VLDL and LDL trigtyceride simulation studies

IDL 1251 IDL 131¡

3.5.2. VLDL and LDL trigtyceride simulation studies

This

section describes results derived

from

simulation studies which

predict

plasma

VLDL, and LDL, triglyceride specific radioactivity

curves

following the

reinjection

of labelled VlDl-triglyceride. The

shape

of

^the

predicted specific radioactivity curves is model

dependent.

This

^section

examines

the

^predicted

triglyceride specific

radioactivity functions ^generated using the Zech

et al

(1979) model and the model developed

in

Section 3.4.4. ln addition, LDL-triglyceride simulation studies

are

^presented.

Simulated functions can

be

derived

by

assuming

that at time f a

labelled

precursor of VLDL triglyceride is

administered.

As this ^precursor

^is

incorporated

into VLDL

triglyceride

the

specific radioactivity

of

triglyceride

in the VLDL

fraction increases, and then decreases as

the

labelled ^{precursor is} depleted

and as a

function

of the

metabolism

and

hydrolysis

of ^VLDL.

^At

different times

throughout

the

course

of the rise ^and fall of the

^VLDL

triglyceride specific radioactivity function

it is

^possible

to

determine, using ^a

model, the

amount

of

radioactivity present

within with

each compartment.

Taking the radioactivity values of the different

compartments

at

^specific

times, such

as 1.5 hrs, it is

^possible

to

^produce

a

simulated function which would

be

^produced

if

labelled

VlDl-triglyceride

had been isolated

at a

specific

time and then reinjected into a donor subject. If

experiments

can

be

performed

which result in functions similar to ^those

^predicted

by

^the

simulation then

the

^model

is

validated.

The early

VLDL

triglyceride reinjection studies

of

^Farquhar

et al

⁽¹⁹⁶⁵⁾

showed

that the

decay curve

of

reinjected labelled

VLDL

triglyceride was slow

relative

to

the rise

of

^the

VLDL

curve after the injection

of

^{labelled glycerol or}

palmitate.

On the

^basis

of ^this

observation

they

assumed

that the

turnover of

the liver

triglyceride compartment was faster than

that of VLDL,

and that the

turnover

rate of the VLDL

triglyceride compartment was equal

to the fall

of

the

triglyceride curve

after a

bolus injection

of

labelled glycerol

or

^palmitate.

Based upon

this

information ttre Zech

et al

(1979) model was developed. Using

the Zech model (Figure

2) a fit

was obtained

to

the YLDL2 triglyceride specific

radioactivity data

of

^subject

K

(Figure 52). Included

in this figure

are three

other panels (1.5, 3.0 and 8.0 hrs) which describe the simulated decay curves of reinjected labelled

VLDL

triglyceride isolated

at

^1.5, 3.0 and 8.0 hours after the

injection of labelled glycerol. These times were

selected because they

corresponded

to the

pre-T6ax, Tmax and post-Tmax

VLDL2

triglyceride specific radioactivity values

of

subject

K.

Clearly

this

figure shows that, irrespective of when

the VLDL

triglyceride

was

collected

for

reinjection,

the

slope

of

^the

VLDL

decay curye was the same as the terminal slope

of

the

VLDL

triglyceride

specific radioactivity curve after ^injection of glycerol, reflecting

^the

turnover

rate of the

plasma

VLDL

triglyceride moiety. Using

the

new model

however

a fit

^{was obtained}

to the

same data (Figure

53)

and, simulated decay

curves were obtained

for

reinjected

VLDL

triglyceride collected

rf

1.5,

3.0

^and

8.0

^hours.

It is

clear

from this

figure that the triglyceride decay curve

of

^the

reinjected

VLDL

contains

a rapidly falling

component,

the

slope

of

^{which is}

equivalent

to the

function describing

the

turnover

rate of the N level

VLDL compartments.

In

the new model (Figure 51), unlike that

of

Zech

et al

^(1979), it

is

assumed

that the liver

triglyceride compaftment

is rate limiting

and that

within the VLDL

^pool there are particles which

turn

over rapidly.

In

subject K

the

turnover rates

of the liver

precursor,

N level

and

R level

compartments

were

0.1

10,

1.246

and

0.089 ¡-

I

respectively.

The terminal

slopes

of

^the

reinjected

VLDL

triglyceride curves were

the

same as that

of the

falling VLDL

curve after

glycerol.

The

slopes

of

these curves (k=0.089 ^h-

1)

_{describe the}

turnover rate of the R level

compartments

rather than the more

^rapidly

turning over liver

precursor.

In

addition,

it is

important

to

^{observe that}

although

the VLDL was

collected

before, during and after the

^maximum

triglyceride specific radioactivity

was

reached

all

reinjected

VLDL

triglceride decay curves displayed

a rapidly falling

component.

At the later

times the

proportion

of slowly

turning

over

particles increased

from

about lOTo

aÍ

^1.5

hours to

30%o

at 8 hours reflecting the

^movement

of label, and

^hence

conversion

of

particles,

from the

^{more rapidly}

N level to

slowly turning ^over

R level

compartments.

Clearly if VLDL were isolated after 10

hours and

reinjected

it would be difficult to

observe

a rapid

component

in the

^decay

curv ^e

Gtv ^1.5 hrs

A

a

E

I

_È

ît Ëd

rtê_c

ú

lÊ.E

at)Ë.

€0 Èo d ts

10

lo

3.0 hrs _8.0 hrs

0 _{10 {0} 50 30 ll

Hours Hours

Figure

52.

Fit of

^Zech

et al

(1979) (Figure

2)

^model

to

YLDL2 triglyceride spécific radioactivity data

of

subject

K ^(Gly).

^The other panels show simulated

VlOl

triglyceride ^decay curyes

of

reinjected

VLDL

isolated

at

^1.5, 3.0 and 8.0

hours after the injection of

labelled glycerol. Triglyceride decay curves of reinjected

VLDL

are

the

^{same as}

the

terminal slope

of the falling

^part

of

^the

VLDL

curve after glycerol.

Glv

3.0 hrs

l-.5 hrs

8.0 hrs

ú

EÈ

€ ',

Ëc rt6

ú

lÉ Io

<ttÀ

€o Èo I à¡

ts{

Hours Hours

Figure 53. Fit of ^{new model}

^(Figure

51) to VLDLZ

triglyceride specific radioactivity data

of

^subject

K (Gly).

The other panels show simulated VLDL triglyceride decay curves

of

reinjected

VLDL

isolated

at

1.5,

3.0

^{and 8.0 hours}

aftei the

injection

of

labelled glycerol. Triglyceride decay curves

of

^reinjected

VLDL show

^presence

of a rapidly turning over

component

in the

VLDL

fraction. The

turnover rate

of this ^fast

^component corresponds

to the

^rapid rise

of

the

VLDL

curve after ^glycerol.

Malmendier and ^Berman (1973) examined the kinetics

of ^LDL

apo

B

^and

triglyceride

simultaneously

in normal and hyperlipidemic

^subj

ects.

In addition

to

^showing

^{that the FCR} for

apo

B

and triglyceride

in LDL

^were different

they

observed, although

didn't

discuss,

a

complex decay function ^for reinjected

LDL

triglyceride.

Using the LDL

model

in Figure 52 a fit

^was

obtained

to

subject

K's LDL

triglyceride specific radioactivity data (Figure ^54).

G

E ÉÈ

€ u_c rto

úc

'EI oÀ

(t)

€0 .E oI d L Er

Glv

15.5 hrs

30

3.0 hrs

30.0 hrs

Hours Hours

Figure 54. Fit of new model (Figure 51) to LDL triglyceride

specific

radioactivity data

of

^subject

K ^(Gly). The

other panels show simulated LDL triglyceride decay curves

of

reinjected

LDL

isolated

at 3.0,

15.0 and 30.0 hours

after the

injection

of

^{labelled glycerol.}

Included

in this figure are

simulated curves describing

the

decay

of

^the

reinjected

LDL

triglyceride moiety ^isolated

at

3.0, 15.5 and 30.0 hours, following injection

of

^{tabelled glycerol.}

At

each time (3.0, 15.5 and 30.0 hours) the decay

curve was monoexponential and

its

slope was

the

same as

that of the

slowly

turning over

LDL R level

compartment (turnover rate

=

^{0.045 h-}

^1). In

subject

H

however

the

decay curve

of

reinjected

LDL

triglyceride was biexponential in shape

(Figure 55). This

biexponential shape \ryas

a result of the

^marked

differences

in

the tumover rates

of

the

N

^and

R

level

LDL

compartments ^(0.187 and 0.040

h-l

respectively). The slope

of the

reinjected

LDL

triglyceride curve

decreased between 3.0 and 30.0 hours as label moved from the

N

^level

^to

^more

slowly turning over

R level

compartments.

In

addition

to the

transfer

of

^label

from the N to R level

compartments,

label

was

lost from the LDL N

^level

compartments as

a

^result

of

hydrolysis

of

triglyceride. Curve peeling

of the

^3.0 hour

LDL

triglyceride decay curve function would result

in two

functions, the

faster of which

represents

the

summer

of the N level LDL

compartments.

Unlike

the

turnover rates

of the VLDL N

^level compartments,

the

turnover ^rate

of the LDL N level

compartments were similar

to

those

of the liver

precursor

compartment.

Gtv ^3.0 hrs

1(

3(

U E ÉÊ

€

Ë_ql

€_c ú

tÊ I

Ë"

U) ,éo E Ð

Er

10 15 20 2a 5

0

L5.5 hrs ^{30.0 hrs}

1C

10 15 20

IIours

2a 3( 5 10 15 20 23 3(

Ilours

Figure 55. Fit of new model (Figure 5l) to LDL triglyceride

^specific radioactivity data

of

subject

H ^(Gly). The

other panels show simulated LDL triglyceride decay curves

of

reinjected

LDL

isolated

at 3.0,

^{15.0 and 30.0 hours}

after the

injection

of

^{labelled glycerol.}