Chapter 5 lipids metabolism

Chapter 5

lipids metabolism

LIPIDS

• Water-insoluble substances that can be extracted from cells by nonpolar organic solvents

• Characteristics of fat• Hydrophobic because of nonpolar FA chain

• Lipids store large amounts of energy• 9 kcal/gram due to energy rich fatty acid chain

Outline

• Classification of FA and Nomenclature

• Digestion of Triacylglycerols

• Metabolism of TAG

• Metabolism of phospholipids

• Metabolism of cholesterol

• Lipoproteins metabolism

Section 1 Classification of FA and Nomenclature （命名）

• According to the number of carbon atom:

short chain(2~4C), medium chain (6~10C) & long chain(12~26C) fatty acid

• According to whether it contains double bond or not

(saturate & unsaturate fatty acid)

• According to the number of carbon atom, the source & property. such as: Butyric acid, Arachidonic acid

• systemic nomination

( catalogue, or n catalogue)

Classification and Functions of Lipids

1. Triglyceride, TG （ Variable lipids ） :

- As storage and transport form of metabolic fuel - To keep the body temperature - Fats are solids; oils are liquids - To protect the visceras2. Lipoid （ Basic lipids ）： Cholesterols, Phospholipids,

Glycolipids et al - As structural components of biological membranes. - Cholesterol serves the precursor of bile salt and

steroid hormones3. Lipid ramification: to involve the different functions

Fatty AcidsAcids obtained by the hydrolysis of fats and oils

• Saturated (have only single bonds)

• Unsaturated (have double bonds)

• Essential -must originate from dietary sources

-the body cannot synthesize

-Polyunsaturated fatty acids

linoleic :(18:2,9,12)

linoleinic:(18:3, 9,12,15)

arachidonic acid :(20:4, 5,8,11,14)

Omega-3 / Omega-6 Fatty AcidsOmega-3 / Omega-6 Fatty Acids

– Sources of omega-3 fatty acid: soybean, salmon……

– Eicosapentaenoic acid(EPA,fish oil): found in oils of shell fish, cold-water tuna, sardines, and sea mammals

• Sources of omega-6 fatty acids– Vegetable oils– Nuts and seeds

Triglycerides （ triacylglycerols ） ,Called “Neutral Fats” - made of 3 free fatty acids and 1 glycerol - FFA 4-22 Carbons long (mostly 16-20) - 95% of dietary lipids (fats & oils)

Triglyceride

Glycerol + 3 FFA TG + H2O

Section 2Digestion of Triacylglycerols

6 Steps of Digestion and absorption of lipids

Minor digestion of triacylglycerols in mouth and stomach by lingual lipase

Major digestion of all lipids in the lumen of the duodenum(十二指肠 ) / jejunum （空肠） by Pancreatic lipases

Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepatic （肠肝） bile acid recycling

Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell ， Glycerol & FAs < 12 carbons in length pass thru the cell into the blood without modification. 2-monacylglycerols and FAs > 12 carbons in length are re-synthesized into TGs in the endoplasmic reticulum TGs then form large lipid globules in the ER called nascent chylomicrons （乳糜微粒）” .Several apolipoproteins are required

Re-esterification of 2-monoacylglycerol, lysolecithin （溶血卵磷脂） , and cholesterol with free fatty acids inside the intestinal enterocyte

Assembly and export from intestinal cells to the lymphatics of chylomicrons coated with Apo B48 and containing triacylglycerols, cholesterol esters and phospholipids

Section 3

Metabolism of TAG

1. Synthesis of TAG2. Catabolism of TAG - Fatty acid bata oxidation -Ketogenesis and Ketone Bodies

3. Lipogenesis: Fatty Acid Synthesis4. Some poly-unsaturated FA ramification

The synthesis of TAG1. Mono-acylglycerol pathway (MAG pathway) (for dietary fat digestion and absorption)

pancreatic lipase

FA

pancreatic lipase

FA

ATP,CoA

acyl CoA acyl CoA

intestinal epithelium

intestinal lumen

Chylomicronslymphatic vessels

adipose tissue

CH2OCOR

CHOCOR

CH2OCOR

TAG

CH2OH

CHOCOR

CH2OCOR

DAGCH2OH

CHOCOR

CH2OH

MAG

CH2OH

CHOCOR

CH2OH

MAG

CH2OCOR

CHOCOR

CH2OCOR

TAG

FA FA

2. Diacylglycerol pathway (DAG pathway) (for TAG synthesis of in adipose tissue, liver and kidney)

CH2O-PO3H2

CO

CH2OH

dihydroxyacetone phosphate

liveradipose tissue

NADH+H+NAD+

phosphoglycerol dehydrogenase CH2O-PO3H2

CHOH

CH2OH

3-phosphoglycerol

ADP ATP

glycerol kinase

liverkidney

RCO¡« SCoA

HSCoA

CH2O-PO3H2

CHOH

CH2OCOR

lysophosphatidate

acyl CoA transferase

acyl CoAtransferase

RCO¡« SCoAHSCoA

phosphatidate

CH2O-PO3H2

CHOCOR

CH2OCORH2OPi

CH2OH

CHOCOR

CH2OCOR

diacylglycerol

RCO¡« SCoAHSCoA

acyl CoAtransferase

glucoseCH2OH

CHOH

CH2OH

glycerol

CH2OCOR

CHOCOR

CH2OCOR

triacylglycerol

phosphatase

Catabolism of TAG

Mobilization of triacylglycerols

Mobilization of triacylglycerols:

in the adipose tissue, breaks down triacylglycerols to freefatty acids and glycerol (fattyacids are hydrolyzed initiallyfrom C1or C3 of the fat)

hormone sensitive lipase cleave a fatty acid from atriglyceride, then other lipasecomplete the process of

lipolysis,and fatty acid are released intothe blood by serum albumin

• The glycerol is absorbed by the liver and converted to glycolytic intermediates

Fatty acid bata oxidation

MITOCHONDRION

cell membrane

FA = fatty acidLPL = lipoprotein lipaseFABP = fatty acid binding protein

ACS

FABP

FABPFA

3

FABPacyl-CoA

4

CYTOPLASM

CAPILLARY

LPL

lipoproteins

2

FAFA

1

albuminFA FA

FA

From fat cell

carnitinetransporter

acyl-CoA

5

Overview of fatty acid degradation

ACS = acyl CoA synthetase

acetyl-CoA TCAcycle

-oxidation6

7

Steps in Beta Oxidation

• Fatty Acid Activation by esterification with CoASH

• Membrane Transport of Fatty Acyl CoA Esters

• ***Carbon Backbone Reaction Sequence• Dehydrogenation

• Hydration

• Dehydrogenation

• Thiolase Reaction (Carbon-Carbon Cleavage)

• Acyl CoA synthetase reaction occurs on the mitochondrial membrane

1. Activation of Fatty Acids

• Carnitine carries long-chain activated fatty acids into the mitochondrial matrix

2.Transport into Mitochondrial Matrix

• Carnitine carries long-chain activated fatty acids into the mitochondrial matrix

• Each round in fatty acid degradation involves four reactions– 1. oxidation totrans-∆2-Enoly-CoARemoves H atoms from the and carbons-Forms a trans C=C bond-Reduces FAD to FADH2

3. Fatty acid Beta oxidation

2. Hydration to L–3–Hydroxylacyl CoA– Adds water across the

trans C=C bond

– Forms a hydroxyl group (—OH) on the carbon

3. Oxidation to– 3–Ketoacyl CoA

– Oxidizes the hydroxyl group

– Forms a keto group on the carbon

4. Thiolysis to produce

Acetyl–CoA

– acetyl CoA is cleaved:By

splitting the bond between the

and carbons.

– To form a shortened fatty acyl

CoA that repeats steps 1 - 4 of

-oxidation

-Oxidation of Myristic(C14) Acid

-Oxidation of Myristic (C14) Acid

7 Acetyl CoA

6 cycles

Cycles of -Oxidation

The length of a fatty acid• Determines the number of oxidations and the

total number of acetyl CoA groups

Carbons in Acetyl CoA -Oxidation CyclesFatty Acid (C/2) (C/2 –1)12 6 514 7 616 8 718 9 8

-Oxidation and ATP

Activation of a fatty acid requires:

2 ATP

One cycle of oxidation of a fatty acid produces:

1 NADH 3 ATP

1 FADH2 2 ATP

Acetyl CoA entering the citric acid cycle produces:

1 Acetyl CoA 12 ATP

ATP for Myristic Acid C14

ATP production for Myristic(14 carbons):Activation of myristic acid -2 ATP

7 Acetyl CoA7 acetyl CoA x 12 ATP/acetyl CoA 84 ATP

6 Oxidation cycles 6 NADH x 3ATP/NADH 18 ATP6 FADH2 x 2ATP/FADH2 12 ATP

Total 102 ATP

Oxidation of Special Cases (monounsaturated fatty acids)

Odd Carbon Fatty Acids

CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA

5 Cycles

5 CH3COSCoA + CH3CH2COSCoA

Propionyl CoA

CO2H

COSCoA

H-C-CH3

CO2H

COSCoA

CH3-C-HHO2CCH 2CH2COSCoA

D-MethylmalonylCoA

L-MethylmalonylCoA

Succinyl CoA

TCA Cycle

Propionyl CoA CarboxylaseATP/CO2

EpimeraseMutase

Vit. B12

Ketogenesis (Ketosis):

formation of Ketone Bodies *****

2 CH3COSCoA CH3COCH2COSCoAThiolase

CH3COSCoA

Acetoacetyl CoA

HO2C-CH2-C-CH2COSCoA

OH

CH3

-Hydroxy--methylglutaryl CoA(HMG CoA)

HMG CoASynthase

Cholesterol(in cytosol)

Severalsteps

Ketogenesis(in liver: mitochon-

drial matrix)

Ketogenesis: formation of Ketone Bodies

HO2C-CH2-C-CH2COSCoA

OH

CH3

HMG CoA

CH3COCH2CO2H

Acetoacetic Acid

HMG CoAlyase

- CH3COSCoA

- CO2

CH3COCH3

Acetone(volatile)

CH3CHCH2CO2H

OH

-Hydroxybutyrate

NADH + H+

NAD+Dehydrogenase

Ketone bodies are important sources of energy, especially in starvation

Acetoacetate-Hydroxybutyrate

-Hydroxybutyrate dehydrogenase

NAD+NADH

CitricAcidCycle

2 Acetyl CoA

CoA

ThiolaseAcetoacetyl CoA

Succinyl CoA

Succinate

CoA transferase

Oxidation of ketone bodies in brain, muscle, kidney, and intestine

Succinyl CoA synthetase = loss of GTP

The significance of ketogenesis and ketogenolysis

• Ketone bodies are water soluble, they are convenient to transport in blood, and readily taken up by non-hepatic tissues

In the early stages of fasting, the use of ketone bodies by heart, skeletal muscle conserves glucose for support of central nervous system. With more prolonged starvation, brain can take up more ketone bodies to spare glucose consumption

• High concentration of ketone bodies can induce ketonemia and ketonuria, and even ketosis and acidosis

When carbohydrate catabolism is blocked by a disease of diabetes mellitus or defect of sugar source, the blood concentration of ketone bodies may increase,the patient may suffer from ketosis and acidosis

TCA

extrahepatic tissues

CO2 + H2O + energy¢Ü

Overview Catabolism of TAG

TAG¢Ù FFAs

glycerol

¦Â-oxidation¢Ú

acetyl CoA

not in adipose tissue and muscle glycolysis

¢Ý

¢Û in liver

Ketone bodies

• Fatty acid are synthesized and degraded by different pathways

– from acetyl CoA

– in the cytosol

– intermediates are attached to the acyl carrier protein (ACP)

– the activated donor is malonyl–ACP

– reduction uses NADPH + H+

– stops at C16

(palmitic acid 软脂酸 )

Lipogenesis: Fatty Acid Synthesis

Reactivity of Coenzyme A

NucleoNucleophilic acyl substitutionphilic acyl substitution

CHCH33CCSCoASCoA

OOHYHY••••

CHCH33CC

OO

YY •••• ++ HHSCoASCoA

Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles(it is an acetyl transfer agent)

Reactivity of Coenzyme A

can react via enol(can react via enol(烯醇 ))

CHCH33CCSCoASCoA

OO

Acetyl coenzyme A reacts with biological electrophiles at its carbon atom

CCSCoASCoA

OHOH

HH22CC

EE++

CHCH22CCSCoASCoA

OO

EE

Formation of malonyl–CoA is the committed step in fatty acid synthesis

Formation of Malonyl Coenzyme A

O || CH3—C—S—CoA + HCO3

- + ATP

Acetyl CoA O O || ||

-O—C—CH2—C—S—ACP + ADP + PiMalonyl (丙二酰 ) CoA

• The intermediates(acetyl-ACP and malonyl-ACP) in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP)

Formation of Acetyl and Malonyl ACP

In bacteria the enzymes that are involved in elongation are separate proteins

In higher organisms the activities all reside on the same polypeptide– To start an elongation cycle, Acetyl–CoA and Malonyl–CoA

are each transferred to an acyl carrier protein

O ||CH3—C—S—ACP ( Acetyl-ACP)

O O || ||

-O—C—CH2—C—S—ACP (Malonyl-ACP)

Condensation and Reduction

In reactions 1 and 2 of fatty acid synthesis:

• Condensation by a synthase combines acetyl-ACP with malonyl-ACP to form acetoacetyl-ACP (4C) and CO2 (reaction 1)

• Reduction converts a ketone to an alcohol using NADPH (reaction 2)

Dehydration and Reduction

In reactions 3 and 4 of fatty acid synthesis:

• Dehydration forms a trans double bond (reaction 3)

• Reduction converts the double bond to a single bond using NADPH (Reaction 4)

Lipogenesis Cycle Repeats

Fatty acid synthesis continues:

• Malonyl-ACP combines with the four-carbon butyryl-ACP to form a six-carbon-ACP.

• The carbon chain lengthens by two carbons each cycle

Lipogenesis Cycle Completed

• Fatty acid synthesis is completed when palmitoyl ACP reacts with water to give palmitate (C16)

and free ACP.

Summary of Lipogenesis

• Endoplasmic reticulum( 内质网 ) systems introduce double bonds into long chain acyl–CoA's

– Reaction combines both NADH and the acyl–CoA's to reduce O

2 to H

2O

Elongation and Unsaturation

• convert palmitoyl–CoA to other fatty acids

– Reactions occur on the cytosolic face of the endoplasmic reticulum.

– Malonyl–CoA is the donor in elongation reactions

Oxidation and Fatty Acid Synthesis

Fatty Acid Formation

• Shorter fatty acids undergo fewer cycles • Longer fatty acids are produced from palmitate

using special enzymes• Unsaturated cis bonds are incorporated into a 10-

carbon fatty acid that is elongated further• When blood glucose is high, insulin stimulates

glycolysis and pyruvate oxidation to obtain acetyl CoA to form fatty acids

• The stoichiometry of palmitate synthesis:– Synythesis of palmitate from Malonyl–CoA

– Synthesis of Malonyl–CoA from Acetyl–CoA

– Overall synthesis

Stoichiometry of FA synthesis

• The malate dehydrogenase and NADP+–linked malate enzyme reactions of the citrate shuttle exchange NADH for NADPH

Sources of NADPH

• Acetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol– Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate:

Citrate Shuttle

• Regulation of Acetyl carboxylase （乙酰羧化酶）– Global

（ + ） insulin

（ - ） glucagon

（ - ） epinephrine

– Local（ + ） Citrate

（ - ） Palmitoyl–CoA

（ - ） AMP

Regulation of Fatty Acid Synthesis

• Eicosanoid horomones are synthesized from arachadonic acid (20:4，二十碳 - 四烯酸 )

– Prostaglandins （前列腺素）• 20-carbon fatty acid containing 5-carbon ring

• Prostacyclins• Thromboxanes（血栓噁烷）

– Leukotrienes （白三烯）• contain three conjugated double bonds

Eicosanoid Hormones （花生四烯酸类激素）

Eicosanoid Hormones

Eicosanoid Hormones

Section 4

Metabolism of phospholipids（磷脂）

PhospholipidsPhospholipids• Structure

– Glycerol + 2 fatty acids + phosphate group

• Functions– Component of cell

membranes– Lipid transport as part of

lipoproteins• Food sources

– Egg yolks, liver, soybeans, peanuts

Phospholipids

• Phospholipids are intermediates in the biosynthesis of triacylglycerols

• The starting materials are glycerol 3-phosphate and the appropriate acyl coenzyme A molecules

Biosynthesis of glycerophospholipids1. DAG shunt is the major pathway for biosynthesis of phosphatidyl choline (lecithin) and phosphatidyl ethanolamine (cephalin)

HO-CH2-CH-COOH

NH2serine

CO2

HO-CH2-CH2-NH2ethanolamine

3(S-adenosylmethionine)HO-CH2-CH2-N(CH3)3

+

cholineATP

ADPkinase ATP

ADPkinase

P -O-CH2-CH2-NH2

phosphoethanolamine P -O-CH2-CH2-N(CH3)3

+

phosphocholineCTP

PPi

cytidyl transferase CTP

PPi

cytidyl transferase

CDP-O-CH2-CH2-NH2CDP-ethanolamine CDP -O-CH2-CH2-N(CH3)3

CDP-choline

phosphatidyl ethanolamine (PE) phosphatidyl choline (PC)

H2C

C

H2C

O C R1

O

HOC

O

R2

OH

DAG

CMP CMP

diacylglycerol transferase

CDP-DAG shunt

CMP

glucose

glycerol 3-phosphate2 acyl CoA

2 CoA

CTP

PPi

phosphatidyl serine

inositol

phosphatidyl inositol

phosphatidyl glycerol

diphosphatidyl glycerol (cardiolipin)

CMP

CMP

serine

Phosphatidic acid

2. CDP-DAG shunt is the major pathway for the synthesis of phosphatidyl serine, phosphatidyl inositol and cardiolipin - in this pathway, DAG is activated as the form of CDP-DAG

Cardiolipin (diphosphatidylglycerol)

C

O

O CHR2

CH2 O C

O

R1

CH2 O P

O

O-

O CH2

P

O

O-

O

CH2

CH

CH2

O C

O

R3

O C

O

R4

C

H2C

HO H

O

CDP-diacylglycerol

Degradation of glycerophospholipids

H2C

C

H2C

O C R1

O

HOC

O

R2

O P O

O

O

X_

H2O

H2O

H2O

H2O H2O

H2O

O P O

O

O

X_

_

H2C

C

H2C

O C R1

O

HOC

O

R2

OH

diglyceride

phospholipase C

XOH

H2C

C

H2C

O C R1

O

HOC

O

R2

O P OH

O

O_

phosphatidic acid

phospholipase D

glycerophospholipid

OHC

O

R1

phospholipase A1

H2C

C

H2C

OH

HOC

O

R2

O P O

O

O

X_

lysophospholipid 2

phospholipase B2OHC

O

R2

H2C

C

H2C

OH

HHO

O P O

O

O

X_

phospholipase A2

OHC

O

R2 H2C

C

H2C

O C R1

O

HHO

O P O

O

O

X_

lysophospholipid 1

OHC

O

R1

phospholipase B1

(glycerophophocholine)

Metabolism of sphingolipids

x = monosaccharide cerebrosidex = sulfated galactose ( = cerebroside sulfate) sulfatide

x = oligosaccharide globoside

x = oligosaccharide + sialic acid ganglioside

note: sialic acid = N-acetylneuraminic acid

Sphingolipids are a class of

lipids containing sphingosine

instead of glycerol

include: glycosphingolipids

phosphosphingolipids

脑苷脂

神经节苷脂

硫酸脑苷脂

红细胞糖苷脂

唾液酸 N-乙酰神经氨酸

The structure of phosphosphingolipids

The structure of glycosphosphingolipids

P

fatty acidR

鞘氨醇 phosphate cholinesphingosine

H3C ( CH2)1 2 C H C H C H C H C H2 O

O H N H

C O

O

O

O

C H2 CH2

N

(CH3)3+

sphingosine

fatty acid

H3C (CH2)1 2 C H C H C H C H C H2 O X

O H N H

C O

R

sugar

Section 5

Metabolism of cholesterol

Structure of Cholesterol

HOHO

CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

Fundamental framework of steroidsFundamental framework of steroids

Structure of CholesterolStructure of Cholesterol

A B

C D1

2

34 5

6

7

89

10

1112

13

14 15

16

1718

19

Cholesterol Biosynthesis 1. Formation of Mevalonate

2 CH3COSCoA CH3COCH2COSCoAThiolase

CH3COSCoA

Acetoacetyl CoA

HO2C-CH2-C-CH2COSCoA

OH

CH3

-Hydroxy-bata-methyl-glutaryl CoA (HMG CoA)

HMG CoASynthase

HO2C-CH2-C-CH2CH2OH

OH

CH3

3R-Mevalonic acid

甲羟戊酸

HMGCoAreductase

CoASH NADP + NADPH + H+

Key control step

Liver is primary site of cholesterol biosynthesis

Cholesterol Biosynthesis 2. processing of Squalene

-O2C-CH2-C-CH2CH2OH

OH

CH3

Mevalonate

-O2C-CH2-C-CH2CH2OPOP

CH3

OH

2 Steps

ATP

5-Pyrophospho(焦磷酸 )-mevalonate

CH2=C-CH2CH2OPOP

CH3

- CO2

- H2O

Isopentenyl(异戊烯 )pyrophosphate

CH3-C=CH2CH2OPOP

CH3

Dimethylallylpyrophosphate

Isomerase

Isoprenoid （异戊二烯）Condensation

H

OPOP

OPOP

Head

TailHead

Tail

IsopentenylPyrophosphate (IPP)

Dimethylallylpyrophosphate Head to tail

Condensation

OPOP

Geranyl ( 牛龙牛儿基 ) Pyrophosphate (GPP)

OPOP

Farnesyl（法尼基）Pyrophosphate (FPP)

Head to tailcondensationof IPP and GPP

Tail to tailcondensationof 2 FPPs

Squalene鲨烯

Head Tail

Head Tail

Isoprenes异戊二烯

3. Conversion of Squalene to Cholesterol

O

H +

CH3H3C

CH3

HO

CH3

CH3

CH3

HO

CH3

Squalene鲨烯

Squalenemonooxygenase

2,3-Oxidosqualene:lanosterol cyclase

Lanosterol羊毛固醇

20 Steps

Cholesterol

O2

Squalene-2,3-epoxide

Transformations of Cholesterol

Cholesterol is the biosynthetic precursor to a large number of important steroids:

Bile acidsVitamin D3CorticosteroidsSex hormones

Section 6

Lipoproteins metabolism

General Features of Lipoproteins Apolipoproteins: specific lipid-binding proteins that attach to the surface

intracellular recognition for exocytosis of the nascent particle after synthesis

activation of lipid-processing enzymes in the bloodstream, binding to cell surface receptors for endocytosis and clearance

Main lipid components: triacylglycerols, cholesterol esters, phospholipids. Major lipoproteins:

chylomicronsvery low density lipoproteins (VLDL)low density lipoproteins (LDL) high density lipoproteins (HDL)

Subfraction: intermediate density lipoproteins (IDL)

Electrophoretic mobility (charge):HDLs = lipoproteinsLDLs = -lipoproteinsVLDLs = pre- lipoproteins (intermediate between and mobility)

_

_origin ¦Ã ¦Â ¦Á2 ¦Á1 A

CM pre ¦Â ¦Á ¦Â

Plasma lipoproteins

Model of low density lipoprotein. Other lipoproteins have a similar structure differing in the core content of lipid and the type of apoproteins on the surface of the molecule

Functions of apolipoproteins

Protein (Enzyme)

Site of Action

Activator Function

LPL (Enzyme)capillary

wallsapo CII

excises FFA from TAGs in chylomicrons and VLDLs for adipose and muscle

CERPplasma

membrane

apo A1 (choles.Induced)

flips cholesterol (and lecithin) to outer layer of lipid bilayer for LCAT action in blood

Apo A1blood, plasma

membranenone

activates LCAT and CERP; binds to apo A1 receptors on cells requiring cholesterol

extraction

Apo B48 Gut none export of chylomicrons from intestinal cells

Apo B100 Various cells noneligand for LDL receptor; export of liver

VLDL

Apo CIIcapillary

wallsnone activates lipoprotein lipase

Apo E liver nonereceptor ligand - clears remnants, IDL, and

HDL

Lipoprotein classes

Total protein (%)

Total lipids (%)

Percent composition of lipid fractionsPL ChE Ch TAG

CM 1.5-2.5 97-99 7-9 3-5 1-3 84-98(B,C-III,II,I)

VLDL 5-10(B,C-III,II,I)

90-95 15-20 10-15 5-10 50-65

LDL 20-25(B)

75-80 15-20 35-40 7-10 7-10

HDL 40-45(A-I)

55 35 4 512

composition of lipoproteins

liver

ApoB48 aids with chylomicron assembly

Lymph system:Chylomicrons to capillaries via lymph

inte

stin

e non-hepatic tissuesnon-hepatic tissues

C E C EC EC E C E

C EC E C E

C E

Chylomicrons carry dietary fatty acids to tissues

Nascent chylo-microns acquire apo CII (C) and E (E) from HDL

chylomicron interacts with lipoprotein lipase removing FFA

Chylomicron (or VLDL)

Apo CII

Lipoprotein lipase

Polysaccharide Chain

EndothelialSurface of cell

Triacylglycerolin core

Free fatty acids

Glycerol

To Liver

Free fatty acidsIn cellulo (muscle & adipose)

Capillary

Lipoprotein lipase action on chylomicron triacylglycerol

(an identical reaction occurs with VLDL)

LIVER

ApoB48chylomicron remnants lose CII to HDL

non-hepatic tissuesnon-hepatic tissues

C E C E

E

E

E

EC

C

C

C EC E C E

C E

EE E

Liver: apo E receptor takes up remnants to deliver cholesterol

Exogenous pathway of lipid transportChylomicrons carry dietary fatty acids to tissues and the remnants take cholesterol to the liver

Lymph system:

C E C EC E

chylomicron acquires apo CII (C) and E (E) from HDL

chylomicron interacts with lipoprotein lipase removing FFA

B100 (B) helps assemble and export nascent VLDL

LIVER

nascent VLDL acquires apo CII (C) and apo E (E) from HDL

C EC E C E C EC E C EC E

C EC E

B B

B

BB

B BB

bile acids

HDL scavenge

cholesterol

C EC E

B BB

The liver-directed endogenous pathway of lipoprotein metabolism

non-hepatic tissuesnon-hepatic tissues

LPL hydrolyze TAGs; FFA uptake; LDL circulate to tissues

apo B100 on LDL bind to receptor

LDL taken into the cell to deliver cholesterol

CII and E release to HDL

Apo E binds liver receptor

Cholesterol uptake; excreted as bile acids

Nascent Chylomicron Assembly in Gut Mediated by B48

Nascent HDL Assembled in liver Loans apo E/ apo CII

to nascent chylomicrons

Mature Chylomicron Apo E and CII

added from HDL

Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle

Mature HDL CE from peripheral cells

activated by apo A1 Apo CII returned by

chylomicrons

Chylomicron Remnant from mature chylomicron apo CII returned to HDL

Chylomicrons: Exogenous Pathway

HDL: Both Pathways

apo CII

Triacylglycerol Cholesterol ester

Phospholipid

E

CII A1

E B48 CII

A1

E

CII

B48

apo E & CII from HDL

B48

adipose &muscleFFA

CII

CII

CII

CII

E

EE

E

CII

CII

Chylomicron Processing and Interface with HDL

Mature Chylomicron Apo E and CII

added from HDL CII activates LPL

B48

Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle

LDL from mature VLDL

A1

CII

B100

Nascent VLDL Assembly in Liver Mediated by B100

VLDL/LDL: Endogenous Pathway

HDL: Both Pathways

E

CIIA1

VLDL/LDL Processing and Interface with HDL

Mature VLDL Apo E and CII

added from HDLE

CII

B100

apo CII & E from HDL

EE

E

E

CII

CII

CII

adipose &muscle FFA

apo CII + EE

CII

EEE

CII

CII

Mature HDLApo CII/E returned by VLDL

B100

B100

Mature VLDL Apo E and CII

added from HDL CII activates LPL

E Receptor

Mature HDL

CE Metabolism Bile acids

Chylomicron Remnant

E Receptor

B100receptor

LDL

Clearance of Cholesterol by Liver from Chylomicron Remnants, HDL and LDL

E

B48

E

B48

E

B48

A1

EA1

E

A1

E

B100

B100

B100

Oxidized LDL

1. Uptake by "scavenger receptors" on

macrophages that invade artery walls;

become foam cells

2. Elicits CE deposition in artery walls

Consequence of Oxidized LDL Formation

Oxidation of LDL

LDL

Atherosclerosis动脉粥样硬化

free pool ofcholesterol

LDLCE

endocytosis

late endosome

ACEHCE cholesterol

Cholesterol Esterase

Cholesterol metabolism to bile acids or steroids

Golgi

Cholesterol release for transport to liver

MembraneCholesterol

ACAT (stimulated by cholesterol)

CE CE

CE stored in droplets

CERPL C A T

Apo A1 receptor

A1

CII

EA1

ECIICE in nascent HDL

Apo A1 binds to receptor, activates CERP to pump out cholesterol, and LCAT to esterify cholesterol

Mature HDL:Cleared by liver

LDL receptor sorting endosome:

ligand/receptor dissociationlysosome

Reverse CholesterolTransport

Lipoprotein classesLipo-

protein Source Apo ProteinsProtein:Lipid/

Major (minor) Lipid Transported

Function

Chylo-microns gut B48, CII*, E* 1:49triacylglycerol (CE)

Dietary:FFA Adipose/muscleCE Liver via remnants

VLDL liver B100, CII*, E* 1:9 triacylglycerol (CE)Synthesized:FFA adipose/muscleCE LDL

LDL blood B100 1:3 cholesterol ester CE to liver (70%) and peripheral cells (30%)

HDL liver A1, CII, E("ACE")

1:1 cholesterol estersupplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport

hypercholesterolemia

家族性高胆固醇血症表现

Guidelines for Appropriate Intake of Fat

☻ reduce fat in diet to <30%

☻ avoid saturated fat (animal fat)

☻ avoid margarine（奶油） , baked goods, fried food

☻ mono/polyunsaturated cooking oils are best (olive, corn)

☻ eat foods rich in -3 polyunsaturated fatty acids

(e.g, soybean ， salmon)

选择题练习脂代谢

1. 脂肪动员的限速酶是 ( )

A 激素敏感性脂肪酶 (HSL)

B 胰脂酶

C 脂蛋白脂肪酶

D 组织脂肪酶

E 辅脂酶

2. 下列不能促进脂肪动员的激素是 ( )

A 胰高血糖素

B 肾上腺素

C ACTH

D 促甲状腺素

E 胰岛素

3. 下列物质在体内彻底氧化后 , 每克释放能量最多的是 ( )

A 葡萄糖

B 糖原

C 脂肪

D 胆固醇

E 蛋白质

4. 脂肪酸氧化分解的限速酶是 ( )

A 脂酰 CoA 合成酶

B 肉碱脂酰转移酶 I

C 肉碱脂酰转移酶 II

D 脂酰 CoA 脱氢酶

E - 羟脱氢酶

5. 脂肪酰进行 - 氧化的酶促反应顺序为 ( )

A 脱氢 , 脱水 , 再脱氢 , 硫解

B 脱氢 , 加水 , 再脱氢 , 硫解

C 脱氢 , 再脱氢 , 加水 , 硫解

D 硫解 , 脱氢 , 加水 , 再脱氢

E 缩合 , 还原 , 脱水 , 再还原

6. 严重饥饿时 , 脑组织的能量主要来源于 ( )

A 糖的氧化

B 脂肪酸的氧化

C 氨基酸的氧化

D 乳酸氧化

E 酮体氧化

7. 通常生物膜中不存在的脂类是 ( )

A 脑磷脂

B 卵磷脂

C 胆固醇

D 甘油三酯

E 糖脂

8. 下列关于HMG-CoA还原酶的叙述哪项事错误的 ( )

A 此酶存在于细胞胞液中

B 是胆固醇合成过程中的限速酶

C 胰岛素可以诱导此酶合成

D 经磷酸化后活性可增强

E 胆固醇可反馈抑制其活性

9. 家族性高胆固醇血症纯合子的原发行代谢障碍是 ( )

A 缺乏载脂蛋白 B

B 由 VLDL 生成 LDL 增加

C 细胞膜 LDL 受体功能缺陷

D 肝脏 HMG-CoA 还原酶活性增加

E 脂酰胆固醇脂酰转移酶 (ACAT) 活性降低

10. 下列有关脂酸合成的叙述不正确的是 ( )

A 脂肪酸合成酶系存在于胞液中

B 脂肪酸分子中全部碳原子来源于丙二酰CoA

C 生物素是辅助因子

D 消耗 ATP

E 需要 NADPH 参与

11. The organ having the strongest ability of fatty acid synthesis is ( )

A fatty tissue

B lacteal gland

C liver

D kidney

E brain

12. Which one transports cholesterol from outer to inner of liver?

A CM

B VLDL

C LDL

D HDL

E IDL

13. Which one is essential fatty acid?

A palmitic acid

B stearic acid

C oleinic acid

D octadecadienoic acid

E eicosanoic acid

14. The main metabolic outlet of body cholesterol is ( )

A change into cholesterol ester

B change into vitamine D3

C change into bile acid

D change into steroid hormone

E change into dihydrocholesterol

15. 下列物质中与脂肪消化吸收有关的是 ( )

A 胰脂酶

B 脂蛋白脂肪酶

C 激素敏感性脂肪酶

D 辅脂酶

E 胆酸

16. 合成甘油磷脂共同需要的原料有 ( )

A 甘油

B 脂肪酸

C 胆碱

D 乙醇胺

E 磷酸盐

17. 参与血浆脂蛋白代谢的关键酶 ( )

A 激素敏感性脂肪酶 (HSL)

B 脂蛋白脂肪酶 (LPL)

C 肝脂肪酶 (HL)

D 卵磷脂胆固醇酰基转移酶(LCAT)

E 脂酰基胆固醇脂酰转移酶(ACAT)

18. 脂蛋白的结构是 ( )

A 脂蛋白呈球状颗粒

B 脂蛋白具有亲水表面和疏水核心

C 载脂蛋白位于表面

D CM VLDL 主要以甘油三酯为核心

E LDL HDL 主要以胆固醇酯为核心

19. Which can be the source of acetyl CoA?

A glucose

B fatty acid

C ketone body

D cholesterol

E citric acid

20. The matters which join in synthesis of cholesterol directly are ( )

A acetyl CoA

B malonyl CoA

C ATP

D NADH

E NADPH