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

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, TGVariable lipids: - As storage and transport form of metabolic fuel - To keep the body temperature - Fats are solids; oils are liquids - To protect the visceras 2. LipoidBasic lipidsCholesterols, Phospholipids, Glycolipids et al - As structural components of biological membranes. - Cholesterol serves the precursor of bile salt and steroid hormones 3. Lipid ramification: to involve the different functions

Fatty Acids
Acids 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 Acids

Sources of omega-3 fatty Sources of omega-6 acid: soybean, fatty acids salmon Vegetable oils Eicosapentaenoic Nuts and seeds acid(EPA,fish oil): found in oils of shell fish, coldwater tuna, sardines, and sea mammals

Triglyceride
Triglyceridestriacylglycerols,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)

Glycerol + 3 FFA

TG + H2O

Section 2 Digestion 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() / jejunum by Pancreatic lipases Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepaticbile acid recycling Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cellGlycerol & 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 .Several apolipoproteins are required Re-esterification of 2-monoacylglycerol, lysolecithin, 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 TAG 2. Catabolism of TAG - Fatty acid bata oxidation
-Ketogenesis and Ketone Bodies

3. Lipogenesis: Fatty Acid Synthesis 4. Some poly-unsaturated FA ramification

The synthesis of TAG

1. Mono-acylglycerol pathway (MAG pathway)
(for dietary fat digestion and absorption)
CH 2OCOR CHOCOR CH 2OCOR TAG

pancreatic lipase

CH 2OCOR CHOCOR CH 2OH DAG

pancreatic lipase

CH 2OH CHOCOR CH 2OH MAG

FA

FA

intestinal lumen
FA
ATP,CoA

FA
acyl CoA
CH 2OH CHOCOR CH 2OH MAG

acyl CoA

CH 2OCOR CHOCOR CH 2OCOR TAG

intestinal epithelium

lymphatic vessels

Chylomicrons

adipose tissue

2. Diacylglycerol pathway (DAG pathway) (for TAG synthesis of in adipose tissue, liver and kidney)
CH 2OH liver adipose tissue CO
NADH+H +

NAD+ CH 2OH

liver kidney
ADP ATP

CH 2OH

glucose

CHOH CHOH phosphoglycerol glycerol kinase dehydrogenase CH 2O-PO 3H2 CH 2OH CH 2O-PO 3H2

dihydroxyacetone phosphate

3-phosphoglycerol

glycerol

RCO SCoA

acyl CoA transferase HSCoA

CH 2OCOR CHOCOR CH 2OCOR

HSCoA RCO SCoACH 2OCOR

CHOCOR

Pi

H2O

CH 2OCOR CHOCOR

HSCoA RCO SCoA

CH 2OCOR CHOH

triacylglycerol

CH 2OH phosphatase CH 2O-PO 3H2 acyl CoA transferase diacylglycerol phosphatidate

acyl CoA transferase

CH 2O-PO 3H2

lysophosphatidate

Catabolism of TAG

Mobilization of triacylglycerols
Mobilization of triacylglycerols:

in the adipose tissue, breaks down triacylglycerols to free fatty acids and glycerol (fatty acids are hydrolyzed initially from C1or C3 of the fat)

hormone sensitive lipase

cleave a fatty acid from a triglyceride, then other lipase complete the process of lipolysis, and fatty acid are released into the blood by serum albumin

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

Fatty acid bata oxidation

CAPILLARY
lipoproteins

LPL

FABP FA

MITOCHONDRION acetyl-CoA TCA cycle 7 -oxidation 6 acyl-CoA

2 FA FA albumin
FA 1 From fat cell cell membrane 3 4 acyl-CoA FABP

FA

FA
FABP

A C S
5

CYTOPLASM

carnitine transporter

FA = fatty acid LPL = lipoprotein lipase FABP = fatty acid binding protein ACS = acyl CoA synthetase

Overview of fatty acid degradation

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)

1. Activation of Fatty Acids

Acyl CoA synthetase reaction occurs on the mitochondrial membrane

2.Transport into Mitochondrial Matrix

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

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

3. Fatty acid Beta oxidation

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

2. Hydration to L3 Hydroxylacyl CoA

Adds water across the trans C=C bond Forms a hydroxyl group (OH) on the carbon

3. Oxidation to
3Ketoacyl CoA Oxidizes the hydroxyl group Forms a keto group on the carbon

4. Thiolysis to produce AcetylCoA

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

6 cycles

7 Acetyl CoA

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 Cycles Fatty Acid (C/2) (C/2 1) 12 6 5 14 7 6 16 8 7 18 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 7 Acetyl CoA 7 acetyl CoA x 12 ATP/acetyl CoA 6 Oxidation cycles 6 NADH x 3ATP/NADH 6 FADH2 x 2ATP/FADH2
Total -2 ATP 84 ATP 18 ATP 12 ATP 102 ATP

Oxidation of Special Cases (monounsaturated fatty acids)

Odd Carbon Fatty Acids

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

5 Cycles 5 CH3COSCoA + CH3CH2COSCoA

TCA Cycle
Mutase Propionyl CoA Carboxylase ATP/CO2

Propionyl CoA
CO2H

Epimerase

CO2 H H-C-CH3 COSCoA

HO 2CCH2CH2COSCoA

CH3-C-H
Vit. B12

Succinyl CoA

COSCoA L-Methylmalonyl CoA

D-Methylmalonyl CoA

Ketogenesis (Ketosis): formation of Ketone Bodies *****

Thiolase

2 CH3COSCoA

CH3COCH2COSCoA Acetoacetyl CoA

CH3COSCoA

HMG CoA Synthase

Cholesterol (in cytosol)

Several steps

OH

HO2C-CH2-C-CH2COSCoA

(in liver: mitochondrial matrix)

CH3

Ketogenesis

-Hydroxy- -methylglutaryl CoA (HMG CoA)

Ketogenesis: formation of Ketone Bodies

OH

HO2C-CH2-C-CH2COSCoA
CH3

HMG CoA lyase - CH3COSCoA

CH3COCH2CO2H Acetoacetic Acid

+

HMG CoA

NADH + H Dehydrogenase + NAD

- CO2

OH CH3CHCH2CO2H -Hydroxybutyrate

CH3COCH3 Acetone (volatile)

Ketone bodies are important sources of energy, especially in starvation

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

NAD+ -Hydroxybutyrate -Hydroxybutyrate dehydrogenase CoA Succinate 2 Acetyl CoA

NADH

Succinyl CoA synthetase = loss of GTP

Acetoacetate Succinyl CoA CoA transferase Citric Acid Cycle

Acetoacetyl CoA Thiolase

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

Overview Catabolism of TAG

glycerol
not in adipose tissue and muscle

glycolysis
acetyl CoA
TCA

TAG

FFAs

-oxidation
in liver

extrahepatic tissues

Ketone bodies

CO2 + H2O + energy

Lipogenesis: Fatty Acid Synthesis

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 malonylACP

reduction uses NADPH + H+ stops at C16 (palmitic acid )

Reactivity of Coenzyme A
Nucleophilic acyl substitution O O

HY

CH3CSCoA

CH3C

Y + HSCoA

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() O CH3CSCoA H2C OH CSCoA E+

Acetyl coenzyme A reacts with biological electrophiles at its carbon atom

E

O
CH2CSCoA

Formation of Malonyl Coenzyme A

Formation of malonylCoA is the committed step in fatty acid synthesis
O || CH3CSCoA + HCO3- + ATP Acetyl CoA O O || || -OCCH2CSACP + ADP + Pi Malonyl () CoA

Formation of Acetyl and Malonyl ACP

The intermediates(acetyl-ACP and malonyl-ACP) in fatty acid synthesis are covalently linked to the acyl carrier protein (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, AcetylCoA and MalonylCoA are each transferred to an acyl carrier protein O || CH3CSACP ( Acetyl-ACP) O O || || -OCCH2CSACP (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

Elongation and Unsaturation

Endoplasmic reticulum() systems introduce double bonds into long chain acylCoA's Reaction combines both NADH and the acyl CoA's to reduce O2 to H2O convert palmitoylCoA to other fatty acids Reactions occur on the cytosolic face of the endoplasmic reticulum. MalonylCoA 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 10carbon 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

Stoichiometry of FA synthesis
The stoichiometry of palmitate synthesis: Synythesis of palmitate from MalonylCoA

Synthesis of MalonylCoA from AcetylCoA

Overall synthesis

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

Citrate Shuttle
AcetylCoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol
AcetylCoA units are shuttled out of the mitochondrial matrix as citrate:

Regulation of Fatty Acid Synthesis

Regulation of Acetyl carboxylase
Global
+ insulin - glucagon - epinephrine

Local
+Citrate - PalmitoylCoA - AMP

Eicosanoid Hormones
Eicosanoid horomones are synthesized from arachadonic acid (20:4-)
Prostaglandins
20-carbon fatty acid containing 5-carbon ring Prostacyclins Thromboxanes

Leukotrienes
contain three conjugated double bonds

Eicosanoid Hormones

Eicosanoid Hormones

Section 4
Metabolism of phospholipids

Phospholipids
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 3phosphate and the appropriate acyl coenzyme A molecules

Biosynthesis of glycerophospholipids
HO-CH2-CH-COOH NH2 serine CO2

1. DAG shunt is the major pathway for biosynthesis of phosphatidyl choline (lecithin) and phosphatidyl ethanolamine (cephalin)
+ HO-CH2-CH2-N(CH3)3 ATP choline
kinase ADP
+ -O-CH -CH P 2 2-N(CH3)3 phosphocholine CTP DAG O cytidyl transferase H 2C O C R 1 PPi O C O C H CDP -O-CH 2-CH 2-N(CH 3)3 CDP-choline H C OH
2

HO-CH2-CH2-NH2 ethanolamine ATP kinase ADP

3(S-adenosylmethionine)

P -O-CH2-CH2-NH2 phosphoethanolamine CTP cytidyl transferase PPi

CDP-O-CH2-CH2-NH2 CDP-ethanolamine

R2

diacylglycerol transferase
CMP

phosphatidyl ethanolamine (PE)

CMP

phosphatidyl choline (PC)

glucose

CDP-DAG shunt
glycerol 3-phosphate

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
CMP

2 acyl CoA

2 CoA

Phosphatidic acid
CTP

PPi

serine

CDP-diacylglycerol
phosphatidyl glycerol

inositol
CMP CMP

phosphatidyl serine
O O R2 CH 2 O O CH CH 2 O C R1 H2C O P OHO C O CH 2 O H

diphosphatidyl glycerol (cardiolipin) phosphatidyl inositol

O P O
-

CH 2 CH O

O C O R3 R4

CH 2

Cardiolipin (diphosphatidylglycerol)

Degradation of glycerophospholipids
R2 O C O C H O H2C O C R1

H2C OH

O O P O

R2

O C O C H

O H2C O C O H2C O P O

R1

diglyceride
phospholipase C

XOH

OH

H2O
O H2C O C O H2C O P O

phosphatidic acid
H2O
R1

phospholipase D

R2

O C O C H

glycerophospholipid
O X

phospholipase A1
O C O C H H2C OH O H2C O P O

H2O

phospholipase A2
H2O
R2 O C OH
O H2C O C HO C H O H2C O P O R1

R2

R1
O X

O C OH

lysophospholipid 1
O X

lysophospholipid 2

H2O
R2

phospholipase B2

O O C OH R1 C OH

H2O

H2C OH HO C H O H2C O P O

phospholipase B1

(glycerophophocholine)

Metabolism of sphingolipids
O H3 C ( C H2)1 2 C H CH CH OH CH C H2 O P O O R O C H2 C H2

sphingosine

NH
C

p h o s p h a te

c holi ne

fa tt y a c id

The structure of phosphosphingolipids

H3C

(C H 2)1 2 C H

CH

CH OH

CH NH C R

C H2

x = monosaccharide cerebroside
x = oligosaccharide

sphingosine

sugar
O

x = sulfated galactose ( = cerebroside sulfate) sulfatide

fatty acid

globoside x = oligosaccharide + sialic acid ganglioside

N-

The structure of glycosphosphingolipids

note: sialic acid = N-acetylneuraminic acid

( C H3)3

Sphingolipids are a class of lipids containing sphingosine instead of glycerol include: glycosphingolipids phosphosphingolipids

Section 5
Metabolism of cholesterol

Structure of Cholesterol
12 18 17 D 15 16 Fundamental framework of steroids

11 19
1 2 10 5

C 13 9 B8 14

A
3 4

7
6

CH3 CH3 CH3 H H CH3

CH3

H Structure of Cholesterol

HO

Cholesterol Biosynthesis
1. Formation of Mevalonate
Liver is primary site of cholesterol biosynthesis
Thiolase

2 CH3COSCoA

CH3COCH2COSCoA Acetoacetyl CoA

CH3COSCoA HMG CoA Synthase

OH

HMGCoA reductase
CoASH

OH

HO2C-CH2-C-CH2CH2OH
CH3

HO2C-CH2-C-CH2COSCoA
CH3

NADP + NADPH +H +

3R-Mevalonic acid

Key control step

-Hydroxy-bata-methylglutaryl CoA (HMG CoA)

Cholesterol Biosynthesis
2. processing of Squalene
OH
-O C-CH -C-CH CH OH 2 2 2 2

OH 2 Steps ATP
-O C-CH -C-CH CH OPOP 2 2 2 2

CH3 Mevalonate

CH3 5-Pyrophospho()mevalonate

- CO2 - H2 O
CH3 Isomerase CH3-C=CH2CH2OPOP Dimethylallyl pyrophosphate CH2=C-CH2CH2OPOP Isopentenyl() CH3 pyrophosphate

IsoprenoidCondensation
Dimethylallyl pyrophosphate

Tail
OPOP OPOP

Head to tail Condensation

H

Head

Tail

Head Head

Tail
Isopentenyl Pyrophosphate (IPP)

OPOP

Geranyl () Pyrophosphate (GPP)

Head to tail condensation of IPP and GPP

Isoprenes
Tail to tail condensation of 2 FPPs

Squalene

OPOP
Head

Farnesyl Pyrophosphate (FPP)

Tail

3. Conversion of Squalene to Cholesterol

Squalene monooxygenase O2 Squalene
O H
+

Squalene2,3-epoxide

2,3-Oxidosqualene: lanosterol cyclase

CH3

CH3 CH3

20 Steps
HO H3 C

CH3

CH3

HO

CH3

Lanosterol

Cholesterol

Transformations of Cholesterol
Cholesterol is the biosynthetic precursor to a large number of important steroids: Bile acids Vitamin D3 Corticosteroids Sex 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: chylomicrons very low density lipoproteins (VLDL) low density lipoproteins (LDL) high density lipoproteins (HDL)

_
_
origin

1 A

Subfraction: intermediate density lipoproteins (IDL)

CM

pre

Electrophoretic mobility (charge): Plasma lipoproteins HDLs = lipoproteins LDLs = - lipoproteins VLDLs = pre- lipoproteins (intermediate between and mobility)

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) LPL (Enzyme) Site of Action Activator Function

capillary walls
plasma membrane

apo CII apo A1 (choles. Induced) none none none none none

excises FFA from TAGs in chylomicrons and VLDLs for adipose and muscle
flips cholesterol (and lecithin) to outer layer of lipid bilayer for LCAT action in blood

CERP

Apo A1 Apo B48 Apo B100 Apo CII Apo E

blood, plasma membrane

Gut Various cells capillary walls liver

activates LCAT and CERP; binds to apo A1 receptors on cells requiring cholesterol extraction
export of chylomicrons from intestinal cells ligand for LDL receptor; export of liver VLDL activates lipoprotein lipase receptor ligand - clears remnants, IDL, and HDL

composition of lipoproteins
Lipoprotein Total protein Total lipids (%) classes (%)

Percent composition of lipid fractions

PL ChE Ch TAG

CM
VLDL

1.5-2.5
(B,C-III,II,I)

97-99

7-9

3-5

1-3
5-10
7-10

84-98 50-65
7-10

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

90-95

15-20 10-15

LDL
HDL

20-25
(B)

75-80

15-20 35-40

40-45
(A-I)

55

35

12

intestine

Lymph system: Chylomicrons to capillaries via lymph

Nascent chylomicrons acquire apo CII (C) and E (E) from HDL
CE CE CECE CE

chylomicron interacts with lipoprotein lipase removing FFA non-hepatic tissues

CECE

CE CE

ApoB48 aids with chylomicron assembly

Chylomicrons carry dietary fatty acids to tissues

liver

Triacylglycerol in core To Liver Glycerol Free fatty acids

Chylomicron (or VLDL) Apo CII

Lipoprotein lipase
Polysaccharide Chain Endothelial Surface of cell

Capillary In cellulo (muscle & adipose) Free fatty acids

Lipoprotein lipase action on chylomicron triacylglycerol (an identical reaction occurs with VLDL)

Lymph system:

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

CE CE CECE CE

chylomicron interacts with lipoprotein lipase removing FFA

non-hepatic tissues
CECE CE CE C E E C E

ApoB48

chylomicron remnants lose CII to HDL Liver: apo E receptor takes up remnants to deliver cholesterol

E C EE E

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

B100 (B) helps assemble and export nascent VLDL

LIVER

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

LPL hydrolyze TAGs; FFA uptake; LDL circulate to tissues non-hepatic tissues

CE

CE

CE CE

CE

CE

CE CECE

B B CE CE B B B B BB B BB

bile acids Cholesterol uptake; excreted as bile acids Apo E binds liver receptor

CII and E release to HDL apo B100 on LDL bind to receptor LDL taken into the cell to deliver cholesterol

HDL scavenge cholesterol

The liver-directed endogenous pathway of lipoprotein metabolism

Chylomicrons: Exogenous Pathway

B48

Chylomicron Processing and Interface with HDL HDL: Both Pathways E E

CII A1

Nascent Chylomicron Assembly in Gut Mediated by B48

E E B48 apo E & CII

from HDL
CII

Nascent HDL Assembled in liver Loans apo E/ apo CII to nascent chylomicrons

CII

Mature Chylomicron Apo E and CII added from HDL E CII activates LPL
CII

E
B48
CII

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

CII

Chylomicron Remnant from mature chylomicron apo CII returned to HDL

FFA apo CII

CII

adipose & muscle

A1

B48

CII

CII

Mature HDL CE from peripheral cells activated by apo A1 Apo CII returned by chylomicrons Cholesterol ester

Triacylglycerol

Phospholipid

VLDL/LDL Processing and Interface with HDL HDL: Both Pathways E E

A1 CII B100

VLDL/LDL: Endogenous Pathway

Nascent VLDL Assembly in Liver Mediated by B100

apo CII & E from HDL

B100

Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle adipose & muscle Mature HDL Apo CII/E returned by VLDL
A1

E
CII CII

B100

Mature VLDL Apo E and CII added from HDL CII activates LPL

FFA apo CII + E CII E E E CII

LDL from mature VLDL
B100

CII

Clearance of Cholesterol by Liver from Chylomicron Remnants, HDL and LDL Chylomicron Remnant Mature HDL LDL
B100

B100

B100

E Receptor

E Receptor

B100 receptor

CE Metabolism

Bile acids

Consequence of Oxidized LDL Formation

LDL

Oxidation of LDL

Oxidized LDL 1. Uptake by "scavenger receptors" on macrophages that invade artery walls; become foam cells 2. Elicits CE deposition in artery walls Atherosclerosis

LDL receptor

sorting endosome: ligand/receptor dissociation late endosome

lysosome

Golgi free pool of cholesterol

ACEH CE cholesterol
endocytosis

ACAT (stimulated by cholesterol) CE stored in Cholesterol droplets CE CE Esterase

Cholesterol release for transport to liver LDL CE Membrane Cholesterol CERP

Cholesterol metabolism to bile acids or steroids

L C A T

Apo A1 receptor A1
CII

Reverse CholesterolTransport

A1

E
CII

CE in nascent HDL

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

Mature HDL: Cleared by liver

Lipoprotein classes
Lipoprotein Chylomicrons
Source

Apo Proteins

Protein:Lipid/ Major (minor) Lipid Transported 1:49triacylglycerol (CE)

Function Dietary: FFA Adipose/muscle CE Liver via remnants Synthesized: FFA adipose/muscle CE LDL CE to liver (70%) and peripheral cells (30%) supplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport

gut

B48, CII*, E*

VLDL LDL

liver

B100, CII*, E*

1:9 triacylglycerol (CE) 1:3 cholesterol ester

blood B100

HDL

liver

A1, CII, E("ACE")

1:1 cholesterol ester

hypercholesterolemia

Guidelines for Appropriate Intake of Fat

reduce fat in diet to <30% avoid saturated fat (animal fat)
avoid margarine, baked goods, fried food mono/polyunsaturated cooking oils are best (olive, corn) eat foods rich in -3 polyunsaturated fatty acids
(e.g, soybeansalmon)

1. (

A (HSL) B C D E

2.

( A B C ACTH D E

3. , ( ) A

B
C D E

4. ( A CoA B I C II D CoA E -

5. -( A ,,, B ,,, C ,,, D ,,, E ,,,

6. ,(

A
B C D E

7. ( A

B
C D

8. HMG-CoA( A

B
C D

9. ( A B

B VLDLLDL
C LDL D HMG-CoA

E (ACAT)

10. (

A
B CoA C D ATP E NADPH

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. ( A B

C
D E

16. ( A B C D

17. ( A (HSL)

B (LPL)
C (HL) D (LCAT)

E (ACAT)

18. ( A

B
C D CM VLDL

E LDL HDL

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