Trigtyceride kinetics

INTRODUCTION

L.7.3. Intermediate density lipoproteins

1.8. Kinetic studies of apolipoprotein B-containing lipoproteins Studies carried out during the last thirty years have demonstrated that

1.8.4. VLDL-IDL kinetics

1.8.4.1. Trigtyceride kinetics

Many VLDL triglyceride kinetic

studies

have

been undertaken using

labelled precursors

of

triglyceride, such

as glycerol or

^palmitate

which

^are incorporated endogenously

into the

triglyceride

moiety. In

^1972,

Barter

and

Nestel demonstrated

a

precursor-product relationship between

VLDL

and LDL triglyceride

and also

^proposed

the

heterogeneous nature

of

^particles

with

ⁱⁿ

the

VLDL

fraction. Earlier studies had described the

VLDL

triglyceride pool as ^a single compartment (Baker and Schotz, 1964; Farquhar

et zl,

^{1965; Eaton}

et

^î1,

1969; Quarfordt

et

â1, 1970) and

it

was

not until

tracer data

of VLDL

apo B

became available (Phair

et al,

^{1975) that the need}

for a

delipidation pathway, a

chain of

compartments

along which there was

progressive

hydrolysis

of triglyceride, became obvious.

This

pathway was incorporated

into the

VLDL- triglyceride model

of

^Zech

et al

(1979) (Figure

1). A

major criticism

of

this

model

is that the

turnover rates

of the four

compartments

in the

delipidation pathway,

like

^those

in the

apo

B

model, are constrained

to be

equal, and in addition,

the

proportion

of

triglyceride hydrolysed

from

each compartment is

the

same

for all

compartments.

VLDL triglyceride

cascade ^{Ð to IDL}

Glycerol sub-system

U(GIy) Glycerol conversion

Figure 1.

Modified version

of

the Zech

et al

⁽¹⁹⁷⁹⁾

VLDL

triglyceride ^model.

This model

incorporates

a glycerol

subsystem (compartments

4 and 5),

^a

glycerol

conversion system (Compartments

10-14 and 24), and the

VLDL triglyceride system.

The

apo

B

^model

of

^Berman

et al

(1978) had highlighted

the

need

for a

delipidation cascade which was subsequently incorporated ^into

this

model (Compartments 1,6,7, and

8).

The pathways

from the

compartments

in the

^cascade

to

compartment

4

^represent the transfer

of

^glycerol

from

VLDL

to the

^plasma

^glycerol pool, a

^process

which occurs during

triglyceride

hydrolysis.

Compartments

10-14 inclusive represent the delay in

^the

appearance

of VLDL

triglyceride often observed after glycerol

is

injected.

Such

constraints

imply that triglyceride

hydrolysis ^proceeds

at a

constant

rate.

Studies using rabbits

as a

model have however shown

that the

rate of hydrolysis

varies

inversely

with the

triglyceride content

of VLDL

^particles

(Streja,

1979). Therefore

the

fraction

of

triglyceride hydrolysed and ^probably

the

turnover

rate of

^each compartment

in the

chain should

be

independently

determined

by the

data.

That

these parameters were constrained indicates that

insufficient information was ^available to determine such values

with confidence.

To

^resolve such

a

^problem more data,

apo B

turnover data or

triglyceride data derived

from

multiple

VLDL

fractions should

be

collected to

provide more information about

the

system

for

the model.

Following the injection of labelled glycerol, very low

density lipoprotein-triglyceride

specific radioactivity

curves

have been

^{descibed as} having

four

phases (Figure

2): an

early rising phase,

a

plateau

at the

peak, a

rapidly decaying phase, and

a

slowly decaying phase (Zech

et

â1, 1979). While

the

plateau

at the

peak

of the VlDl-triglyceride

specific radioactivity curve

can be

^explained

by the

delipidation cascade,

the

analysis

and

physiological interpretation

of the early and later

phases

(1 and 3) of the

curve

is

the

subject

of

much debate (Baker, 1984).

Time

Figure 2. Typical VLDL triglyceride specific radioactivity curve

^after

injection of

labelled glycerol. Generally

four

phases

are

identified:

an

early

rapidly

rising

phase

(1), a

^plateau

at the

^peak

(2), a

rapidly decaying ^phase (3), _and

a

slowly decaying

tail

^(4).

2

4 3

1 I

(J

Ë.¡

Ø'i

tt ^g)

J3 9E^cÉ

.90 É

L F<

The

conversion

of ^glycerol or free fatty acid to ^plasma

^VLDL

triglyceride is a

complex multi-step ^process.

Initial

studies

of

triglyceride metabolism used labelled

free fatty

acids

as

triglyceride precursors ^(Carlson, 1960;

Havel, 196l;

Freidberg

et ô1,

^1961).

In

more recent studies however

labelled glycerol has been used as the

precursor

for VLDL

triglyceride (Farquhar

et

â1, 1965; Reaven

et al,

1965). Critical

to the

model proposed by

Farquhar et al

⁽

1965) was the

assumption

that the turnover of

^liver

triglyceride precursors was greater than

that of the

plasma

VLDL

triglyceride.

Quarfordt

et al

(1970) however showed

that liver

triglyceride precursors and

plasma

VLDL

triglyceride turnover

rates in man were similar, and yet,

in other studies where

VLDL

triglyceride has been reinjected

in

man ^{(Havel and} Kane, 7975), and

in

animals (Laurell, 1959; Havel

et al,

1962; Baker and ^Schotz, 1964; Gross

et â1,

1967;

Lipkin et al,

1978; Hannan

et al,

^{1980) plasma}

triglyceride

turn

over

is

more rapid than

that in liver

^(Figure

3).

^Malmendier

and

Berman (197S)

also

observed

similar

findings when

they

compared the

decay curve

of

reinjected

IDL

triglyceride

with the initial fall of the

specific

radioactivity curve of IDL triglyceride after labelled palmitate. If

these

observations

are valid then the

interpretation

of a

^human

VLDL

triglyceride specific radioactivity curve,

after

glycerol, must

be

different

to that

made by

Farquhar

et al

^(1965).

In

non-human studies

the initial

rise

to the

triglyceride

specific radioactivity curve represents

the

turnover

rate of VLDL

triglyceride

while the falling slope must

^represent

either liver

triglyceride turnover ^or some

other slowly turning over pool of

triglyceride. Although predominantly derived

from

animal studies, observations

that the

turnover rate

of the

^plasma

VLDL triglyceride pool is greater than that of the liver

suggest ^that triglyceride

flux,

and hence production, from

the liver

and

into VLDL

^{may be}

grossly

underestimated.

Iluman Species Non-Human Species

\

\

YLDL.TG

\

^Liver

Liver TG .vLDL-TG

Tlme Time

Figure 3. This figure

illustrates

the

differences observed betweon rates of

liver and VLDL triglyceride turnover in

human

and

non-human species.

Human studies

have

shown

that the

turnover

rate of VLDL

triglyceride ^is slower than

that of ^liver

triglyceride.

This

has been confirmed

in only a

^few

studies where

the falling

slope

of the

reinjected

VLDL

triglyceride ^specific radioactivity curve was

the

same as

that

observed

for VLDL

triglyceride after

labelled glycerol.

The

rapid

rise of the

triglyceride specific radioactivity curve

after

glycerol was therefore attributed

to the

more

rapidly

turning over liver

triglyceride pool. In

^non-human species

however, where labelled

VLDL triglyceride has been reinjected several studies have demonstrated

that

VLDL triglyceride turnover

is rapid

and faster than

that of liver

triglyceride.

In

developing

their VLDL

triglyceride model, Zech

et al

^{(1979) have}

assumed

that the rate limiting

step

in the

turnover

of

triglyceride

is in

the

plasma compartment.

They have

however recognized

the

need

for a

slowly

turning over

compartment

within the liver which

^produces

the tail of

^the

VLDL

triglyceride specific radioactivity curve. Melish

et al

^{(1980) developed a}

simpler

model for VLDL

triglyceride although

their model was

based upon

similar assumptions

to

those used

by

Zech

et al

^(1979).

Several early studies had

demonstrated

higher triglyceride

^specific

radioactivities

in the

small-VLDL fraction

(Sf

20-60) than that ^measured

in

^the

large-VLDL fraction (Sf

100-400) (Streja

et al,

1977; Steiner and

llse,

1981).

Similar

observations \ryere

also made in the

simultaneous

apo B

^and

triglyceride studies of ^Steiner and

Reardon

(1983). These studies

also demonstrated

the direct input of

triglyceride

into the Sf

12-60

fraction.

The conclusion

to be

drawn from these and apo

B

studies

is

that entry and

exit

of

.9

9tË.b

Ø',oE tt9.F6

€, .Y ]?619!

}pÍ

Ér .9

I

t¡

2'.iE9

'c rI 9.=9rt l? 6l .go E

¡r

both apo B and

triglyceride

can occur rt any

stage

within the Sf

^12-400

fraction, and probably also

from within the LDL

fraction.

. Collectively these studies

demonstrate

that not all

^small-VLDL

triglyceride

is

derived

from

large

VLDL.

That

the

triglyceride

in

small VLDL have

a

higher specific radioactivity than large

VLDL

^may

be

explained

by

the

secretion

of

nascent triglyceride

from the liver directly into the

circulation.

An

alternative may

be

that as large

VLDL

are synthesized they exchange lipids

with intracellular lipid droplets resulting in a

reduced VLDL-triglyceride specific radioactivity (Chao

et al,

1986). Smaller

VLDL

^{particles would however} exchange

lipid to a

lesser

extent, and as

consequence

would have

^higher

specific

radioactivities.