从抑制胆固醇吸收谈如何减少血液中胆固醇.ppt
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Anti-inflammation may delay heart attack, but when your LDL-C is below 70 mg/dL, your chance to develop atherosclerotic lesions is very, very low.
2020/10/2
Molecular Mechanisms of Cholesterol Transport in Liver and Intestine
PCSK9, ARH ApoB
ABC transporters
2020/10/2
ApoB
Monogenic Hypercholesterolemia
Inheritance
2. Inhibit cholesterol absorption: Ezetimibe, bile acid resins, plant sterols
3. Reduce lipoprotein-cholesterol production: ApoB antisense oligos (ISIS)
4. Raise LDLR: statins, PCSK9 inhibition (drugs and antisense oligos)
2020/10/2
Targets of Cholesterol Lowering Drugs (continue)
HDL-C is controversial. Just a marker or a real cause?
Why as low as 70?
Because what matters is “Not Just How Low, But Also How Long”.
(PCSK9 mutants, Framingham study)
How to get there?
2020/10/2
Zetia
2020/10/2
Winston-Salem, NC, USA Beijing, October 26, 2019
2020/10/2
Plasma Cholesterol and Coronary Heart Disease (CHD)
CHD Deaths Per 1000 patients per 10 yr
MRFIT:
Multiple Risk Factor
Intervention Trial
(USA)
Shanghai
Serum Cholesterol Level (mg/dl)
2020/10/2
From Dr. John M. Dietschy
Lifetime Exposure to LDL-Cholesterol American vs. Chinese Men
PSCK9
Autosomal Recessive Hypercholesterolemia
Sitosterolemia
ARH ABCG5/G8
Targets of Cholesterol Lowering Drugs
1. Inhibit cholesterol synthesis: HMG-CoA reductase inhibitors statins
Mean LDL-Cholesterol
Lifetime LDL Exposure Index
FEMALE
SMOKING HTN DIABETES CHR. 9 etc.
2020/10/2
AGE (YEARS) From Dr. Helen H. Hobbs
Elbow Tube来自百度文库ous Xanthoma (15Ys Chinese Girl, FH?)
Reduce Blood Cholesterol by Targeting Cholesterol Absorption
Liqing Yu, M.D., Ph.D. Department of Pathology-Lipid Sciences Wake Forest University School of Medicine
2020/10/2
Net Cholesterol Balance in Humans
Total Body Cholesterol
~ 700 mg
Hepatic and Extrahepatic
Synthesis
~ 300 mg Bile acids
~ 100 mg Skin slough
~ 50 mg Steroids
~ 375 mg
Intestinal absorption:~50%
~ 100 mg Intestine slough
~ 400 mg
Bile FC
~750 mg
Dietary+Biliary Cholesterol
2020/10/2
~50%
~ 375 mg
Feces
Von Bergmann K, …Grundy SM, Gastroenterology 1979:77:1183
Autosomal Dominant
Autosomal Recessive
2020/10/2
Disease Gene Defect
Familial Hypercholesterolemia
LDLR
Familial Defective ApoB-100
APOB
Autosomal Dominant Hypercholesterolemia
2020/10/2
From Dr. Luya Wang in Beijing
“Cholesterol Is Good”
Fluid-Mosaic Model of Cell Membrane: Cholesterol is a structural component of mammalian cell membranes
The body does not need HDL to get rid of cholesterol. Consequence of raising HDL: Why did CETP inhibitor fail?
Does reverse cholesterol transport (RCT) quantitatively important?
2020/10/2
Molecular Mechanisms of Cholesterol Transport in Liver and Intestine
PCSK9, ARH ApoB
ABC transporters
2020/10/2
ApoB
Monogenic Hypercholesterolemia
Inheritance
2. Inhibit cholesterol absorption: Ezetimibe, bile acid resins, plant sterols
3. Reduce lipoprotein-cholesterol production: ApoB antisense oligos (ISIS)
4. Raise LDLR: statins, PCSK9 inhibition (drugs and antisense oligos)
2020/10/2
Targets of Cholesterol Lowering Drugs (continue)
HDL-C is controversial. Just a marker or a real cause?
Why as low as 70?
Because what matters is “Not Just How Low, But Also How Long”.
(PCSK9 mutants, Framingham study)
How to get there?
2020/10/2
Zetia
2020/10/2
Winston-Salem, NC, USA Beijing, October 26, 2019
2020/10/2
Plasma Cholesterol and Coronary Heart Disease (CHD)
CHD Deaths Per 1000 patients per 10 yr
MRFIT:
Multiple Risk Factor
Intervention Trial
(USA)
Shanghai
Serum Cholesterol Level (mg/dl)
2020/10/2
From Dr. John M. Dietschy
Lifetime Exposure to LDL-Cholesterol American vs. Chinese Men
PSCK9
Autosomal Recessive Hypercholesterolemia
Sitosterolemia
ARH ABCG5/G8
Targets of Cholesterol Lowering Drugs
1. Inhibit cholesterol synthesis: HMG-CoA reductase inhibitors statins
Mean LDL-Cholesterol
Lifetime LDL Exposure Index
FEMALE
SMOKING HTN DIABETES CHR. 9 etc.
2020/10/2
AGE (YEARS) From Dr. Helen H. Hobbs
Elbow Tube来自百度文库ous Xanthoma (15Ys Chinese Girl, FH?)
Reduce Blood Cholesterol by Targeting Cholesterol Absorption
Liqing Yu, M.D., Ph.D. Department of Pathology-Lipid Sciences Wake Forest University School of Medicine
2020/10/2
Net Cholesterol Balance in Humans
Total Body Cholesterol
~ 700 mg
Hepatic and Extrahepatic
Synthesis
~ 300 mg Bile acids
~ 100 mg Skin slough
~ 50 mg Steroids
~ 375 mg
Intestinal absorption:~50%
~ 100 mg Intestine slough
~ 400 mg
Bile FC
~750 mg
Dietary+Biliary Cholesterol
2020/10/2
~50%
~ 375 mg
Feces
Von Bergmann K, …Grundy SM, Gastroenterology 1979:77:1183
Autosomal Dominant
Autosomal Recessive
2020/10/2
Disease Gene Defect
Familial Hypercholesterolemia
LDLR
Familial Defective ApoB-100
APOB
Autosomal Dominant Hypercholesterolemia
2020/10/2
From Dr. Luya Wang in Beijing
“Cholesterol Is Good”
Fluid-Mosaic Model of Cell Membrane: Cholesterol is a structural component of mammalian cell membranes
The body does not need HDL to get rid of cholesterol. Consequence of raising HDL: Why did CETP inhibitor fail?
Does reverse cholesterol transport (RCT) quantitatively important?