Charpter 7

lipid metabolism

Section 1

Lipids and biomembrane

一、 lipid

•Lipids are substances that are insoluble or immiscible in water, but soluble in organic solvents.

Lipids

Lipoids

Fats (Triglyceride or triacylglycerole)

To store and supply energy

Phospholipids Glycolipids Cholesterol

Cholesterol ester

To be important membrane components

（一）、脂肪（一）、脂肪 ((Triglyceride ））

COR1

COR2

COR3

1 分子甘油和 3 分子脂肪酸结合而成的酯。

脂肪酸

saturated ：软脂酸（ 16C）、硬脂酸（ 18C）。

Unsaturated

含 1 个双键（油酸）

含 2 个双键（亚油酸）

含 3 个双键（亚麻酸）

含 4 个双键（花生四烯酸）

（二）甘油磷酸酯类

CH2OCOR1

R2OCOCH

CH2—O— HP—O

O-

O

HX

非极性尾非极性尾

极性头

第三个羟基被磷酸酯化，其他两个羟基被脂肪酸酯化，

磷脂酰胆碱磷脂酸

磷脂酰乙醇胺 磷脂酰肌醇

磷脂酰丝氨酸 磷脂酰甘油

磷脂在水相中自发形成脂质双分子层。

（三）鞘脂类

—— 由 1分子脂肪酸， 1分子鞘氨醇或其衍生物，以及1分子极性头基团组成。

鞘脂类

鞘磷脂类

脑苷脂类（糖鞘脂）

神经节苷脂类

（四）固醇（甾醇）类

固醇类都是环戊烷多氢菲的衍生物。不含脂肪酸。

二、 biomembrane

—— 电镜下表现出大体相同的形态、厚度 6~9nm左右的 3片层结构。

膜的化学组成1.膜脂：主要是磷脂、固醇和鞘脂。

2.膜蛋白3.膜糖类

• 生物膜是以磷脂、胆固醇和糖脂为主构成的双层脂膜

膜蛋白

Membrane structure

双层脂分子构成（ E. Gorter, F.Grendel, 1925)三明治式结构模型 (H.Davson, J.F.Danielli, 1935)单位膜模型 (J.D.Robertson, 1959)流动镶嵌模型 (S.J.Singer, G.Nicolson, 1972)

膜的流动镶嵌模型结构要点

1.膜结构的连续主体是极性的脂质双分子层。

2.脂质双分子层具有流动性（取决于膜磷脂分子中不饱和脂肪酸的百分比，百分比越高，膜的流动性越大）。

3.内嵌蛋白“溶解”于脂质双分子层的中心疏水部分。

4.外周蛋白与脂质双分子层的极性头部连接。

5.双分子层中的脂质分子之间或蛋白质组分与脂质之间无共价结合。

6.膜蛋白可作横向运动。

膜的功能

1.物质传递作用。

2.保护作用。

3.信息传递作用。

4.细胞识别作用。

5.能量转换作用（线粒体内膜和叶绿体类囊体膜）。

6.蛋白质合成与运输（糙面内质网膜）。

7.内部运输（高尔基体膜）。

8.核质分开（核膜）。

Section 2 lipid metabolism

Lipid enzymaticLipid enzymatic degradationdegradation

catabolismcatabolism

anabolismanabolism

§1 enzymatic degradation§1 enzymatic degradation

提问：脂类水解的产物是什么？答案：脂肪酸、醇（甘油、鞘氨醇、固醇、脂肪醇、氨基醇）、磷酸等。提问：影响水解的因素有哪些呢？

—— 酶的种类

—— 溶解度

CH2O

CHO

CH2O

C

C

P O

OH

O

O

O

OR1

OR1

X

磷脂酶 A1

磷脂酶 B

磷脂酶 A2

磷脂酶 C 磷脂酶 D

脂肪的酶促水解

第二节 脂肪的分解代谢第二节 脂肪的分解代谢当饥饿、禁食时，血液中激素（肾上腺素、胰高糖素）浓度升高，激活脂肪细胞内脂肪水解酶，脂肪水解。产物（甘油、脂肪酸）被蛋白质载运通过在血液运输。

一、一、 glycerol oxidationglycerol oxidation

CH2OH

CHOH

CH2OH

ATP ADP

甘油激酶

CH2OH

CHOH

CH2OPO32-

糖代谢糖代谢

活化（磷酸化）→脱氢→进入糖代谢彻底氧化或异生为葡萄糖。目前发现只有肝脏细胞具有甘油激酶，这意味着什么

3-3- 磷酸甘油磷酸甘油 ((α-α-磷酸甘油）磷酸甘油）

NADHNAD++ ++H

---- 脱氢酶脱氢酶

CH2OH

C O

CH2OPO32-

磷酸二羟丙酮磷酸二羟丙酮

甘油只能在肝脏中氧化。脂肪组织己骨骼肌等因甘油激酶活性很低，甘油只能在肝脏中氧化。脂肪组织己骨骼肌等因甘油激酶活性很低，故不能很好地利用甘油故不能很好地利用甘油

？ 。

§2 triglycerol catabolism

二、 fatty acid catabolism

β-氧化作用α-氧化作用ω-氧化作用不饱和及奇数碳链脂肪酸的氧化

五、酮体的代谢

CH3-(CH2)n - CH2 - CH2 -COOH

（一） β-oxidation

（ 3 ） β-氧化过程中能量的释放及转换效率

2 、氧化过程

1 、 β-氧化作用的概念及试验证据

（ 1 ） 脂肪酸的活化和转运

（ 2 ） β-氧化的生化过程

β-氧化作用的概念及试验证据 概 念

试验证据 1904年 F.Knoop根据用苯环标记脂肪酸饲喂狗的实验结果，推导出了 β-氧化学说。

脂肪酸在体内氧化时在羧基端的 β- 碳原子上进行氧化，碳链逐次断裂，每次断下一个二碳单位，既乙酰 CoA ，该过程称作 β- 氧化。

-CH2-(CH2)2n+1-COOH

-CH2-(CH2)2n-COOH

-COOH （苯甲酸）

-CH2COOH （苯乙酸）

奇数碳原子：

偶数碳原子：

Stage 1 Activation of FAs

Acyl-CoA Synthetase (Thiokinase), which locates on the cytoplasm, catalyzes the activation of long chain fatty acids.

+ HSCoAacyl-CoA

synthetase

Mg2+ATP AMP + PPi

R CO

O

Fatty acid

R CO

S CoA

acyl-CoA

Key points of FA activation

1. Irreversible

2. Consume 2 ~P

3. Site: cytosol

Stage 2Transport of acyl CoA into the mitochondria ( rate-limiting step)

Carrier: carnitine

Rate-limiting enzymecarnitine acyltransferase Ⅰ

H3C N CH2 CH CH2

CH3

CH3

OH

COO+R

C

SCoA

O

H3C N CH2 CH CH2

CH3

CH3

O

COO+

C

R

O

Carnitine

Fatty acyl carnitine

HSCoA

carnitine acyltransferase ¢ñ

Stage 3: β-oxidation of FAs

β-oxidation means β-C reaction.

Four steps in one round

step 1: Dehydrogenate

step 2: Hydration

step 3: Dehydrogenate

step 4: Thiolytic cleavage

Step 1. Dehydrogenate

H3C (CH2)n C C C SCoA

H

H

H

H O

H3C (CH2)n C C C SCoA

H

H O

FADH2

FAD

Fatty acyl-CoA

acyl-CoA dehydrogenase

trans-¦¤2-enoyl-CoA

Step 2. Hydration

H3C (CH2)n C C C SCoA

H

H O

H3C (CH2)n C C C SCoA

H

O

H2O

OH

Trans-¦¤2-enoyl-CoA

H

H 3-L-Hydroxyacyl-CoA

enoyl-CoA Hydratase

Step 3. Dehydrogenate

H3C (CH2)n C C C SCoA

H

OOH

H3C (CH2)n C CH2 C SCoA

OO

NADH + H+

NAD+

H

H 3-L-Hydroxyacyl-CoA

hydroxyacyl-CoAdehydrogenase

β -Ketoacyl-CoA

Step 4. Thiolytic cleavage

H3C (CH2)n C CH2 C SCoA

OO

CH3 C SCoA

O

H3C (CH2)n C SCoA +

O

HSCoAβ -Ketoacyl-CoA

Acetyl-CoAFatty acyl-CoA(2C shorter)

β -Ketothiolase

β- oxidation of fatty acids

The β-oxidation pathway is cyclic

one cycle of the β-oxidation:

fatty acyl-CoA + FAD + NAD+ + HS-

CoA →fatty acyl-CoA (2 C less) +

FADH2 + NADH + H+ + acetyl-CoA

Summary

The product of the β-oxidation is in the form of FADH2, NADH, acetyl CoA, only after Krebs cycle and oxidative phosphorylation, can ATP be produced.

The net ATP production: 131 － 2 = 129

Energy yield from one molecule of palmitic acid

TAC

palmitoyl-CoA 8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+

-2 ~P respiratory chain

palmitic acid

activation

7 turns of ¦Â-oxidation

8¡Á12

7¡Á2

respiratory chain

7¡Á3

§ 2.1.3 Other Oxidations of Fatty acids

1. Oxidation of unsaturated fatty acids

2. Peroxisomal fatty acid oxidation

3. Oxidation of propionyl-CoA

1. Oxidation of unsaturated fatty acid

• Mitochondria

• Isomerase: cis → trans

• Epimerase: D (-) → L (+)

2. Peroxisomal fatty acid oxidation

Very long chain fatty acids

Acyl-CoA oxidase

shorter chain fatty acids

β-oxidation

FAD

3. Oxidation of propionyl-CoA 丙酰辅酶 A

propionyl-CoA

Carboxylase (biotin)EpimeraseMutase (VB12)

succinyl-CoA

§ 2.1.4 Ketone Bodies Formation and Utilization

• Ketone bodies are water-soluble fuels normally exported by the liver but overproduced during fasting or in untreated diabetes mellitus, including acetoacetate, β-hydroxybutyrate, and acetone.

The formation of ketone bodies (Ketogenesis)

Location: hepatic mitochondria

Material: acetyl CoA

Rate-limiting enzyme: HMG-CoA synthase

thiolase

HSCoAHMG-CoA synthase

NAD+

NADH+H+

¦Â-Hydroxy-butyrate

CO2Acetone

Acetoacetyl-CoACH3 C

O

S CoA

2 Acetyl-CoA

CH2 C

O

S CoAC

O

CH3

CH2 C

O

S CoAC

OH

CH2

CH3

OOC

¦Â-Hydroxy-¦Â-methylglutaryl-CoA¡¡ ¡¡ ¡¡ ¡¡ £¨HMG-CoA£©

Acetoacetate

HMG-CoAlyase

C CH3

O

CH3

HSCoA

CH CH2

OH

CH3 COO

CH2 COOC

O

CH3

CH3 C

O

S CoA+

Acetyl-CoA

¦Â-hydroxybutyrate dehydrogenase Acetyl-CoA

Utilization of ketone bodies (ketolysis) at extrahepatic tissues

Succinyl-CoA transsulfurase

HSCoAATP

AMP PPi

Acetoacetate thiokinase

-

Lack of succinyl-CoA transsulfurase and Acetoacetate thiokinase in the liver.

Biological Significance

Ketone bodies replace glucose as the major source of energy for many tissues especially the brain, heart and muscles during times of prolonged starvation.

Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation.

Glucose Glucose exported as fuel for tissues such as brain

oxaloacetate

Fattyacids Acetyl-CoA

β-oxidation

gluconeogenesis

CitricAcid cycle

Ketone bodiesexported as energy source for heart, skeletal muscle, kidney, and brain

Ketone body formation

Hepatocyte

Acetoacetate, β-hydroxybutyrate,

acetone

CoA

Plasma concentrations of metabolic fuels (mmol/L) in the fed and starving states

Ketosis consists of ketonemia, ketonuria and smell of acetone in breath

Causes for ketosis

Severe diabetes mellitus

Starvation

Hyperemesis (vomiting) in early pregnancy

ββ 氧化的产能效率氧化的产能效率以软脂酸为例以软脂酸为例

C16H32O2

？次 β 氧化彻底转化

8 乙酰 CoA +7FADH2

+7NADH +7H+

当：乙酰 CoA及脱下的氢经过三羧酸循环、氧化磷酸化彻底氧化

C16H32O2 16CO2 +16H2O+131ATP△G=-2340Kcal/molATP净产率

131-2 （活化消耗 1×2 ） =129获能效率

（ 129×7.3 ） /2340=40%单位重量脂肪酸转化的 ATP 储能（ kcal/kg) =2.3 糖？？

脂肪酸中 HH 含量高

7

~SCoAC

O

268111315 417

10 9

不饱和脂肪酸的不饱和脂肪酸的 ββ 氧化氧化

3HSCoA 3CH3COSCoA

γ- 烯脂酰 CoA

异构化酶异构化酶

β- 烯脂酰 CoA

ββ 氧化氧化

β 氧化

βCH

O～SCoA

~SCoAC

O

CH

Oγ

ATP 、 CoASH

奇数碳原子脂肪酸的氧化——丙酸的代谢

甲基丙二酸单酰 CoA琥珀酰 CoA

硫激酶

羧化酶

变位酶三羧酸

循环

ATP 、 CO2 生物素

CoB12

（包括支链氨基酸降解形成的丙酸、反刍动物消化道中的丙酸）

乙酰辅酶 A 的代谢结局1 ，最主要的是进入柠檬酸循环彻底氧化为 CO2

和 H2O2, 合成胆固醇3 ，合成脂肪酸4 ，合成酮体在肝脏线粒体中，决定乙酰辅酶 A 去向的是草酰

乙酸，它带动乙酰辅酶 A 进入柠檬酸循环。但是在饥饿、糖尿病时，草酰乙酸因参与糖异生而浓度十分低，乙酰辅酶 A 进入柠檬酸循环的量也随之变少，这有利于酮体的生成。

肝不能降解酮体产能（缺酶），为什么制造肝不能降解酮体产能（缺酶），为什么制造酮体酮体呢？呢？

由血液传递给其它组织，尤其是心脏、脑的快捷能源，过多酸中毒。

§ 2.2 Lipogenesis

§ 2.2.1 Synthesis of fatty acid

oleic acid (C18:1 9)

oleoylCoA

palmitic acid (C16:0) palmitoylCoA

H3C

C-S-CoAO

9

H3C18

1

stearic acid (C18:0) stearoylCoA

H3C

C-S-CoAO

C-S-CoAO

1. Palmitic Acid Synthesis

Location: cytosol of liver, adipose tissue, kidney, brain and breast.

Precursor: acetyl CoA Other materials: ATP, NADPH, CO2

Citrate-pyruvate cycle

citrate

oxaloacetate

pyruvate

NADH

NADPH

malate

cytosolmitochondrion

CO2

malate

oxaloacetate

citrate

pyruvate

Acetyl CoA Acetyl CoA

glucose

TCAC

The sources of NADPH are as follows:

• Pentose phosphate pathway

• Malic enzyme

• Cytoplasmic isocitrate dehydrogenase

Process of synthesis:

(1) Carboxylation of Acetyl CoA

(2) Repetitive steps catalyzed by fatty acid synthase

(1) Carboxylation of Acetyl CoA

Malonyl-CoA serves as the donor of two-carbon unit.

CH3 C

O

SCoA

acetyl-CoA

+ HCO3acetyl-CoAcarboxylase

ATP ADP + Pibiotin

OOC CH2 C SCoA

O

malonyl-CoA

Acetyl-CoA Carboxylase is the rate limiting enzyme of the fatty acid synthesis pathway.

The mammalian enzyme is regulated, by

phosphorylation

allosteric regulation by local metabolites.

acetyl-CoA + HCO3 + H+

acetyl-CoA carboxylase (biotin)

malonyl-CoA

long chain acyl-CoA

ATP ADP + Pi

glucagon insulin

citrateisocitrate

Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that are:

in bacteria catalyzed by seven separate enzymes.

in mammals catalyzed by individual domains of a single large polypeptide.

(2) Repetitive steps catalyzed by fatty acid synthase

Fatty acid synthase complex(multifunctional enzyme)Acyl carrier protein (ACP)Acetyl-CoA-ACP transacetylase (AT)β-Ketoacyl-ACP synthase (KS)Malonyl-CoA-ACP transferase (MT)β-Ketoacyl-ACP reductase (KR)β-Hydroacyl-ACP dehydratase (HD)Enoyl-ACP reductase (ER)Thioesterase (TE)

Cys

HS

PhP

HS

AT

KS

MTHD ER KR

ACP

TE

Cys

HS

PhP

HS

AT

KS

MTHDERKR

ACP

TE

Fu

nctio

nal

divisio

n

Subunitdivision

ACP contains 4’-phosphopantotheine.

ATMT

KS① condensation

②

KR

③ dehydration

④

HD

ER

AT

TE

NADPH + H+

NADP+

(CH2)14 C O

O

CH3

NADP+

+ H+NADPH

CH3 C S

O

CH3 C S

O

OOC CH2 C S

O

C CH2 C S

O

O

CH3

CH CH2 C S

O

OH

CH3

CH CH C S

O

CH3

CH2 CH2 C S

O

CH3

KS-HSACP-HS

CH2 CH2 C S

O

CH3CO 2

H2O

H2O

OOC CH2 C S CoA

O

CH3 C S

O

CoA

HS CoA

HS

reduction

(After 7 rounds)

HS CoA

HS

HS

HS

HS

HS

HSHS

reduction

acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+

palmitate + 7 CO2 + 14 NADP+ + 8 HSCoA + 6H2O

The overall reaction of synthesis:

Differences in the oxidation and synthesis of FAs β-oxidation Fatty acid synthesis

Site Mitochondria Cytoplasm

Intermediates Present as CoA derivatives

Covalently linked to SH group of ACP

Enzymes Present as independent proteins

Multi-enzyme complex

Sequential units

2 carbon units split off as acetyl CoA

2 carbon units added, as 3 carbon malonyl CoA

Co-enzymes NAD+ and FAD are reduced

NADPH used as reducing power

Routes of synthesis of other fatty acids

2. Elongation of palmitate

Elongation beyond the 16-C length of the palmitate occurs in mitochondria and endoplasmic reticulum (ER).

Fatty acid elongation within mitochondria uses the acetyl-CoA as donor of 2-carbon units and NADPH serves as electron donor for the final reduction step.

Fatty acids esterified to coenzyme A are substrates for the ER elongation machinery, which uses malonyl-CoA as donor of 2-carbon units.

3. The synthesis of unsaturated fatty acid

Formation of a double bond in a fatty acid involves several endoplasmic reticulum membrane proteins in mammalian cells

Desaturases introduce double bonds at specific positions in a fatty acid chain.

§ 2.2.2 Synthesis of Triacylglycerol

Monoacylglycerol pathway (small intestine)Diacylglycerol pathway (liver, adipose tissue)

1. Monoacylglycerol pathway

CH2

C

CH2

HSCoAacyl CoA

acyl CoA transferase

2-monoacylglycerol 1,2-diacylglycerol

triacylglycerol

CR2

O

HO

OH

OH CH2

C

CH2

CR2

O

HO

OH

O C

O

R1

HSCoAacyl CoA

acyl CoA transferase

CH2

C

CH2

CR2

O

HO

O

O C

O

R1

C

O

R3

2. Diacylglycerol pathway

glycolysis

Summary

Places: small intestine, liver, adipose tissue

Materials:

Endogenous: glucose 、 amino acid 、 glycerol

Exogenous: free fatty acid and monoacylglycerol

Adipose tissue generate fat mainly from glucose

• In adipose tissue, the acetyl CoA for the synthesis of fatty acid is mainly from glucose.

• The lack of glycerol kinase make the only source of glycerol 3-phosphate in adipose tissue is glucose.

Obesity results from an imbalance between energy input and output

adipose tissue

Heat

Work or

Growth

ADP

ATP

fatty acids & triacyl-glcerols

Obesity

CO2 + H2O

Food

Section 3 Metabolism of Phospholipids

Phospholipid refers to phosphorous-containing lipids.

Phospholipids

Glycerophospholipids

Sphingolipids

§ 3.1 Classification and Structure of Glycerophospholipids

Glycerophospholipids are lipids with a glycerol, fatty acids, a phosphate group and a nitrogenous base.

Phosphatidylcholine

fatty acids

nitrogenous base

glycerol

CH2 O

C H

CH2

O

O

C

C

P

R1

R2

O

O

O

O

OH

X

甘油

脂酰基

脂酰基

含氮化合物

The basic structure of glycerophospholipid

glycerolfatty acyl group

Nitrogenous basefatty acyl group

In general, glycerophospholipids contain a saturated fatty acid at C-1 and an unsaturated fatty acid (usually arachidonic acid) at C-2.

The major function of phospholipids is to form biomembrane.

Hydrophobic tail = fatty acids Polar head = nitrogenous base

Some common glycerophospholipid

Some common glycerophospholipid (continue)

§ 3.2 Synthesis of Glycerophospholipid

Location:All tissue of body, especially

liver & kidneyEndoplasmic reticulum

Pathways:CDP-diacylglycerol pathwayDiacylglycerol pathway

a. FA Glycerol

b. poly unsaturated fatty acid from plant oil

c. choline ethanolamine serine inositol

d.  ATP, CTP

e. Enzymes and cofactors

The system of synthesis

from carbohydrate

from food or synthesis in body

Diacylglycerol pathway

SerineEthanolamine

CO2

ATP

ADP

CTP

PPi

DG

CMPCO2

ATP

ADP

CTP

PPi

DG

CMP

3 SAMHO CH2 CH

NH2

COOH HO CH2 CH2 NH2 HO CH2 CH2 N(CH3)3

Choline

PhosphoethanolamineO CH2 CH2 NH2P O CH2 CH2 N(CH3)3

CDP

P

Phosphocholine

CDP-ethanolamineO CH2 CH2 NH2 O CH2 CH2 N(CH3)3CDP

CDP-choline

Phosphatidylethanolamine

Phosphatidylcholine

3 SAMPhosphatidylserine

CDP-Diacylglycerol pathway

PhosphotidateCTP

PPi

CDP-diacylglycerol

CMP

CMP

CMP

Glycerol 3-phosphate

G

Phosphatidyl serinePhosphatidyl inositol

Phosphatidyl glycerol

Diphosphatidyl glycerol(cardiolipin)

SerineInositol

Dihydroxyacetonephosphate

Phosphatidylethanolamine (Cephalin)

Phosphatidylcholine (Lecithin)

Phosphatidylserine

CDP-diacylglycerol

Diphosphatidyl glycerol (Cardiolipin)

Phosphatidylglycerol

Phosphatidylinositol

§ 3.3 Degradation of glycerophospholipids by phospholipase

CH2 O

C H

CH2

O

O

C

C

P

R1

R2

O

O

O

O

OH

X

A2

A1

C

D

CH2 O

C H

CH2

HO

O

C

P

R1

O

O

O

OH

X

B1

CH2 OH

C H

CH2

O

O

C

P

R2

O

O

O

OH

XB2

Lysophospholipid-1 Lysophospholipid-2

Actions of phospholipases on lecithin

PLA1: fatty acid + lysolecithin

PLA2: fatty acid + acyl glycerophosphoryl choline

PLC: 1,2 diacylglycerol + phosphoryl choline

PLD: phosphatidic acid + choline

Lysophospholipids, the products of Phospholipase A hydrolysis, are powerful detergents.

CH2

C HO

CH2O

O C R1

O

P O

O

O

X

H2O

CR2

OOCR2

O

CH2

C HHO

CH2O

O C R1

O

P O

O

O

X

Lysophospholipidphospholipid

PLA2

Section 4 Metabolism of Cholesterol

§ 4.1 Structure and function of cholesterol

1. Function of cholesterol:

(1) It is a constituent of all cell membranes.

(2) It is necessary for the synthesis of all steroid hormones, bile salts and vitamin D.

2. Structure of cholesterol All steroids have cyclopentano penhydro phenanthrene ring system.

CH3

CH3

HO

H3C CH3

CH3

A B

C D

12

34

56

7

89

10

1112

13

14 15

1617

18

19

20

2122 23 24 25

26

27

Cholesterol ester

OCR

O

§ 4.2 Synthesis of cholesterolLocation:

All tissue except brain and mature red blood cells.The major organ is liver (80%).Enzymes locate in cytosol and endoplasmic reticulum.

Materials: Acetyl CoA, NADPH(H+), ATP

Acetyl-CoA is the direct and the only carbon source.

HMG CoA reductase is the rate-limiting enzyme

Acetoacetyl-CoA

Acetyl-CoAHMG-CoA

The total process of cholesterol de novo synthesis

Regulation of cholesterol synthesis

MVAHMG CoA reductase

cholesterol

bile acid

fasting Glucagon

after meal insulin thyroxine

HMG CoA

§ 4.3 Transformation and excretion of cholesterol

Steroidhormones

Bile acids

Cholesterol

Vitamin D

1. Conversion of Cholesterol into bile acid

(1) Classification of bile acids

The primary bile acids are synthesized in the liver from cholesterol. The 7-hydroxylase is rate-limiting enzyme in the pathway for synthesis of the bile acids.

The secondary bile acids are products that the primary bile acids in the intestine are subjected to some further changes by the activity of the intestinal bacteria.

Classification of bile acids Classificati

on Free bile

acidsConjugated bile acids

Primary bile acids

Cholic acidGlycocholic

acidTaurocholic

acid

Chenodeoxy-cholic acid

Glycocheno-deoxycholic

acid

Taurocheno-deoxycholic

acid

Secondary bile acids

Deoxycholic acid

Glycodeoxy-cholic acid

Taurodeoxy-cholic acid

Lithocholic acid

Glycolitho-cholic acid

Taurolitho-cholic acid

(2) Strcture of bile acids

HO OH

OH

H

COOH

HO OH

OH

H

CONHCH2COOH

HO OHH

COOH

HO OH

OH

H

CONHCH2CH2SO3H

cholic acid chenodeoxycholic acid

glycocholic acid taurocholic acid

3 7

12

HO

OH

H

COOH

HO H

COOH

deoxycholic acid lithocholic acid

(3) Enterohepatic Cycle of bile acids

Conversion to bile salts, that are secreted into the intestine, is the only mechanism by which cholesterol is excreted.

Most bile acids are reabsorbed in the ileum , returned to the liver by the portal vein, and re-secreted into the intestine. This is the enterohepatic cycle.

(4) Function of bile acids Bile acids are amphipathic, with

detergent properties.

Emulsify fat and aid digestion of fats & fat-soluble vitamins in the intestine.

Increase solubility of cholesterol in bile.

2. Conversion of cholesterol into steroid hormones

Tissues: adrenal cortex, gonads

Steroid hormones: cortisol (glucocorti-coid), corticosterone and aldosterone (mineralocorticoid), progesterone, testosterone, and estradiol

Steroids derived from cholesterol

3. Conversion into 7-dehydrocholesterol

cholesterol

(mitochondria in the kidney)

1¦Á-hydroxylase

7-dehydro-cholesterol

ultraviolet light

cholecalciferol (VD3)

25-hydroxylase

(microsome in the liver)

1,25-(OH)2-D3

£¨ in skin£©

£¨ active Vit D3£©

25-OH-D3

§ 4.4 Esterification of cholesterol

in cells

HO OCR

O

cholesterol cholesteryl ester

acyl CoA cholesterol

acyl transferase(ACAT)

acyl CoASHCoA

in plasma

Section 5 Plasma lipoprotein

§ 5.1 blood lipid Concept: All the lipids contained in plasma, including fat, phosphalipids, cholesterol, cholesterol ester and fatty acid.Blood lipid exist and transport in the form of lipoprotein.

blood lipids

freeTG

cholesterol

phospholipidslecithinsphingolipidscephalin

ester

FFA

§ 5.2 Classification of plasma lipoproteins

1. electrophoresis method:

- Lipoprotein fastpre -Lipoprotein-LipoproteinCM (chylomicron) slow

2. Ultra centrifugation method ：

high density lipoprotein (HDL) high

low density lipoprotein ( LDL)very low density lipoprotein

( VLDL) CM (chylomicron )

low

electron microscope

－ ＋

Origin CM

LDL VLDL HDL

Pre-

CM

Separation of plasma lipoproteins by electrophoresis on agarose gel

§ 5.3 Structure

§ 5.4 Composition of lipoproteinCM VLDL LDL HDL

Density(g/ml)<1.00

60.95-1.006

1.006-

1.063

1.063-1.210

Protein 2 10 23 55

Phospholipids 9 18 20 24

Cholesterol 1 7 8 2

Cholesteryl esters

3 12 37 15

TG 85 50 10 4

§ 5.5 Apolipoproteins

Functions of apolipoproteins

a . To combine and transport lipids.

b .  To regulate lipoprotein metabolism.

apo A II activates hepatic lipase （ HL ）

apo A I activates LCAT apo C II activates lipoprotein lipase

（ LPL ）

c. To recognize the lipoprotein receptors.

§ 5.6 Metabolism of plasma lipoprotein

1. CM

Chylomicrons are formed in the intestinal mucosal cells and secreted into the lacteals of lymphatic system.

Cholesterol phospholipids

Triacylglycerols andcholesteryl esters

Apolipoproteins structure of CM

Metabolic fate of CM

summary of CMSite of formation: intestinal mucosal cells

Function: transport exogenous TGkey E: LPL in blood

HL in liver

apoCⅡ is the activator of LPL

apo E and apo B-48 will be recognized by the LRP receptor

2. VLDL

Very low density lipoproteins (VLDL) are synthesized in the liver and produce a turbidity in plasma.

Metabolic fate of VLDL and production of LDL

Nascent VLDL

Summary of VLDL

Formation site: liver

Function: VLDL carries endogenous triglycerides from liver to peripheral tissues for energy needs.

key E: LPL in blood

HL in liver

3. LDL

Most of the LDL particles are derived from VLDL, but a small part is directly released from liver. They are cholesterol rich lipoprotein molecules containing only apo B-100.

Internalization Lysosomal hydrolysisLDL binding

LDL receptors

Cholesterolester

protein

LDL

Cholesterol

Cholesteryloleate

Amino acids

Michael Brown and Joseph Goldstein were awarded Nobel prize in 1985 for their work on LDL receptors.

Summary of LDL

Formation site: from VLDL in bloodFunction: transport cholesterol from liver to the peripheral tissues. LDL concentration in blood has positive correlation with incidence of cardiovascular diseases.

Fates of cholesterol in the cells

1. Incorporated into cell membranes.

2. Metabolized to steroid hormones.

3. Re-esterified and stored. The re-esterification is catalyzed by ACAT.

4. Expulsion of cholesterol from the cell, esterified by LCAT and transported by HDL and finally excreted through liver.

4. HDL

LDL variety is called “ bad cholesterol” whereas HDL is known as “ good cholesterol” .

VLDL LDL

HDL

Cholesterol

HeartLiver

“BAD”

Deposit

Excretion

“Good”

Forward and reverse cholesterol transport

Reverse cholesterol transport

Cholesterol from tissues reach liver, and is later excreted. This is called reverse cholesterol transport by HDL.

Metabolism of HDL in reverse cholesterol transport

CETP

Cholesterol ester transfer protein (CETP) transfer cholesterol ester in HDL to VLDL and LDL.

Summary of HDL

Formation site: liver and intestineFunction: transport cholesterol from peripheral tissues to liver

summary of lipoprotein metabolism

§ 5.7 Hyperlipidemias

classification

Lipoprotein Blood lipids

Ⅰ CM TAG↑ ↑ ↑ CH↑

Ⅱa LDL CH↑ ↑

Ⅱb LDL, VLDL CH↑ ↑ TAG↑ ↑

Ⅲ IDL CH↑ ↑ TAG↑ ↑

Ⅳ VLDL TAG↑ ↑

Ⅴ VLDL, CM TAG↑ ↑ ↑ CH↑