPL TG and TC TG TC

Cholesterol Synthesis Pathway Acetyl-CoA Acetoacetyl-CoA S-COA S-COA HMG-CoA(羟甲基戊二酸甲酰辅酶A S-COA HMG-COA Reductase OH Mevalonate(甲羟戊酸,MVA Dolichol 人人人 oPP Farnesyl-PP Haem Ubiquinone Farnesylated Proteins (人人人), Squalene Lipoprotein Cholesterol Vitamin D Bile Acids Steroid Hormones Istvan E and Deisenhofer J Science 2001: 292: 1160-1164

Cholesterol Synthesis Pathway （羟甲基戊二酸甲酰辅酶A） （甲羟戊酸，MVA）