Chemistry of Medicine I
医用化学第一Lecture III

12. Atherosclerosis 動脈硬化

1. What is atherosclerosis 動脈硬化とは
2. biosynthesis and metabolism of lipid 脂質の合成と代謝

3. Cause of Atherosclerosis 動脈硬化の原因
4. Prevention and treatment of atherosclerosis 動脈硬化の予防と治療

22.1 What is atherosclerosis
動脈硬化とは3references“athero-sclerosis”
athero: 粥腫（シュクシュ）。脂肪などからなる塊のこと。
sclerosis: 硬化症。
4

Cause of death in Japan

Death ratio (per 105 people)

Cancer悪性新生物（がん）Cerebral infarction
脳血管疾患（脳卒中etc）

Heart disease
心疾患（心筋梗塞etc）
Pneumonia 肺炎Accidental death
不慮の事故
Suicide 自殺
Lever disease 肝疾患
Tuberculosis 結核

1947556575859505

115QuizPlease speculate the cause of atherosclerosis.
Why artery?
Why accumulation of cholesterol happens?
Why AS is mismatch disease?

6Arteriosclerosis 動脈硬化症(⊃ Atherosclerosis 粥状硬化症)• AS related to 75% of all cardiovascular-related death in USA. AS is found in 80%of adults (> 30 years old).
• Thickening, hardening and loss of elasticity (弾性) of the walls of arteries (動脈).
This process gradually restricts the blood flow to organs.

• The lesions of arteriosclerosis begins as the intima (内膜) of the walls of arteries.
• Atherosclerosis is a specific form of arteriosclerosis caused by fibro-fatty plaque(線維脂肪性プラーク) created by foam cell (泡沫細胞) and smooth muscle cell (平滑筋細胞). This is a chronic inflammation (慢性炎症), resulting in thrombosis (血栓).
• Thrombosis stopping blood flow is called infarction (梗塞).
• Thrombosis occurs in large high-pressure artery such as coronary (冠動脈：myocardial infarction), cerebral (大脳), femoral (大腿部) arteries.

7Atherosclerosis 粥状硬化症

lipid plaques on the intimal surface.
(not serious AS)

8Structure of artery

elastic fiber

SMC

elastic fiber endothelium
adventitia

blood vessel

media

intimanerve

9Myocardial infarction

10Fine chronic intimal hyperplasia (FC) in coronary artery
び慢性内膜肥厚• Coronary artery causes FC after birth.
• Thick intima will accommodate more accumulation of LDL.

25 um

7-day old2016 Drug Discov Today 1578

50 um

15-year old

100 um29-year old

Cerebral infarction• Chimpanzee does not cause cerebral infarction.
• Due to the increase of brain volume, blood flow to brain increased.
-> cerebral infarction.

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Atherosclerosis Movies

MEDICAL - How cholesterol clogs your arteries(atherosclerosis)(5:30)

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Development of AS lesions (1)2011 Nature 317

Endothelial cell

Intima
内膜
Media
中膜

SMC
平滑筋細胞

Adventitia
外膜

Fibroblast
線維芽細胞

Mast cell
肥満細胞

1. Exposure to risk factors (diabetes, hypertension, hyperlipidemia)
2. activation and permeability increase of endothelial layer
3. penetration of LDL to intima and monocyte adhesion
4. oxidation of LDL and conversion of monocyte to macrophage
5. macrophage engulfs oxLDL to become foam cell （泡沫細胞）

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Development of AS lesions (2)2011 Nature 317

血管栄養血管

1. SMC migration from media to intima
2. SMC proliferation in intima
3. SMC produces extracellular matrix (ECM:細胞外マトリックス）such as collagen4. advancing lesion contains apoptotic cells (SMC & MΦ), cholesterol crystal and vasa vasorum(血管栄養血管).
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Development of AS lesions (3)血栓の形成2011 Nature 317

血小板
繊維性皮膜の破裂

1. Rupture of fibrous cap
2. Thrombus formation on the exposed ECM
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Low density lipoprotein (LDL) Water-soluble lipid particle with suitable size for long blood circulation (diameter: 20nm).
 Secreted from hepatocyte to cells of whole body.
 ApoB-100 works as targeting ligand for LDL receptor which expresses in target cells.

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Oxidized LDL (oxLDL) Oxidization of lipid of LDL results in introduction anionic carboxyl group in the acylchains.
 Scavenger receptors on macrophage engulf oxLDL to remove it from the blood.
 Oxidation of LDL is accelerated in injured lesions because of high permeability ofendothelium and high conc. of ROS.

18oxLDL recognition by scavenger receptor (CD32)
 Exposition of carboxylic acid-terminated acyl chain from the LDL surface.
 Recognized by multivalent interaction.
(ligand/receptor interaction is weak: Kd > 3 uM).

19
2008 JBC 15527

Negatively charged molecules are waste for us
Glycated protein(removal of lysine)

Oxidized lipid(addition of carboxyl)

Scavenger receptors(non-specific receptor for negative molecules)
macrophage

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Thrifty gene hypothesis 倹約遺伝子仮説
 In 1962, James Neel (USA) proposed this hypothesis to explain why people areprone to diabetes, although it is disadvantageous genotype for survival.
 Thrifty genotype would have been advantageous for hunter-gatherer population,
because it would allow them to fatten more quickly during times of abundance.
“Survival of the fattest”.
 However, in modern societies with a abundance of food, this mismatch results inchronic obesity and related problems like diabetes.
 Thrifty gene will be reducing basal metabolic rate (基礎代謝量) and promoting thestorage of fat.
 Example of thrifty gene: b3-adrenaline receptor, hormone-sensitive lipase, andlipoprotein lipase which regulate lipolysis.

James Neel
Farther of Darwinian medicine
212.2 biosynthesis and metabolism of lipid脂質の合成と代謝22

Why fatty acid (FA) was chosen?
 High oxidation density. 酸化密度が高い。
 Stored with high density because of no solubility in aqueous media.
 Also works as cell membrane.
 Providing stable polymer (polymers of nitrogen or sulfur are not stable)
Why carboxylic acid?
 Able to be stored as neutral ester (triacyl glycerol) Activated ester is useful both for cleavage and elongation.

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b-oxidation of fatty acid Proceeded in mitochondria.
 Producing acetyl CoA which is utilized for TCA cycle.

double bondalcohol

ketone24

Lipogenesis by fatty acid synthase (FAS) Huge homodimer (272 kDa x 2)
 Reverse reaction of b-oxidation.
 working in cytosol of adipose, liver and brain to synthesize C16 (palmitic acid).
Longer and unsaturated FAs are synthesized from C16 in mitochondria and ER.
 Human’s FAS is efficient to support the rapid synthesis of neuron’s myelin sheath(髄鞘).
ERKRDHKSMAT25

Lipogenesis by fatty acidsynthase (FAS)

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PCTG

Lipid digestion
and absorption in intestine

panc.
lipaseCEPLA2

middle chain FAGClipase
long chain FAPC

LPCcholCE

apo LPGA
chylomicronER

portal vein

27

lymph vessel

Lipid digestion
and absorption in intestine

28

Lipid transport system
TG: triglyceride
CE: cholesterol ester
P: phospholipid
LPL: lipoprotein lipase
LCAT: lecithin-chol. acyltransferase

secreted from liver
chylomicron
remnant R
secretedfrom intestine

LDL R

7

23chylomicron34, 7chylomicron
remnant
145glycerol
Cell of other tissueFAglycerolFA

6LDL Rchol29

(continued)
1. Chylomicron’s lipid is hydrolyzed by LPL (lipoprotein lipase)
2. Chylomicron remnants are taken up by liver
3. Liver secrets VLDL and HDL
4. VLDL is converted to LDL by releasing lipid through LPL.
5. LDL is taken up by cells including liver.
6. Excess cholesterol in cells are picked up by HDL through LCAT. Then HDL isconverted to IDL followed by LDL, which is taken up by liver30

Lipid transport system

31

Cholesterol synthesis Three functions of cholesterol:
1. component of cell membrane to tune membrane fluidity.
2. synthesis of steroid hormone.
3. synthesis of bile acids.
 Mammals synthesize
cholesterol in ER ofhepatocyte. Plants
synthesize a little amountand prokaryotes do not
synthesize cholesterol.
 Cholesterol can not be anenergy source.

32Cholesterol metabolism to bile acid
 Cholesterol is converted to bile acids (胆汁酸) in liver which is secreted to intestine
through bile duct (胆管).
 Bile acids allow digestion of dietary fats
and oils by acting as a surfactant thatemulsifies them into micelles.
 95% of bile acids are reabsorbed throughtransporter (ASBT) in ileum (回腸) andrecycled back to the liver for further
secretion into gallbladder (胆のう)(“enterohepatic circulation”).
gallbladder33

2.3 Cause of atherosclerosis 動脈硬化の原因
lipid abnormality (obesity)
high blood pressure
diabetic mellitus
oral bacteria

脂質代謝異常（肥満）

高血圧

糖尿病

口内細菌

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Atherosclerosis is caused by metabolic syndrome

High visceral fat in adipose

High fatty acid conc. in portal blood

Adipokine secretion
Adiponectin: low
TNF-a: highTG: highinsulin resistance

Apo B

Fatty liverVLDL: high
LPL: low
hyperlipidemia

hyperinsulinemia

diabetesNa+ reabsorption: highhypertension

Atherosclerosis
35

Atherosclerosis is caused by metabolic syndrome36

High blood pressurehigh blood pressure -> added force against artery wall -> damage arteries-> plaque formation -> atherosclerosis• 300/180 mmHg
• Never die by cardiovasculardisease• Thick SMC-rich medial layer
37

Lipid abnormality

38Oral bacteria exist beneath intima

2014 mBio e01206

 More than 90% of AS patients possesseubacterium (pseudomonoas spp) in internal
elastic laminal

Hypothesis of stress-induced AS
1. Bacteria is dormant in steady state.
2. Under very stressful condition, increase incortisol secretion from adrenal gland (副腎).

3. Release of free iron from transferrin (ligand
exchange reaction?).
4. Abrupt growth of bacteria, then rupture of AS.

cortisolAccumulation of anti-Gc antibody

enzymeN-acetylneuraminic acid (Ac)N-glycolylneuraminic acid (Gc)

• Human lost the enzyme to be resistant against malaria.
• Food intake Gc can be incorporated into saccharide synthesis.
-> Attack of Gc by anti-Gc antibody.
-> Worsen inflammation in AS.

2.4 Prevention and treatment of atherosclerosis
動脈硬化の予防と治療

lipid-lowering medicine 脂質低下薬

anti-hypertensive medicine 抗高血圧薬
anti-obeisty medicine 抗肥満薬

exercise 運動41

HMG-CoA reductase inhibitor: statin
 To target rate determining step inmevalonate pathway.
 One of the best selling pharmaceuticals.
Mechanism
1. Reduction of blood conc. of cholesterol.
2. LDL uptake in liver is activated due to theincrease of LDL receptor expression.
3. Blood conc. of LDL is reduced.

statin42

Anion-exchange resin (イオン交換樹脂):
cholestyramine
 Polystyrene-based anion exchangeresin.

Mechanism
1. Forming complex with bile acids.
2. Preventing the bile acids from being
taken up at intestine and remove asfeces.

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PCSK9 inhibitor••••

LDLR/LDL complex is recycled back to cell surface after releasing LDL.
LDLR/PCSK9 complex is not recycled but degraded in lysosomes.
Blocking the LDLR/PCSK9 complex formation accelerate the cellular uptake of LDL.
Combination of anti-PCSK9 IgG and statin shows synergetic effect.
anti-PCSK9 IgG

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