lipidi metabolizam

V. Metabolizam LipidaA. Probava, apsorbcija i raspodjela B. Mobilizacija uskladištenih triacilglicerola

C. Metabolizam masnih kiselina

1. Oksidacijaa. Energetika

b. Keto-tijela

2. Biosinteza




b. Keto-tijela

2. Biosinteza

Emulgiranje

Hidroliza

TG

Re-esterifikacijaMukoza

crijeva

Hilomikroni

Emulgator

Lipoprotein lipaza




b. Keto-tijela

2. Biosinteza

Lipaza adipoznog tkiva (ATL)

G protein regulira porast cAMP




b. Keto-tijela

2. Biosinteza




b. Keto-tijela

2. Biosinteza

R

O

OH

CoASH ATP

AMP + PPi

R

O

S CoA

R

O

S CoA

Inner Mitochondrial Membrane Carnitine Transporter

Cytosol Side

Matrix Side

Fatty Acid

Fatty Acyl CoA

Fatty Acyl CoA

FAD

FADH2

ETS2 ATP

R

O

S CoAalpha-beta unsat.Fatty Acyl CoA

H2O

R

O

S CoA

OH

R

O

S CoA

NAD

NADH + HETS

3 ATP

O

CoA-SH

R

O

S CoA H3C

O

S CoA

Beta-hydroxy-Fatty Acyl CoA

(trans)

Beta-keto-Fatty Acyl CoA

Thiolase

Kreb'sCycle

+

Fatty Acyl CoA Acetyl CoA

Aktivacija i unos u mitohondrije

acil CoA sintetaza2 Pi

R

O

S CoA

Inner Mitochondrial Membrane Carnitine Transporter

Matrix Side

Fatty Acyl CoA

FAD

FADH2

ETS2 ATP

R

O

S CoAalpha-beta unsat.Fatty Acyl CoA

H2O

R

O

S CoA

OH

R

O

S CoA

NAD

NADH + HETS

3 ATP

O

CoA-SH

R

O

S CoA H3C

O

S CoA

Beta-hydroxy-Fatty Acyl CoA

(trans)

Beta-keto-Fatty Acyl CoA

Thiolase

Kreb'sCycle

+

Fatty Acyl CoA Acetyl CoA

oksidacija

Hidratacija

oksidacija

Tiolitičko cjepanje

1

2

3

4

H van

H2O ulazi

H van

Cjepanje




b. Keto-tijela

2. Biosinteza

Energetika oksidacije

H3C S

O

CoA

acetyl CoA

FADH2

NADH

H3C OH

O

ETS

ETS

___ ATP

___ ATP

TCA

ETS____ ATP

_____ ATP per cycle

- 2 ATP for activation

23

12

17

17171712




b. Keto-tijela

2. Biosinteza

Problemi koji vode stvaranju keto-tijela fatty acids

To the blood

glucose

acetyl CoA

TCACycle

OAA

Kod dijabetesa i gladovanja, u jetri se odvija glukoneogeneza

Izvor energije za jetru

Keto-tijela

H3C SCoA H3C C

H2

O

H3C SCoA

OO

S

O

CoA

acetoacetyl CoA

H3C SCoA

O

OOC

CH2

CH2

S

OOH

CH3

CoASH

CoA

hydroxy-methyl-glutaryl CoA (HMG CoA)

H3C SCoA

O

OOC

CH2

C

CH3

O

acetoacetate

CO2

H3C

C

CH3

O

acetone

OOC

CH2

CH

CH3

OHNADH NAD+

-hydroxybutyrate

cholesterol

CoASH

+Thiolase

KETONE BODIES

2. Biosinteza masnih kiselina

a. Nastajanje Malonil-CoA

b. Sintaza masnih kiselina

c. Reakcije

d. Nezasićene masne kiseline

e. Eikozanoidi

D. Biosinteza triacilglicerola i fosfolipida

Piruvat karboksilaza

Piruvat dehidrogenaza

Kada je potreba za energijom zadovoljena, citrat se usmjerava u citoplazmu

Inducira Inzulin

H3C C

O

H3C CH2 CH2 C

O

H3C CH2 CH2 CH2 CH2 C

O

malonyl CoA malonyl CoA

acetyl CoA acetyl CoA

Dodavanje acetila na karboksi kraj

2. Biosinteza



c. Reakcije


e. Eikozanoidi


Nastajanje Malonil CoA

H3C SCoA

OCO2

Biotin

ATP

acetyl CoAcarboxylase ADP + Pi

CH2

SCoA

O

OOC

acetyl CoA malonyl CoA

Slično karboksilaciji piruvata u glukoneogenezi

2. Biosinteza



c. Reakcije


e. Eikozanoidi


Dimer

12

Svaka podjedinica ima 7 katalitičkih domena

Svaka podjedinica ima 2

SH-skupine

Cisteinski ostaci

Pantotein

2. Biosinteza



c. Reakcije


e. Eikozanoidi


1 Dodatak malonila na SH pantoteina iz ACP-a

2 Kondenzacija malonila s acilom na cys-SH

3 Redukcija keto u hidroksi skupinu

4 Dehidratacija stvara dvostruku vezu

5 Redukcija dvostruke veze

Pomak na cys-SH skupinu

CoASHCoASH

SC

O

H3C

SC

OCH3

SC

OCH3

SC

O

H3C

SC

OC

O

-O

SC

O

C

O

O-

SC

OCH3

SC

O

H3C

SC

H2C O

SC

OCH2

CO2

CO2

SC

O

C

O

CH3

SC

OC

O

H3C

SC

OCH

HO

H3C

SC

O

CHCH3

OH

SC

OH3C

SC

O CH3

H2O

H2O

SC

OH3C

SC

O CH3

SC

O CH3

SC

OH3C

Sljedeći malonil

2. Biosinteza



c. Reakcije


e. Eikozanoidi


Sinteza nezasićenih masnih kiselina

SATURATED FATTY ACIDS

palmitic acid (16:0) palmitoleic acid (16:19)DS

UNSATURATED FATTY ACIDS

stearic acid (18:0)DS

oleic acid (18:19)

DS

?18:26,

9

2. Biosinteza



c. Reakcije


e. Eikozanoidi


Diet

Linoleic acid18:29,12

Desaturase

18:39,12

Add 2 carbons

COOH

CH3

CH3

PG1 SeriesTX1 SeriesLT3 SeriesDesaturase

COOH

eicosatrienoic acid

20:3

eicosatetraenoic acid20:4

PG2 SeriesTX2 SeriesLT4 Series

Diet

Linolenic acid18:39,12,15

Desaturase

18:49,12,15

Add 2 carbons

COOH

Desaturase

eicosatetraenoic acid

20:4

CH3

eicosapentaenoic acid

20:5

CH3

COOH

PG3 SeriesTX3 SeriesLT5 Series

8

1114

5

Dietary Essential Fatty Acids (linoleic acid)

Arachidonic Acid

CH2

CH

CH

O

O

O P O Choline

C

O

R1

arachidonic acid

phospholipase A2 Glucocorticosteroids

COOH

CH3

Arachidonic Acid

Membrane Phosphoacylglycerol

Prostaglandins Thromboxanes Leukotrienes

Inhibicija glukokortikosteroidima

COOH

CH3

Arachidonic Acid

O

O

O2

NSAIDS

O2

2. Biosinteza



c. Reakcije


e. Eikozanoidi


Izvor Glicerol-3-fosfata

LiverLiver and Adipose Tissues

Glycerol-3-PGlycerol DHAP Glucose

ATP ADP NAD+ NADH + H+

glycerol kinaseFA1CoA

FA2CoA

CoASH

CoASH

O C

O

R1

OC

O

R2

O P2-

Phosphatidic acid

1

2

O C

O

R1

OC

O

R2

O P2-

Phosphatidic acid

O C

O

R1

OC

O

R2

O

PPi CTP

PO

PO

cytidine

O C

O

R1

OC

O

R2

O PO

head group

HO head group

CMP

H2O

Pi

O C

O

R1

OC

O

R2

OH

Diacylglycerol

head groupHO

O P O P O

CTP

Pi

head group cytidine

O C

O

R1

OC

O

R2

O PO

head group

FA3CoA

CoASH

O C

O

R1

OC

O

R2

O C

O

R3

Triacylglycerol

Store in Adipose Tissue

Liver

Transport in the Blood

CMP

2. Biosinteza



c. Reakcije


e. Eikozanoidi


E. REGULACIJA

Glucose

Glucose

G-6-P

F-1,6-BP

glyceraldehyde-3-P DHAP

pyruvate

pyruvate

OAA acetyl CoA

citrate citrate

OAA

acetyl CoA

malate

NADPH NADP+

PPP

NADP+

NADPH

malonyl CoA

ACC

Fatty acidsynthase

Fatty acyl CoA

Fatty Acids

Glycerol-3-P

TG

LIVER OR ADIPOSE CELL

malic enzyme

* Inducira inzulin

*

**

*

*

*

*

Pi

Stimulira inzulin

F. Kolesterol 1. Biosinteza2. Regulacija3. Uloga

a. Steroidni hormonib. Žučne soli

G. Transport Lipida 1. Podjela lipoproteina2. Specifična uloga transporta3. Metabolizam lipoproteina4. Hiperlipoproteinemije




H3C SCoA H3C C

H2

O

H3C SCoA

OO

S

O

CoA

acetyacetyl CoA

H3C SCoA

O

OOC

CH2

CH2

S

OOH

CH3

CoASH

CoA

CoASH

+Thiolase

OOC

CH2

CH2

CH2

OH

CH3

OH NADPH

NADP+

NADPH

NADP+

HMG CoA HMG CoA Reductase

mevalonic acid

CoASH

Keto-tijela

HH

OOC

CH2

CH2

CH2

OH

CH3

OH

mevalonic acid

OOC

CH2

CH2

CH2

O

CH3

O

3 ATP

3 ADP

P

P O PPi

H2C CH2

CH2 O P O P

CH3CO2

H3C CH

CH2 O P O P

CH3

H2C CH2

CH2 O P O P

CH3

+

isopentenyl pyrophosphate

dimethylallyl pyrophosphate isopentenyl pyrophosphate

Isomerization

Reakcije polimerizacije

H3C CH

CH2 O P O P

CH3

H2C CH2

CH2 O P O P

CH3

+

dimethylallyl pyrophosphate isopentenyl pyrophosphate

PPi

O P O P

Geranyl pyrophosphate

Monoterpenes

a

b

c

2 Pi

(C10)

O P O P

Geranyl pyrophosphate

PPi

isopentenyl pyrophosphate

O P O P

Sesquiterpenes

Diterpenes (C20)

(C15)

IPP

PPi

Farnesyl pyrophosphate

Dodatak IPP

(C15)

Kondenzacija u skvalen

O P O P

Farnesyl pyrophosphate

2 PPi

NADPH

NADP+

Squalene (C30)

*

**

Ciklizacija i pretvorba lanosterola u kolesterol

HO HO

Squalene

CholesterolLanosterol

1)

3)

2)

(C30)

A B

C D

O2

NADPHNADP+O

H2O

Izlaze 3 metilne grupePomak = veze

Redukcija = u pobočnom lancu




H3C SCoA H3C C

H2

O

H3C SCoA

OO

S

O

CoA

acetyacetyl CoA

H3C SCoA

O

OOC

CH2

CH2

S

OOH

CH3

CoASH

CoA

CoASH

+Thiolase

OOC

CH2

CH2

CH2

OH

CH3

OH NADPH

NADP+

NADPH

NADP+

HMG CoA HMG CoA Reductase

mevalonic acid

CoASH

HH

Inducira inzulin

Aktivnost je regulirana fosforilacijomdefosforilacijom

Glucagon fosforilacijom gubi na aktivnosti

Insulin stimulira fosfataze koje povisuju aktivnost

Kolesterol inhibira aktivnost

Aktivnost inhibiraju i statini (lovastatin, pravastatin, itd.)




Kolesterol

Vitamin DUV

Steroidni hormoniglukokortikosteroidi

spolni hormoni

Žučne soli




Hipofiza




Metabolizam žučnih soli

Vlakna iz prehrane

Lijekovi: smole ionski izmjenjivači (kolestiramin)

Kolesterol u krvi

Sinteza kolne kiseline

OHHO HO

OHHOOHHO

OH

COOH

OHHO

COOH

OHHO

OH

O2 H2O

XH2 X

Reduction of DBEpimerization of OH at C3 to

Hydroxylation

7

7

12

7

3

33

Removal of 3 carbons from sidechain and oxidation to COOH

12

73 73

Cholic acid Chenodeoxycholic acid

CholesterolHydroxylation

COOH

OHHO

COOH

OHHO

C

OHHO

OH

OH

H2N COOH

12

73

C

OHHO

OH

12

73

CH3

CH3 C

OHHO73

C

OHHO73

12

73 73

Cholic acid Chenodeoxycholic acid

H2NSO3H

glycinetaurine

O

HN COOH

O

O

O

HN

HN COOH

SO3H HN SO3H

Glycocholic acid

Taurocholic acid

Glycochenodeoxycholic acid

Taurochenodeoxycholic acid

H2N COOH

glycine

H2NSO3H

taurine







Lipoproteini

TG

Sastav lipoproteina

CLASS DENSITY PERCENTPROTEIN

PERCENT LIPID

TG PL CHOL &ESTERS

FFA

Chylomicrons < 0.96 2 98 85 8 3 0

VLDL 0.96-1.006 9 91 55 20 17 1

IDL 1.006-1.019 11 89 26 23 38 1

LDL 1.019-1.063 20 80 10 20 45 1

HDL 1.063-1.210 45 55 8 25 20 0

Albumin-FFA > 1.280 99 1 0 0 0 100

PERCENT OF TOTAL WEIGHT







Lipoprotein lipase

HDL nosi apoproteine

HDL nosi apoproteine

Apo CII aktivira LPL

Endocitoza putem receptora

Endocitoza putem receptora

TG se uklanjaju u jetri

Unos LDL-a u stanice na periferiji

Metabolizam HDL-a

HDL

ApoCII

ApoE

Nascent chylomicron

Chylomicron

Nascent VLDL

VLDL

HDL

HDLC

ExtrahepaticTissues

C

LIVER

To LDL

C

Cchylomicronand VLDL remnants




Hiperlipoproteinemije

TYPE ELEVATEDLIPOPROTEIN(S)

MAJOR LIPID(S) ELEVATED

RELATIVE INCIDENCE

I chylomicrons triglycerides rare

IIa LDL cholesterol common

IIb LDL & VLDL chol & TG common

III IDL chol & TG uncommon

IV VLDL triglycerides common

V chylomicrons & VLDL triglycerides uncommon

LDL i Ateroskleroza

Documents

lipidi metabolizam