Post on 14-Jan-2016
description
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↑