Download Intermediary metabolism of fructose3

Intermediary
Peter
metabolism
of fructose3
A Mayes
ABSTRACT
due
Most
to its rapid
phofructokinase
reaching
of
regulatory
and
fatty
acids,
absorption
increase
nemia.
ished
loading
inorganic
ATP
enzymes
acid
of the
synthesis.
formation
metabolism.
to esterification
secretion
effects
liver
with
and
of veryby
fructose
hyperinsuli-
causes
sequestra-
fructose-l-phosphate
the
nucleotide
and
inhibition
degradation
with
dimin-
Al?
is removed
consequent
of the
and
hyperuricemia.
significance
or hyperuricemic
by
eg,
sylation
tabolism.
of proteins,
lactacidemia,
The paper concentrates
uric
hyperlipidemia,
fructose,
particularly
and punine metabolism.
of other
Of
reviews
further
hyperuricemia,
concerning
Other
in this
with
an increase
in plasma
fructose
insulin
Thus whenever
intake
added effect of insulin
is this
alent
to hydrolyzed
50%
fructose
athletes
the
case
with
contain
sucrose
itself
but
because
fructose
cause
does
(2).
by glucose,
into account.
are
HFSs
50%
-
apply
and
intake.
directly
feeding
some
they
considerations
both
not
is accompanied
must be taken
sucrose
sucrose
secretion
of fructose
does
whereas
of fructose
secretion
insulin
effects
feeding
(1)
(3). Similar
that
augmented
of the metabolic
glucose,
only
meof
its impact
on carbohydrate,
lipid
aspects
referred
to are the subjects
is whether
for some
Compared
fructo-
in copper
metabolism
volume.
consideration
is responsible
nonenzymic
and disturbances
on the general
the
Not
are
equiv-
glucose
and
to supplements
for
glucose.
These
to potentially
hypertrigly-
Am
individuals.
terious,
of
are augmented
tolerance,
Consequently,
of particular
ceridemic
These
in
accelerates
are
lipid
far
hepatic
increases
in pyof pyruvate
dehydro-
in increased
glucose
phosphate
of adenine
effects
and
to
of fructose,
which
causes
enzyme
adaptalipogenesis
and VLDL
secretion,
leading
to
decreased
Acute
of
arc
the phos-
leading
oxidation
resulting
(VLDL).
triglyceridemia,
glycolysis,
from
fructose
J Clin
Nutr
General
metabolism
1993;58(suppl):754S-765S.
Utilization
KEY
WORDS
Fructose,
immediate
olism,
effects,
lipid
long-term
metabolism,
low-density
intermediary
pertriglyceridemia,
effects,
enzyme
lipoproteins,
metabolism,
liver,
sucrose,
carbohydrate
adaptation,
insulin,
metab-
lipogenesis,
nonesterified
The
fatty
very-
acids,
hy-
of blood
foods
absorption
and
into
the
tube
Virtually
all
to two
ulatory
step.
substrate
its
science
or
pressant,
as
the
not,
syrup
fructose
feeding,
are
and
at the
phosphofructokinase
is the
its
tnreg-
provision
pathways
metabolism
a sweetener
corn
as a food
by the liver,
gluconeogenesis
consequence
in fructose
use
of fructose
leading
of infrom
tn-
because
of
1).
(Fig
interest
increased
bypassing
metabolic
uptake
or
in all the metabolic
of high-fructose
enteral
after
properties
its rapid
of glycolysis
The
phosphate
metabolic
factors:
level
creased
Current
unique
pathway
phosphate
ose
the
primary
to the
ose
ognized
in the
(HFS).
has
been
has
food
Also,
industry
promoted
in the
based
as
for non-insulin-dependent
and as a food
arisen
whether
an
supplement
for endurance
form
on sound
appetite
diabetics,
half
for many
of the sucrose
years
as being
molecule,
largely
fructose
responsible
abolic
effects
of high-sucrose
diets. Concern
of the realization
that fructose,
at elevated
promote
metabolic
changes
that are actually
754S
of
portal
enzyme
vein.
system
de-
Am
J C/in
tissues
by
Therefore,
of
the
intestinal
fructose
the
for metabolizing
fructose,
a fractional
presented
rats
(4).
fructose-
vegetables,
is
epithelium
absorbed
presence
accounting
for
of the fructose
fed or starved
other
some
all
Because
and
and
of
flows
an
active
fructose
readily
uptake
of 55%
to the liver after
In humans
it was
shown
that
the
fractional
high
rate
extraction
of
of fructose
extraction
low concentrations
vessels
after meals
of
(6).
fructose
of fructose
containing
by
As a consequence
the
liver,
of the
correspondingly
are found
in the
fructose
or sucrose
systemic
blood
are consumed
(4, 7, 8). Some 20% of fructose
administered
intravenously
up by the kidney
(9). Thus, somewhat
less than this amount
be
expected
the
liver
smaller
to be
taken
up
takes
up some
fraction
would
by
50%
be
this
organ
after
of the initial
available
for
oral
influx.
is taken
would
feeding
where
A considerably
adipose
tissue
(10)
and
for parathletes.
has been
red-
for the met-
has arisen
because
concentrations,
can
or potentially
deleNutr
feeding
fruits,
fructose
initially.
into
of sucrose
the liver metabolized
at least half of the fructose
injected
intravenously
(5). In the perfused
rat liver
we found
a value
of 40%
for
I
Representing
transport
liver
and uptake
digestion
as honey,
passes
into the liver,
and 71%, respectively,
Introduction
entry
such
hepatic
the
hepatic
due
of the
containing
through
hyperuricemia
fructose
consequence
1993;58(suppl):754S-65S.
From
the Division
of Biochemistry,
Sciences,
Royal
Veterinary
2 Supported
by the British
3
Address
Department
University
reprint
of
Printed
requests
Veterinary
of London,
in USA.
College,
Heart
Department
University
Foundation.
to PA Mayes,
Basic
Sciences,
London
NW1
© 1993
American
0Th,
of Veterinary
Basic
of London.
Division
Royal
of Biochemistry,
Veterinary
College,
UK.
Society
for
Clinical
Nutrition
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
long-term
tions that
in
of
it by-passing
immediate
activation
in balance
low-density-lipoprotein
tion
step
include
production,
a shift
nonesterified
effects
and
to carbohydrate
consequences
and lactate
genase,
metabolic
by the liver
consequences
These
ruvate
the
utilization
METABOLISM
OF
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Glyceraldehyde
FIG
1. Fructose
phosphatase;
skeletal
tose
muscle
is infused
(11).
above
which
oxidation
is above
and
review
Of particular
centrations
vein.
2.2
of
(13)
values
rats were
(4).
In humans
was
recorded
to
resting
in peripheral
concentration
fructose
maximum
concentrations
recorded
with
glucose
and
fatty
acid
metabolism.
Pase,
that
when
fruc-
this
fruc-
the
metabolic
many
investiga-
out using
deductions
after
pathways
involves
(Fig
uptake
in adipose
is the
three
particular
the
and
blood,
metabolism
attained
in
(8) maximal
after
arc
the
the
hepatic
conportal
concentrations
a fructose
or
sucrose
not
of
meal.
when
(14).
of 1.0 mmol
Because
no fructose
the
fructoscfL
normal
is being
blood
absorbed,
offructose
utilization
in individual
tissues
of most hexose
fructose
is present
absorbed
in
the
which
do
not
essary
for
releasing
by
respect
fructose
aldolase
and
of fructose
is rapidly
ketohexose
of
to glucose
model
catalyzed
of human
This
enzyme
physiological
much
of the fructose
aldolase
droxyacetonc
phosphate,
intermediates.
Aldolase
significance
underlies
passing
(aldolase
through
it.
B) into
a member
B also
in the
the ability
this
rats
necthere
is
In this
metabolism.
to form
of the fructose
specific
fructose
diet.
is
(17),
enzyme
in the liver
for
is the
only
high
ac-
to extract
so
The
of the liver
Fructose-i-phosphate
glyceraldehyde
of the glycolysis
functions
or
is virtually
and
and
as the
are able
absorption.
fructose
by AlP
metab-
kidney
species
by the first enzyme
(20).
of fructokinase
two
during
it is a kctohexokinase,
tivity
by liver
the
in these
phosphorylated
pathway-fructokinasc
because
(19)
far
(15),
However,
humans
glucose-6-phosphatasc,
1-phosphate,
fructose
glucose.
either
Thus
Hers
for fructose
in liver
into
of
glucose.
the rat is a good
Fructose
fructose
Of
(fructokinase,
arc specific
arc present
intestine
contain
no conversion
split
the phosphorylation
However,
when
some
possible
enters
muscle.
discovered
enzymes
enzymes
it is probably
from
tissue
pathway
two of which
1). These
its phosphorylation
Nevertheless,
to convert
be
in blood
will vary from zero up to the
above,
according
to the quantity
in the diet.
Hexokinase
will catalyse
sugars,
including
fructose.
fructose,
B, and triokinase),
olism
(10).
to hepatic
blood
pathways
that
significance
which
unphymade
concentrations
by glucose
probably
in the small
intestine
of some
species-such
golden
hamster
(16), guinea
pig (17), and dog (18)-that
concentration
is zero
route
greater
that
at physiological
inhibited
via
muscles.
out
glucose
and
concentrations
more
with
is largely
a concentration
be misleading,
particularly
when
normal
quantities
of sucrose
and
baboons
recorded
a maximum
metabolic
its interrelationship
within
the range
1.1-2.2
mmolfL,
when fed or
given a large fructose
meal by gastric
intubation
fructose
Specific
and
been
We found
starved
likely
(14)
showing
is considerably
we pointed
relevance
have
showed
in vitro had been carried
of fructose
and that
fructose
In humans
mmol/L
liver
to maintain
there
exercising
in vivo and
concentrations
(12)
physiological
from such observations
could
applied
to humans
consuming
fructose.
in the
subjects
concentration,
by
In a previous
tions both
siological
study
exercising
the glucose
tose
A recent
into
of 5.5 mmol/L,
utilization
P, phosphate.
in the
liver
is
and
dihy-
sequence
in glycolysis
of
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
Co2
756S
MAYES
to split
fructose-1,6-bisphosphate
and dihydroxyacetone
to glyceraldehyde-3-phosphate
phosphate.
The
pathway
is tniokinase
(21), which
glyceraldehyde
by Al?
to form
other
intermediate
from
this point
tose
has
arrived
through
glycolysis,
possibly
tose
(23).
acid
metabolism
Smaller
without
in glycolysis
estenification).
in the
quantities
Thus,
passing
products
sition of fructose
carbon
by changes
in nutritional
(13).
The
of 0.5 and
of fructose
fructose
These
will
of
fruc-
lactate
ketonc
on glycolysis,
As
a result
of the
metabolism
there
loading
lactate
This
initial
resulting
by increased
concentrations
enzyme
allostenic
metabolite
(36,
is normally
under
37).
Glycogen
synthesis
and breakdown
series
of reactions
involving
covalent
(polyol)
and
The
is responsible
for fructose
in activity
as glucose
concentrations
tissues
that are not
undergoes
reduction
reductase,
followed
bitol
(polyol)
bitol
and
causing
ogenesis
aldose
version
Effects
damage,
of diabetic
in the
which
of fructose
with
After
venous
there
in those
liver
(28-31),
cent
investigations
kidney
in the path-
dehydnogenase,
of important
the perfused
administration
loading
1-phosphate
but
not
liven
of fructose
is a rapid
tissues
and
32),
‘
and
(23,
either
marked
orally
or by
increase
small
intestine
pathway,
(33,
P magnetic-resonance
though
most
by using
logical
concentrations
were
of fructose,
obtained
experiments
34).
with
Re-
in the
(35). Alunphysio-
isolated
enhanced
passage
phosphorylation
ters around
other
phosphoenzymc,
lated.
Protein
whereas
hand
control
of pyruvate
carbon
kinase
and
is controlled
modification
out
dephosphorylations
is dephosphoryand protein
from
that
of glycogen
by Hers
(39).
of the literature
metabolism
reveals
promoter
osition
cogen
of glycogen
appears
to result
synthase
(40, 41) and inhibition
of glycogenesis
6-phosphate
fusions
to be brought
a is inhibited
accumulates
after
increases
and
inhibits
with
acids into
physiological
the
by
liver
of fed
has been
on whether
with the balance
that fructose
(31).
The
about
by several
of
is a
net dep-
mechanisms.
fructosc-1-phosphate
(42-44),
of fructose.
Also,
and activates
(45).
rats,
and
from both activation
of glyof glycogen
phosphorylase
in concentration
phosphorylase
enzymes.
in results
is glucose
administration
concentrations
which
than
these
allostenic
modidiffers
in some
in muscle
a disparity
better
thase
of
promotes
liven glycogen
deposition,
in vivo in the fed condition
indicating
appears
censynthase
the inactive
synthase
b is phosphorylactive
glycogen
phosphorylase
a is the
detail
which
by a complex
by protein
ref 25 for a general
review.)
synthase
(synthase
a) is the de-
are controlled
by hormonal
and
of glycogen
metabolism
in liver
This
fa-
(See
carry
42).
thus
lactate.
regulation
whereas
the inactive
b form
kinases
carry
out phosphorylations
Phosphorylase
of
increases
a similar
(38),
to pyruvate
processes
Control
A study
because
are the large
which
extend
Both
fiers.
fructose
studies
and lackinase.
Although
this
fructose
is added
phosphatases
reviewed
to
of glycolytic
and dephosphorylation.
Briefly,
rate-controlling
enzymes-glycogcn
two
phosphoenzyme,
ated. On the
We
using
whole
of glucose,
was infused
glucose,
rates (46). When
either
have
amino
glucose-
glycogen
carried
blood
acids,
synout
per-
containing
and free fatty
fructose,
or both sugars
at
sugar
was infused
alone.
there was a net output
of glucose
from the liver, with no change
in glycogen
concentration.
However,
when glucose
and fructose
were infused
together,
there was a marked
uptake
of glucose
and
an increase
he-
of fructose
glycogen
phosphorylase.
active
form of glycogen
physiological
ie,
spectroscopy
1-phosphate
of fructose
effects
intra-
in glucose
the fructose
more
(40,
26, 27) and cath-
that in the starved
state,
to glucose
and up to 25%
8% may form glycogen
containing
(30,
using
intermediates
have confirmed
the accumulation
of fructose
human
liver after intravenous
administration
of these
son-
metabolism
etenized
human
subjects
(9) indicate
66% of a fructose
dose is converted
is released
as lactate.
Up to a further
(23).
Both
in diabetics,
involved
on carbohydrate
both
lens
in liver and is responsible
for the conderived
sorbitol
to fructose.
on the concentrations
Experiments
of NAD.
human
Sorbitol
in those
as the lens. Glucose
catalyzed
by aldose
to fructose
by son-
is probably
cataract.
reductase,
is found
of any exogenously
Effects
in diabetics
in the presence
accumulate
osmotic
rise
insulin
sensitive,
such
by NADPH
to sorbitol,
by oxidation
of sorbitol
dehydrogenase
fructose
forma-
in the lens, seminal
above.
It increases
span
to pyruvate
by pyruvate
feed-forward
olism
of fructose
is not complete
without
a very brief reference
to its synthesis
in a few specialized
tissues.
Free fructose
is found
in the lens, seminal
fluid, and the fetal
circulation
of ungulates
and whales.
It is formed
by the sorbitol
which
In the
activation
by fructosc-1,6-bisphosphatc.
may double
in concentration
when
cilitating
of fructose
of glycolysis
from glyceraldehyde-3-phosphate
rate-controlling
step is catalyzed
activation
(25),
in5cc-
in an increased
flux through
lactate
formation
and raised
but
pathway
pathways
for intermediates
Although
the primary
purpose
of this paper
is to review
the
effects
of exogenously
derived
fructose,
discussion
of the metab-
tissues
tion from glucose.
This pathway
is present
vesicles,
and placenta
of the groups
mentioned
and
in following
and gluconeogenesis
of the
is a tendency
increase
in concentration,
the pathway,
evidenced
reactions
tate, the
or ad-
glycogenesis,
of more significance
concentrations,
in mammalian
3-phos-
ATP,
without
in glycogen.
a concomitant
Fructose
glucose
uptake
infusion.
was
the
same
with
or
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
diabetes,
Effects
blood
dispo-
between
its major end products
is altered
and endocrine
status,
eg, gluconeogen-
offructose
which
meal.
may alter
glycerol
lactate,
be discussed
to hepatocytes
(31),
in fructose-1-phosphate
Biosynthesis
fructosc/L,
include
pyruvate,
demon-
1-phosphate
after a fructose
concentrations
administration
(Pi).
(31)
fructose
1 .0 mmol
in vivo
whose
2,6-bisphosphate,
phosphate
of
tions.
and
general
fructose
is increased
during
starvation,
of ethanol
or glucagon
(24).
phate,
of fructose
elevations
by
liver are glucose,
glycogen,
and
arc oxidized
to carbon
dioxide,
to tniacylglyccrol
concentrations
at concentrations
organic
catalyzed
graded
significant
are available
in the portal
vein
Other important
intermediates
Fruc-
lipogenesis,
major
occurred
as a result
on presentation
increased
subtriose
phosphate
gluconeogenesis,
that
in the
and
similar.
(22). In this way fructose,
phosphorylated,
providing
pathways
leading
from
or converted
esis from
ministration
step
using
strated
of
an-
metabolism
of metabolism
in metabolism,
glycogenesis,
fatty
bodies
stage
fructose
stage
is qualitatively
rate-controlling
phosphofructokinase
to the liver, is rapidly
strate to the metabolic
(ie,
metabolism
at this
the main
patocytes
in the fructose
pathway.
of glucose
and
triose
phosphate
on, their
enzyme
catalyzes
the phosphorylation
glyceraldehyde-3-phosphate,
of the glycolytic
Thus, the pathways
liver converge
at the
third
METABOLISM
Thus,
fructose
in the
sucrose
take
on its own
synthesis
activation
of glycogen.
of glycogen
but fructose
an increase
creased
which
(22).
It was
the fed state, fructose
lyzed to lactate rather
oral load
increases
from
would
appear
than converted
lactate
The
glycolysis
and
nonequilibrium
and
also
unique
1). Their
producthe
many
in vitro,
make
to each
use
of
arc
both
often
phatase
(50).
The
in liver
activating
concentration
from
fed
fructose-i
of fructose,
the
locus
phosphatase
of
(51).
gluconeogenesis
the
from fructose
Therefore,
effects
which
leads
However,
Unaccu-
at the triose
inhibition
of
hepatocytes
there
under physiological
and
there
gluconeogenic
to increased
substrate
is
cy-
fructosc-i,6-bis-
is no evidence
that
this
inhibits
fructose.
of a high
most
ganism
when
exhibited
data
have
been
consuming
quirement
between
as fructose.
7.5%
and
Long-term
diets
to adaptive
increases
leads
in the pathways
of fructose
grouped
into those
involved
metabolism
synthesis
and
(13).
may differ
from
moiety
of sucrose
turn
would
those
Long-term
those
may
be expected
of opinion,
however,
sucrose
diet as being
involved
effects
from
humans
or animals
70% of their energy-intake
feeding
of fructose-containing
in the activity
metabolism.
initially
of many
feeding
and
adaptive
does
(54).
not
63).
creased
This
glycogen
to increased
appear
insulin
of individual
plasma
feeding
resistance,
brought
fatty
(NEFA)
acid
in the whole
or -fructose
tissues.
high-fructose
effects.
for
to be an insuf-
(60, 61).
of glucose,
as found
on a high-sucrose
is no doubt
a starchreason
by the hypoglycemic
(59).
Thus
decreased
nonestenified
by an increased
there is decreased
activity
The
rather the reverse.
Increased
been reported
after sucrose
increased
and utilization
utilization
in studies
accompanied
in the liver
diet,
However,
this
or-
is also
is usually
ability to metabolize
fructose.
Thus,
utilization
and oxidation
of glucose
due
to depressed
glucokinase
of glucose-6-phosphatasc
in the
and
liver
after
infruc-
diets are consumed
(64). As opposed
to the
of fructose
in facilitating
conversion
of glucose
in the liver
(46),
long-term
feeding
imto
of fructosc-containing
diets reduces
the conversion
of glucose
to liver glycogen
(65, 66).
However,
conversion
of fructose
to liver glycogen
is increased
because
of enzyme
adaptation
(64). Consumption
of a sucrose
diet
Muscle
of a sucrose
lactate
tissue
compared
also
shows
of glucose
in adipose
oxidation,
and
tissue
conversion
load
did
with
a starch
decreased
and increased
ability
been fed high-fructose
Effects
of fructose
Immediate
not elicit
diet
ability
any
extra
in-
(67).
to metabolize
to oxidize
fatty acids
diets (68). Likewise,
glu-
after animals
the utilization
is impaired
with
respect
to glycogen
(62,
69).
to its uptake,
effects
on lipid
metabolism
on the initial
pathways
of lipid
metabolism
and on lipogenesis
Fructose
has
metabolism.
both
result
of fructose
whereas
long-term
to diets
immediate
Short-term
and
or acute
metabolism
effects
result
containing
high
long-term
effects
effects
on
that
occur
arc those
by existing
mainly
from
concentrations
enzyme
enzyme
of sucrose
Because
of the importance
of the liver in fructose
the blood,
many of its effects
on lipid metabolism
organ.
They
involve
the
major
pathways
The
For
diets
glucose
This in
majority
would
regard
the long-term
effects
of a
due mainly
to its fructose
content
(52).
example,
it is likely
that
important
pathway
in rats than in humans,
be confined
to the liver and where
even
of lipogenesis
enzymes
triglyceride
of feeding
sucrose,
because
the
cause increased
insulin
secretion.
to cause
re-
These
enzymes
can be
with fructose
uptake
and
in lipogenesis
of
humans
has been
with
may
In the liver,
dihydroxyacetone
acetone
phosphate
be low
in activity
secreted
or fructose.
of fatty
acid
lipogenesis
oxi-
dangers
must be
is a more
where lipogenesis
may
there the key enzymes
(70).
lipid metabolism
is affected
by fructose
at the
phosphate
and pyruvate
locations.
Dihydroxyis in equilibrium
with
by the
liver
and
which
endogenously
derived
plasma
triglyceride
generates
pyruvate,
which,
besides
forming
mitochondnion
as a
uptake
from
arc found
in
glycerol-3-phosphatc,
cosubstrate
for esterification
of long-chain
acyl-CoA
thesis of triglyceride
and phospholipids.
Triglyceride
precursor
and
determinant
of very-low-density
(VLDLs)
lipid
capacity,
adaptation
dation
and estcnification,
and lipogenesis.
In this respect,
of applying
results
in experimental
animals
to humans
intake
obtained
by
placed
appreciated.
Experimental
tolerance
is due
likely
concentrations
The decreased
this
fructose
and
tolerance
compared
is
thus
glycolysis.
does
not
metabolites
there
is no
tolerance
about
cose
have
ac-
(53)
glucose
and insulin
sensitivity,
as measured
to administered
insulin,
is less
glucose
by
starvation,
and
phosphofructokinasc
from
Long-term
and
by fructose.
In isolated
in fructose-2,6-bisphosphate
concentrations
at
during
phosphofructokinasc
fructose1,6-bisphosphate
mulate
even when the flux
phosphate
level increases.
cling
falls
,6-bisphosphatase
pathway
and inhibiting
der these
conditions,
gluconcogenesis
some increase
but
(55-58)
response
consumption
on the
regime
in insulin
secretion,
concentrations
have
in blood
of fructose-2,6-bisphosphatc
rats
glucose
crease
key regulatory
molecule-fructosc-2,6-bisphosphatc-which
tivates
phosphofructokinase
and inhibits
fructosc-1,6-bisphoselevated
the decreased
before
induced
acting
that
sucrose
in animals
and
These
arc catalyzed
fructose-i,6-bisphosphaactivities
both
(25).
arc reciprocal
modifiers
diet,
the case
a long-term
tose-containing
mediate
effect
by
pathway
based
(62,
rates
but arc controlled
the activities
by allostenic
to
of fructose
(ic
present
discus-
pathways
enzymes
these
pathways.
in glycolysis
and
(Fig
and
glucose
exceeding
Unfortunately,
particularly
gluconeogenic
for which
in gluconeogenesis
by hormones
and
even
also leads
(47, 48).
high concentrations
be considered
in the
enzymes
reactions,
the uptake
of
lactate
pro-
not glucose,
in humans
process.
intermediates
pivotal
in-
to be predominantly
glycoto glycogen
or glucose.
An
lactate
(23, 49).
from fructose,
unphysiologically
and will not
common
concentrations
it has been
under
ficiency
insulin
of phosphorylase,
gluconcogenesis
is an active
coordinated,
dominate
phosphofructokinase
tase
that
Generally,
worse
to form
acetyl-CoA
constitute
in the synis the major
lipoprotcins
the bulk
(71).
Fructose
lactate,
enters
as a result
of pyruvate
of
also
the
de-
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
used
5 mmol/L)
by
use of the facility
because
inhibits
fructose-i,6-bis-
of a fructose
infusion,
account
for the increased
condition
fructose
presumably,
757S
FRUCTOSE
but
case after a
glucose
up-
of a simultaneous
glucose
infusion,
there
increment
in lactate
production.
Thus in
of gluconeogenesis
from
studies
on gluconcogenesis
several
inhibition
of fructose
or sucrose,
but
in blood lactate concentration
In the starved
Two
and
significant
duction.
In the presence
was an additional
small
many
is achieved,
synthase
only in the presence
into the liver could
sion.
to be glycogenic
This
itself is not able to make
in fructose-1,6-bisphosphate
phosphatase
have
not seem
presence
of extra glucose,
as would
be the
meal, fructose
‘ ‘opens
the door’ ‘ for hepatic
and
tion
does
OF
758S
MAYES
hydrogenase
for
(PDH)
three
acid
activity.
products:
cycle;
carbon
long-chain
Here
it can
dioxide,
after
fatty
acids,
after
act
as a carbon
oxidation
entering
the
sequence
of reactions;
and, ketone
bodies
is the major carbon
source
for lipogenesis.
(72, 73).
However,
esis
must
occurs
through
CoA
in
the
cytosol,
in the cytosol
citrate
lyase.
via the
important
pathways,
and
acyl
concentrations
the
carbon
of the
acylglycerol
in pyruvate
of NEFA
of [ATP]
to [ADP]
may
hypcruriccmia,
which
is known
adcninc
[ATP]
was
concentrations
nucleotides
not
the fate of
to [ADP]
in reference
change
of fructose
to follow
(77,
78).
depletion
However,
found
in fructose-fed
and PDH activity
Oral
produces
of Al?
adenine
nucleotides
were
At a fructose
concentration
ceptible
by any
more
increase
change
in PDH
in adenine
significance
was
of fructose,
NEFA)
on PDH
activity
support
the view
that
by increasing
the ratio
the
pyruvate
of [Al?]
that
at this
inhibitory
was
causes
of
fructose
an immediate
and pyruvate
ministration
in PDH
rather
than
liver
activity
though
transient
increase
in glycerol-3-phosphate
concentrations
(82). In contrast,
after glucose
there was no immediate
increase.
When fructose
adwas
intrapenitoneally
(27,
there
phosphate,
Similar
results
84, 85).
was
an
rats
increase
glycerol-3-phosphate,
have been obtained
Acetyl-CoA
concentrations
in hepatic
pyruvate,
in the peralso
increase
as a result
of lipid
mobilization
lysis of triglyceride-rich
established
in the perfused
dized
liver
between
and kctonc
in liver
acylglyccrols
balance
a reciprocal
the liver,
more
major
ification.
site for
cation
lies
its metabolites
in both
the
and
branches
of
acetyl-CoA
its metabolism.
Although
many lipogenic
intermediates
increase
in concentration
after administration
of fructose,
there
is little
evidence
that fructose
on its own has an immediate
effect
on
lipogenesis.
Thus,
fructose
stimulated
lipogenesis
from acetate
in chick liver slices,
Using
the tnitiated
but not when
water
technique
fructose
was added
we were unable
strate
in lipogenesis
in perfused
any
increase
in the presence
of physiological
concentrations
livers
alone (87).
to demonfrom
of fructose
than
and
the
Palmitoyltransfcrasc
concentration
fed rats
(13).
was
oxidized
and those
and
starved
that
animals,
acids
from
where
The
fatty
failing
fasted
the
can
explain
and oxidation
animals.
fructose
of fatty
are
the
raising
though
the
and
insulin
do not
in fact
Also,
we
acyltransferase
(90),
there is
in balance
acids
between
belivers
and immediate
together
additive
with
of estenification
may
influence
have
increase
the
shown
activity
triglyceride
with
fructose,
carboxylase
is activated
by glucagon
also
91).
a further
decrease
in oxand VLDL
secretion.
of acctyl-CoA
independently
(46,
of a physioand increased
of VLDL
added
enhance
the concentration
of glyccrol-3-phosphate
this seems
unlikely
if physiological
(82).
immedi-
concentration
secretion
was
Fructose
mediate
phosphate
can
in
by
mitochon-
esterified
had direct
physiological
is the product
fructose
acyl
by the liver, we perfused
livers from
into which
[‘4C]oleate
NEFA
was in-
effects
were
enhancement
and fructose
regulatory
and esterifi-
long-chain
change
of fatty
and insulin
acids
When
of malonyl-CoA.
animals
rate-limiting
step
acids is catalyzed
to enter
but
and it is known
that this enzyme
fication
by insulin
and inhibited
insulin
in
demonstrat-
I is inhibited
by malonyl-CoA
increases
in the fed condition
when
a constant
liver.
of
by the nutritional
between
these two
Increased
concentrations
of insulin
or an infusion
logical
quantity
of fructose
decreased
oxidation
the
to carbon
esterified
secretion
established
that
between
oxidation
pathway,
effects
on VLDL
secretion
fed rats with whole
blood
from
oxidem-
Regulation
VLDL
livers
accumulate
This
to maintain
either
load of fatty acids taken
up by
oxidized
less fatty acids
but
(89)
I. Fatty
To test whether
are
on the other.
from
oxidative
lipogcnesis.
hydro-
fractional
rate of cstcrification
irrespective
demonstrating
that
glycerol-3-phosphate
have been rate limiting
in fatty acid ester-
do not
twecn
esterification
of fed and starved
arise
relationship
exists,
which
is affected
the partition
of fatty acids
showed
and
acids
or from
per pass,
inverse
the mitochondrion
(90).
oxidation
of long-chain
for oxidation
fused
that
imme-
lipoprotcin
lipase.
We
NEFAs,
which
are taken
ketogenesis
did livers
We
in
Malonyl-CoA
of
concen-
marked
fatty
tissue
by
in VLDLS
It has now been firmly
controlling
the balance
groups
enter
mitochondnial
ately.
whose
An
both
maintained
a constant
of the NEFA
load,
availability
could
not
causes
glycolytic
equal
marked
have
These
of 30-40%
and
pathways.
any
the quantity
of fatty acids
bodies
on the one hand,
ing that a mechanism
state, for regulating
the separate
idation
and
and
in insulin
it does
of NEFAs.
manner.
For a given
livers
from fed animals
esterified
to cause
in adipose
89).
controlled
in hepatocytes
in the presence
of lactate
and pyruvate
(86), both
of which
increase
in the presence
of fructose.
Thus,
fructose
concentrations
(88,
onstrated
dioxide
estenification
increased
an
lipogenesis,
and esterification
itself,
lipoprotcins
rat liver
to the extent
or esterified
(72). It is also likely that malonyl-CoA
concentrations
rise when
fructose
is administered
because
an increase
has been recorded
glycerol-3-phosphatc
by
on the fate
active
into
with
increased
by a rise
not seem
effects
dna
appear
physiological
conto the depressant
intravenously
does
in lipogenesis
palmitoyltransferasc
by decreasing
it would
was
dihydroxyacetone
and lactate
(83).
fused
injected
(a
results
there
administered
was
oleate
these
In summary,
Of
concen-
increased
increases
concentrations,
(81).
accompanied
(13).
Generally,
that some activation
of PDH occurs
with high
centrations
of fructose,
especially
in antagonism
effect of increased
concentrations
of NEFAs.
When
concenAlP
and
physiological
effect
reversed.
fructose
to [ADP]
in he-
decreased
and PDH was activated
of 1 .5 mmol/L
there was a per-
the fact
tration
and
no decrease
activity,
which
was not
nucleotide
concentrations
be
accompanied
immediate
this
rats (79). Adenine
nudedid not change
when fruc-
tose was added
to the perfused
rat liver at physiological
trations
of 1 .3 mmol/L.
However,
at 1 1 .0 mmol/L
both
total
(80).
76,
appreciably.
fructose
increase
up by the
causes
detherefore,
to humans
was
well
the concentration
estenification
by
(93, 94)
concentrations
alof
concentration
that
of this
mitochondnial
is enhanced
activity
by covalent
modi(92). Therefore,
by
inter-
glycerol
insulin
(95),
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
amounts
diate
by increased
As discussed
Although
acid
molecule.
particularly
at high amounts,
but of all adenine
nucleotides;
of large
patic
otide
75).
if this
administered
might
AlT-
the glycerol
it is inhibited
were
there
Immediate
effects on fatty acid oxidation
on lipoprotein
formation
and utilization
By these
for both
if fructose
tration.
acetylfatty
in determining
ratio of [AlT]
(74);
(74,
administration
other
atoms
is a key factor
by a decreased
administration,
not only of AlT
ratio
malonyl-CoA.
provides
by an increase
fructose
pletion
intermediate
that
of glucose,
particularly
transported
enzyme,
to long-chain
cytosolic
portions
of the lipogenic
likely
amount
lipogenesis
reforming
is converted
It is
citric
Acetyl-CoA
as lipogen-
be
as citrate,
by the action
Acctyl-CoA
fructose
the
membrane
The activity
of PDH
pyruvate.
It is activated
and
acetyl-CoA
the mitochondnial
source
in the
METABOLISM
and
this
moting
could
These
this
also
account
esterification
effects
sugar.
providing
a direct
VLDL
of fructose
In a direct
infusion
for
and
on NEFA
comparison
of the perfused
infusion
of
glucose.
Perfusions
tose
metabolism
with
were
also
glucose,
liver
were
compared
Only
the
fructose
against
carried
above
a concentration
one-third
Because
quining
process,
amount
lower
ATP
fructose
triglycerides
decreased
whereas
a comparable
both
sexes
likely
the
the
fall
(96).
result
in female
solution
Although
the
of a direct
effect
in triglyceride
in NEFA
strate
mans,
mmol/
cut to
associated
with
intravenously,
serum
but increased
in males,
caused
a decrease
in
in triglycerides
the
liver,
in turn
is most
as described
due
provides
NEFA
sub-
less VLDL
production.
In huin NEFAs
with little change
in
(97), indicating
to decreased
NEFA
that any reduced
secretion
availability
and any in-
creased
secretion
of fructose.
The
is most likely
due
net output
of VLDL
to the direct
hepatic
action
by the liver is therefore
a
balance
these
effects
between
Fructose
is both
circumstances.
opposing
antiketogenic
In vivo,
of fructose
and
in the starved
is antiketogenic.
hibition
of NEFA
results
liver.
two
This
ketogenic
state,
from
depending
on the
a physiological
is nearly
mobilization
always
adipose
intake
due
tissue
to its in-
(97),
which
in reduced
uptake
of the main ketogenic
substrate
by the
It appears
that there is also a direct antiketogenic
effect of
fructose
on the liver, as demonstrated
a constant
plasma
NEFA
concentration
have
been
cytes
in the
of these
unclear
carried
out
presence
experiments
whether
immediate
were
or not
carried
out
these
in the
inhibition
these
acctyl-CoA
of
liver and isolated
hepato(72, 84, 91, 99, 100). Most
NEFA
malonyl-CoA
of
under
in vivo in the presence
(98). Similar
experiments
perfused
I can explain
activation
reported
phate
cation
in the
of added
mitoyltransferase
been
of fructose.
results.
starved
of carnitine
It would
carboxylase,
conditions.
state.
Although
to ketonc
fructose
bodies
can also
livers from starved
The phenomenon
rats
was
metabolism
was
first shown
triglyceride
istered
glucose
fructose
triglyceride
have
but
as fructose
glucose
and
from
of i .5 mmol
fruc-
is converted
fatty
specific
acid
radioactivity
be obtained
of the
into
metabolism,
the metabolism
compared
of starved
reported
pigs
data
a similar
reflect
the
by the liver whereas
tissues.
In liver
for
(104)
and
as from
fructose
quantity
of adminfructose
that
is
glucose
is utilized
slices,
radiolabeled
plasma
After
lipids
in
administration
of
is found
in glyceride
glycerol
of hepatic
triglyceride
(102,
103),
due in part to greater
dilution
and exchange
way from fructose
to long-chain
fatty acids
erol-3-phosphatc
(Fig
maintain
a concentration
either
fact
into
(105).
[‘4C}fructosc,
more
radioactivity
than in the fatty acid portions
given
carbon
dioxide,
and
(103).
Similar
results
incorporation
baboons
rats
total body glucose
of the administered
with
These
of administered
by gastric
intubation
was com2.5 times as much
newly
came from
twice as much
(102).
of intermediary
fate
is converted
to lactate,
pyruvate,
more
rapidly
than is glucose
been
guinea
of label in the paththan in that to glyc-
1). When
[U-’4Clfructose
was
of 1.5 mmol/L
in the perfusate
infused
to
of livers
prepared
from fed rats, 12% was oxidized
to carbon
dioxide
and
2.4% was converted
to ketone
bodies;
4.1% was in liver lipids,
1.6%
was
incorporated
cholesterol
(13).
into
VLDLS,
As the fructose
and
load
only
was
0.4%
was
increased,
in total
proportion-
ally less of the labeled
fructose
entered
lipid products
except
for
ketone
bodies,
which
remained
the same.
Thus,
ketonc
bodies
and lactate
act as overflows
of excess carbon
as fructose
saturates
Long-term
pathways.
liver
with
are present
Hence,
respect
ketone
bodies
to carbohydrate
fulfill
a similar
as they
do when
in excess.
in perfused
infused
with the sugar at 20 mmollL
(72).
also demonstrated
with livers
from
fed
effects
of a high fructose
adaptation
is also
term effects
of a high-fructose
as for the long-term
effects
liver,
less
(98).
be ketogenic
when
formed
Enzyme
concentration
That
bodies
came
the
not
the normal
and
of the
may
triglyceride
fructose,
acids
has
of NEFAs
with
or [U-’4C]fructose
shown
that although
it was
synthesized
administered
fatty
cause
oxidation
Thus,
pal-
glyccrol-3-phos-
of fructose
half
concentration
fructose,
idea
[ U-’4C]glucosc
in the
could
estenification
fructose.
metabolic
above
as a result
at 8.9 mmol/L,
pathways.
Initially,
there is no endog-
knowledge
role
does not appear
to be rate-limiting
on esterifiit is possible
that boosting
its concentration
fractional
[‘4C]fructosc.
in ketone
in the various
metabolic
of fructose
label because
of free
some
the
availability
of NEFAS,
a greater
used
a
in the ab-
from fructose
(73).
to follow
the course
common
It is
require
which
also
was
originated
been used
taken up predominantly
mainly
by the extrahepatic
above,
to a decrease
less
whereas
perfusions
found
of
there
the label is extensively
diluted.
Therefore,
although
it is not possible to quantify
the fate of fructose
in a whole
animal
or tissue
pared,
given
atoms
of the carbon
atoms
fructose
has also
pool
pools,
for the
control
studies
(72)
concentration
fructose/L,
of these
by the sugar
is no dilution
without
concenenergy-re-
the reason
is probably
which
(1.5
was
physiological
increase
liver and therefore
causes
a decrease
insulin
concentrations
of VLDL
is due
range
Some
as the
mmol
with
at the physiological
intermediates
mmollL)
is a complex
baboons
of glucose
concentration
concentration,
for the
fructose
enous
production
and
1.5
all of the carbon
fructose
tose/L,
15%
Radiolabeled
of a fruc-
availability
on
fructose
taken
there
(8.9
from
At
compared
of fructose.
came
there were
as VLDL.
the
was
sence
At 20 mmol/L,
increased
(13).
increase
of an
absorption,
or secretion
(76) was probably
these conditions.
solution
significant
raised
in the
boosted
the effect
progressively
was
fructokinase
(106).
Fructose
glycerol-3-phosphate
conversion
intermediate
activity
intake
responsible
for many
diet on lipid
on carbohydrate
increased
or sucrose
feeding
dehydrogenase,
longas well
In the
in rats on a fructose-rich
also
(107,
on a fructose
diet,
rats increased
creased
liver
substantially
PDH activity
tamed
genesis
and triglyceride
formation,
ATP-citratc
lyase (108,
111,
112),
acetyl-CoA
carboxylase
(111-113),
fatty
acid synthase
with
fructose
within
in perfused
physiological
livers
from
concentrations
fed animals
we studand
showed
diet,
via the glycolytic
108). After 50 d
animals
by using
lower but still unphysiological
concentrations
of fructose
(73, 101). To test whether
this effect
could
be obied ketogenesis
not on a sucrose
diet
increased
the activity
of
which
is necessary
for the
of fructose
to glycerol-3-phosphate
dihydroxyacetone
phosphate
but
of the
metabolism.
metabolism.
pyruvate
(109).
Similarly
fructose
in rats (1 10). In the pathway
kinase
in
diets
inof lipo-
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
a 20%
ketogenesis
(46). When
simultane-
range
production
to
a comparable
infusion
to test
under
that
secretion
then infused
VLDL
found
high-fructose
concentrations
reduced
VLDL
output
under
When
(73)
with
the physiological
lipoprotein
the
the effect
of fructose
physiological
concentration,
of the
tration.
out
the
within
L). At the higher
are unique
concentrations
sucrose
digestion
and
in NEFA esterification
concentration
in pro-
759S
FRUCTOSE
fructose
[‘4C]NEFA
estenification
and [‘4C]VLDL
similar
amounts
of the two sugars
were
ously
to simulate
no further
increases
of insulin
secretion.
physiological
perfusate
effect
OF
760S
MAYES
(1 1 i-i
14),
and
phosphatidate
phosphohydrolase
(1 15)
are
re-
plasma
triglyceride
crose
ing power
(107-109,
poprotcin
trations
lipase
activity
of triglyceride
cluding
humans,
(107,
for lipogencsis-glucose-6-phosphatc
iii,
112, 116), 6-phosphogluconate
108,
1 1 1, 1 12),
enzyme’)
Many
(107,
of these
unique
their
for
adaptive
fructose
activities
of soluble
NADP
changes
(107),
kinase,
reduces
this
the activities
lyase,
malate
dehydrogenase
or starch
enhances
activity
will
general
interest
is that
tissue,
(52).
whereas
It would
that lipogenesis
tissue of sucrose-
fed
with
conclusion
animals.
In keeping
acctyl-CoA
acyl-CoA
(1 17, 1 18), acetoacetyl-CoA,
(1 17).
However,
to increase
(120)
in liver
or sucrose
(121,
122),
long-chain
(lipogenesis)
rats
as measured
fed
has
either
directly
by using
la-
than in rats on a glucose
diet (125).
In isolated
livers
perfused
with whole
blood,
pogenesis
in rats that had been fed the standard
we studied
laboratory
or a sucrose-supplemented
the
diet
(13,
126).
Half
with fructose
to maintain
a physiological
of 1 .4 mmolfL.
Incorporation
of 3H2O
acylglycerol
fatty
of perfusions
acids
Thus,
lipogenesis
fructose
specifically
to those
found
enhanced
ids,
not
fructose
in liver
slices
from
and
rats
of the lipogenic
clearly
based
tose (127).
This
view of the fact
in the group
into sucrose-fed
diet,
slices
from
on
into fatty
specific
to different
adaptations
to fatty
rats
acids but not
and selective
sugars
previously
in the diet,
discussed.
increase
in both humans
and
carbohydrate,
especially
sucrose
has been,
that raised
ac-
a fructose
and still is, of considerable
concentrations
of plasma
previously
triglyceride
described,
from
all lead
the liver,
to increased
interest
triglyceride
increasing
the
amount
tion. The resultant
concentration
of triglyceride
the rate of hydrolysis
by lipoprotein
lipase and
of this
enzyme
would
also
lead
to increased
output
in
of VLDL
of secretion
adipose
61),
because
under
conditions
precursors
they
of fruc-
of VLDL
will
augment
or -sucrose
triglyc-
VLDL
diets.
for-
Mindful
of
[1-’4C]oleate
in those
oxidation
derived
animals
more
than
and
NEFA
in both
from
were
(126).
the
livers
with
Because
estenification
rats.
When
fructose,
shifts
of NEFAs
tnwith
sucrose-fed
infused
doubled.
VLDL
infused
the
in balance
in the
direction
of estenification
have been shown
to increase
secretion
of VLDL
triglyceride
(89), we also measured
these indexes.
Oxidation
of
[ 4C]oleatc
to 4C0
was highest
and estenification
was lowest
in
perfusions
infusion
bination
lowest
when
livers from
or sucrose
feeding
and
increased
output of [‘4C]VLDL.
in the combined
group
has been
reviewed
a review
of a large
number
Similar
average
It was
that
cornthe
and
metabolism
concluded
normal
quantities
conclusions
of fructose
to plasma
normal
addition,
the combination
would
appear
to favor
have
this is only
information
of triglycerides,
condition
was exac-
defects
in carbohydrate
metabolism
even with low intakes
of fruc-
apply
than
from
individuals
concentrations.
However,
clearance
and does not give
and postprandial
concentrations
be raised
on these diets. The
if higher
The
on lipid
131).
of studies
in individuals
having
to hypertniglycenidemia,
increase
126).
of fructose
(130,
containing
normal
fasting
triglyceride
a measure
of triglyceride
tose.
of [‘4C]VLDL.
The marked
extra increase
in VLDL
output
was probably
due to increased
lipogenesis
in humans
erbated
leading
animals
were used.
the balance
in favor
plus sucrose
feeding
showed
the highest
rate of estenification
from fructose
in this group
(13,
The potential
adverse
effects
diets
normal
shifted
output
of fructose
infusion
rate of oxidation
and
of fructose
amounts
cholesterol,
which
of VLDLS
may
arc present.
In
of saturated
fat and fructose
in the diet
elevated
cholesterol
concentrations.
of
on
The hyperuricemic
It was
and
effect
first reported
intravenously
uric acid.
depends
on
impairment
concentrations
Effects
fructose
in the circulaalso
any
from
(60,
rats when
and fruc-
may be an independent
factor associated
with coronary
heart discase (128).
The adaptive
changes
in enzyme
activity,
evidence
of increase
in lipogenic
potential,
plus the direct actions
of fructose
major
increased
and
on prandial
which
might
which
with
sucrose-fed
consuming
rats.
diets but only when
This finding
is similar
of [‘4C]glucose
where
adaptations
on the enzyme
Plasma
triglycerides
diets are enriched
with
perfusate
into liver
on a glucose
incorporated
[‘4Cjfructose
They demonstrate
the highly
nature
only
infused
the conversion
‘4Cjfructose,
diet selectively
[‘4C]glucose.
significantly
was
is increased
on sucrose
acts as the substrate.
selectively
but
increased
in which
lidiet
perfusions
were infused
concentration
alone
of estenification
diet
by
of NEFAs
within
adipose
in adipose
tissue depends
on
on high-fructose
infused
from
control
Fructose
was incorporated
more rapidly
into fatty acids and
glycerol
in plasma
and liver in rats on a fructose
secretion
catabolism.
of NEFAs
concentration
Therefore,
production
between
beled acetate
or tritiated
water.
Increased
incorporation
of labeled
fructose
has also been shown
(118,
i23).
In the whole
animal,
incorporation
of tritiated
water into liver fatty acids was elevated
in rats fed fructose
compared
with those fed glucose
(124).
Also,
F‘4C]fructosc
acylglycerol
livers
livers
been
of li-
the fact that NEFAs
arc always
present
in plasma,
we studied
the
effects
on VLDL
secretion
of a physiological
infusion
of fructose, and of sucrose
supplementation
of the diet, in isolated
per-
fructose
fructose
of VLDL
of VLDL
is depressed
are the
(71).
in animals
glyceride
concentrations
acids
from
rate
the release
which
liver
su-
increases
an enhancement
rate
its plasma
NEFAs
in the
mation
rate
slices
enhances
utilization,
fused
pyruvate,
and
glycerol-3-phosphate
apparently
do not increase
(119).
Biosynthesis
of long-chain
fatty
shown
glucose
from a
is elevated
in
or fructose-
are elevated:
an increased
an increased
increasing
feeding.
eride
the concentrations
in the liver
indicating
or
and
(52). Therefore,
raised
plasma
concenin fructoseor sucrose-fed
animals,
in-
with
feeding
fructose
(55-58)
to both
intolerance,
The
specific
detectible
because
(132)
there
infusion
metabolism
of fructose
that
normal
hyperunicemic
the fructose
to cause
purine
when
children
was
appears
to be > 0.5
hyperunicemia.
comparable
and
an increase
effect
needs
fructose
infusions
Also,
was
those
administered
with
in serum
to be dose
gkg
the
of either
hereditary
and
body
effect
glucose
urinary
dependent
wt
‘
is fructose
or galac-
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
malate,
this
intermediates
tose
NADP
feeding
appear
activities
in adipose
glucose
fatty
and
long-term
of a decreased
rate of re-esterification
tissue (69). Esterification
of NEFAs
pyruvate
carboxylase,
review
of these enzyme
the livers but depressed
of the following
effect
activity,
reflects
together
(60),
However,
in hyperinsulinemia
lipolytic
Fructose
tissue
sucrose
of hexokinase,
dehydrogenase,
in adipose
their activities
increase
results
hepanin
the liver
arc not
also
is a more
acetyl-CoA
glucose-6-phosphatc
in activity.
enzyme
feeding
that
(‘malic
increased
Of considerable
ATP-citrate
synthase,
in liver
illustrating
feeding
PDH,
dehydrogenase
all
glucose
post
dehydrogenase
dehydrogcnase
malate
1 16)-are
because
carbohydrates.
or fructose
acid
and
1 1 1, 1 12,
feeding
(129).
ported
to be increased
in activity
in animals
on fructose-containing diets. Also, the enzymes
responsible
for generation
of reduc-
METABOLISM
tose
do
tients
not
raise
the
suffering
istration
plasma
from
than
are
uric
gout
arc
normal
acid
more
as
are
diabetics
(130).
effect
The
curred
in all groups
those
subjects,
suming
9%
but
or
higher
of feeding
than
as fructose)
it was
offspring
of
18%
showed
hyperunicemia
have
tose
lower
serum
diets;
cemia
marked
energy
increases
healthy
Adenosine
con-
as sucrose
in serum
Note
that
conccntrations
individuals
a diet
when
Adenylo-
may
high
be
at
9 steps
Inossne
of
5-Phosphoribosylamine
p
do
ATP
AMP.
MJdIEOS1O#{128}
lower-fruc-
risk
IMP4
acid
patients
fed
2ADP
1
(ic,
uric
gouty
3.f
in
Subjects
intake
1P
gout,
oc-
prolonged
gout.
AMP+ATP
of 1 g!
that the average
intake
of fructose
is on the borderline
for provoking
acid
consuming
and
with
individuals.
uric
even
when
more
parents,
significant
in normal
at a dose
subjects,
in patients
with
gout (78).
Hyperunicemia
of their
(130).
These
results
suggest
or sucrose
in a mixed
diet
fructose
FRUCTOSE
e
consumed
studied
in healthy
of parents
with
FRUCTOSE
These
administered
parenterally,
but is it posuric acid concentrations
when fructose
is
orally?
ICT1
(133).
Pato fructose
admin-
results
apply to fructose
sible to increase
blood
kg body wt was
and in children
76lS
FRUCTOSE
concentration
sensitive
subjects,
OF
GMP
I
4
hyperuni-
PRPP
GL.UTAMYI.
M4IDOTR4jG:ER*.SE
Hypoxanthine
in fructose.
A
Pathways
of adenine
catabolism
mechanism
of the
and biosynthesis
PRPP
(O)DASE)
To
understand
the
fructose
regulation
a knowledge
is necessary.
between
the
(ADP),
and
three adenine
adenine
However,
pathway
of
reverse
of
action
as with
the
pathway
of AMP
patocytes
for AMP
many
of
of
other
adenine
deaminase.
indicated
as that
intracellular
of this
enzyme.
xanthine
and
its
common
is then
Alternatively,
but experiments
appears
adeninc
Inosinc
by
5’-
1-pyrophosphate;
be
he-
a route
reaction
is an important
down
and
to uric
other
step
and
inhibitor
acid
primates
via
hypo-
this
is the
end product
of purinc
metabolism
and is excreted
as such, but
other mammals
possess
the enzyme
unicase,
which
allows
further
oxidation
to the much more soluble
allantoin.
A consequence
of
the absence
of unicase
in humans
is the occurrence
of gout, which
is associated
with
hypcruniccmia.
IMP is also the first formed
punine
nucleotide
of de novo synthesis
from nibose 5-phosphate.
volves
no less than 1 1 separate
first two need to be mentioned
controlling
reactions,
both
in the pathway
This pathway
in-
steps (137).
Of these,
because
they catalyze
of which
are held
in check
back regulation
because
of high concentrations
otides.
In addition,
5-phosphonibosyl-1-pyrophosphatc
the product
of the
first
reaction
in the
activator
of the second
reaction
PRPP glutamyl
amidotransferase
Mechanism
The
fructose
underlying
essential
finding
administration
the observation
that
that
caused
it was
by a feed-
of puninc
pathway
in the pathway
(Fig 2).
the hyperuricemic
only the
the rate-
action
nude(PRPP),
by
of fructose
led to the explanation
as to why
increased
uric acid formation
was
accompanied
by a sharp
fall
Ribose
GMP,
in hepatic
guanosine
IMP,
AlT
(27).
Thus,
involves
the
rapid
adenosine
this
sequence
but also
of events
phosphorylation
because
in total
became
apparent
accumulated
and
after
not only
Pi, organic
5-phosphonibosyl-
of a shortage
adeninc
nucleotides
when
it was
Pi concentrations
fructose
of the
phate because
of the high activity
depletion
of ATP due to inhibition
of ADP
triphosphate;
PRPP,
monophosphate.
concentration
(76). The reason
for
that fructosc-1-phosphatc
fructose
metabolism
and uric acid
AMP, adenosine
monophosphate:
monophosphate;
inosine
5-P
sugar
shown
fell
administration
to fructose-1-phos-
of fructokinase.
of oxidative
This leads
phosphorylation
of Pi sequestered
in fructose-i-
to
phosphate.
The lowering
of AlP
concentration
is also assisted
by the activity
of tniokinase
in utilizing
Al?
in the phosphorylation of glyceraldehyde
to glyccraldehyde-3-phosphatc.
The depletion
of Pi and
hibition
deaminase
on the
and
centration
that
pletion
ATP
leads
depletion
to the
adenine
removal
degrade
There
to increased
of the total
The
leads
enzymes
that
5’-nuclcotidase.
formation
nucleotide
of adenine
of the
cleotides
removes
in the pathway
amidotransferase.
the
of uric
also
tivator
of PRPP
thesis.
If 5’-nucleotidase
uric
acid
rather
glutamyl
than
inhibition
by PRPP
production
leads
converted
production
of uric acid from
mented
by dc novo synthesis.
active,
to AMP.
the adenine
acid
with
de-
to stimulation
as a feedback
of adenine
of the
synthetase
of PRPP
first
renu-
two
steps
and PRPP glutamyl
acts as a further
ac-
amidotransferase,
is still
inAMP
con-
pool.
nucleotides
allostenic
catalyzed
The
allostenic
AMP,
respectively,
is a rise in inosinc
of the pathway
of punine
nucleotide
synthesis
action
(Fig 2). The lowering
of the concentration
is an allostenic
catalyzed
acid
FIG 2. The relationship
between
formation
in the liver. P. phosphate;
ADP, adenosine
diphosphate;
ATP,
inosine
may
in isolated
to be the rate-limiting
nucleotides
(134-136),
is broken
In humans
Uric
phosphate;
that this is not as important
via IMP. In addition,
the
concentrations
xanthinc.
path-
removed
PRPP
SYN1ETASE
all
via
by the
AMP
I
XANTHINE
simple
degradative
from
AlP
S
(OXIDASE)
the
the
ADP.
4
o&{DmGB
metabolites,
In the
AMP.
Xanthine
_____________
diphosphate
is not
is formed
Phosphate
catalyzed
by AMP deaminase
in the breakdown
of hepatic
Pi at normal
metabolism
and
maintains
equilibrium
nucleotides
(IMP)
to form
inosine.
AMP via adenosinc
(31) have
degradation
of
adenosinc
biosynthesis.
monophosphate
nucleotidase
formed
from
ATP,
effect
monophosphate
(AMP)
(Fig 2). Thus,
are able to be degraded
and formed
degradation
inosine
nucleotide
kinase
nucleotides
adenosine
nuclcotides
AMP.
way,
of puninc
Adenylate
hyperunicemic
leading
IMP
will
In this
nuclcotidc
to IMP
syn-
be degraded
way
the
pool
to
initial
is aug-
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
nucleotide
XANTHINE
762S
MAYES
The
reduction
in concentration
phosphates
has
functions
of free
dependent
energy,
eg,
synthesis
other
of ATP
profound
effects
and
other
high
on metabolism
on a continual
supply
inhibition
of protein
energy
and
of these
(76) and
It will
other
be apparent
contributions
vital sources
nucleic
acid
(138).
lular
and
processes
Many
investigations
both
in vivo
and
in vitro
out by using unphysiological
concentrations
tions made
from such observations
can
larly
when
sucrose
applied
and
compiling
to humans
fructose.
this
This
been
of fructose.
be misleading,
consuming
aspect
have
normal
has been
Deducparticu-
taken
into
account
allows
a greater
liver-fructokinase,
ready
access
saturation
lactate
of the
production,
aldolase
B, and
tniose phosphate
to the
and
Glucose
hanced
production,
glycogenesis,
but there is an immediate
and
pathways
body
leading
production
estenification
of
fructose
changed.
and
shift
with
and
domi-
dioxide
under
for-
fructose
load.
lipogenesis
are not enin the balance
between
of NEFAs
of enzyme
in favor
of estenification.
and
enzymes
liver,
in the
adaptation
glucose-6-phosphatase
and glucose.
Enhanced
but
not
leads
long-term
tissue,
is
gly-
more fructose
of lipogenic
stimulates
Fructose
consequent
raised
VLDL
production.
plasma
NEFA
The increased
centrations
utilization
glucose
tolerance
and
quent
hypeninsulinemia.
metabolism
concentrations
triglyceride
in adipose
of glucose
and
with
Acute
loading
little
hyperunicemia.
This
rylation
of fructose
preventing
the
in LDL
liver
with
Both
can
be
adeninc
demonstrated
tentially
hyperlipidemic
quantities
of fructose
pool
and
of AlT
in humans.
and
a cause
from
generation
hyperuricemic
ADP.
of uric
effects
Although
and
critical
pro-
in humans
both
are
of fructose
con-
in the blood,
at which
and hyperunicemia
ddeoccur.
spectroscopy
is clearly
in monitoring
metabolites.
these
Be-
acid.
of fructose
effects
may
be at increased
who
risk.
take
of value
intracellular
changes
as
in
U
Proc
Nutr
Soc
1973;32:
of
with
12A-B.
DL, Mayes
Crossley
PA. Comparative
and
carbohydrate
effects
metabolism
of fructose
and glu-
of perfused
rat liver.
1976;36:113-26.
I, Turner U. Serum fructose levels after sucrose
monosaccharides.
Lancet 1968; 1:841-3.
JN,
Macdonald
I. The
influence
in male
baboons
or its
of a high
sucrose diet on the portal and arterial levels of glucose and fructose
following
a sucrose meal. Nutr Metab 1970;12:171-8.
9. BjOrkman
0, Felig P. Role of the kidney in the metabolism
of
fructose in 60-hour fasted humans.
Diabetes
1982:31:516-20.
10. Froesch ER, Ginsberg
JL. Fructose
metabolism
of adipose tissue.
I. Comparison
of fructose and glucose metabolism
in epididymal
adipose tissue of normal rats. J Biol Chem 1962;237:3317-24.
1 1 . Bergstrom
J, Hultman E. Synthesis
of muscle glycogen
in man after
glucose
ministration
15.
16.
17.
18.
seem
in average
fructose.
on the lipid
Br J Nutr
7. Macdonald
constituent
of
individuals
on normal
diets,
individuals
on
diets and individuals
who are actually
or p0or hyperunicemic
cose
14.
is also
of Al?
in the phosphoof Pi in fructose-1-phos-
regeneration
nucleotide
the hyperlipidemic
minimal
in healthy
very-high-fructose
amounts,
resonance
technique
of key
and
1953;2:450-8.
VLDLS
conrise in plasma
cholesterol.
fructose
is due to utilization
and sequestration
oxidative
with consethe already
cause
the enzymes
of adeninc
nucleotide
degradation
are inhibited by AlT and Pi, removal
of the inhibition
leads to destruction
of the total
precise
invasive
investigations
and
fructose
infusion.
Acta
Med
Scand
1967;182:93-107.
12. Ahlborg
G, BjOrkman
0. Splanchnic
and muscle fructose
metabolism during and after exercise.
J Appl Physiol 1990;69:1244-51.
13. Mayes PA, Laker ME. Effects of acute and long-term
fructose ad-
decreasing
increasing
insulin
resistance
This, in turn, will stimulate
change
of
eswith
and increased
NEFA
con-
in muscle,
increased
VLDL
production
by the liver. Because
tam
20% cholesterol,
there is a corresponding
cholesterol,
investi-
2. Reiser 5, Michaelis
0, Putney J, Hallfrisch
J. Effect of sucrose
feeding on the intestinal
transport
of sugars in two strains of rats.
J Nutr 1975;105:894-905.
3. Silliman
K, Coulston
AM. Sugars in the diet. In: Kretchmer
N,
Hollenbeck
CB, eds. Sugars and sweetners.
London:
CRC Press,
1991: 17-35.
4. Topping
DL, Mayes PA. The concentrations
of fructose,
glucose
and lactate in the splanchnic
blood vessels of rats absorbing
fructose. Nutr Metab 1971;13:331-8.
5.
Mendeloff
Al, Weichselbaum
TE. Role of the human liver in the
assimilation
of intravenously
administered
fructose.
Metabolism
8.
long-
causes
impaired
glucose
utilization
and impaired
of fatty acids, which promotes
release
of NEFAs
impair
noteworthy
most
1. Bruckdorfer
KR, Kang 55, Yudkin
J. Plasma concentrations
insulin, corticosterone,
lipids and sugars in rats fed on meals
of
augments
the immediate
hepatic
VLDL
triglyceride
output.
This
to hypertniglycenidemia.
phate,
feeding
allow
activity
in adipose
chain fatty acid synthesis,
which
actions
of fructose
in promoting
tissue
also
tenification
to the
diets,
the pattern
of fructose
metabolism
activity
of fructose-1,6-bisphosphatase,
cogen
synthase,
to form glycogen
the
magnetic
6. Topping
or sucrose
Enhanced
involving
systematic
of its concentration
such as hyperlipidemia
a noninvasive
the concentration
glucose
pathway
PDH,
to carbon
when
the phosfed state,
This leads to augmented
output
of VLDLS
from the liver. In the
liver of starved
animals,
the enzymes
of gluconeogenesis
are active and fructose
will form much more glucose
under these conditions.
As a result
been
19.
in man.
20.
on liver
lipid
metabolism.
In:
Macdonald
I, Vrana
A,
eds. Metabolic
effects
of dietary
carbohydrates.
Prog Biochem
Pharmacol
1986;21 :33-58.
Holdsworth
CD, Dawson AM. Absorption
of fructose in man. Proc
Soc Exp Biol Med 1965;118:142-5.
Hers HG. Fructose
metabolism.
(La m#{233}tabolisme du fructose.)
Brussels:
Arscia, 1957 (in French).
Wilson TH, Vincent TN. Absorption
of sugars in vitro by the intestine of the golden hamster. J Biol Chem 1955:216:851-66.
Ginsburg
V, Hers HG. On the conversion
of fructose to glucose by
guinea pig intestine.
Biochim
Biophys
Acta 1960:38:427-34.
Shoemaker
WC, Yanof HM, Turk LN, Wilson TH. Glucose
and
fructose
absorption
in the unanesthetized
dog. Gastroenterology
l963;44:654-63.
Cook GC, Jacobson
J. Individual
variation
in fructose metabolism
Br J Nutr
1971;26:187-95.
Hers HG. Fructokinase
Biochim
Biophys Acta
of the liver.
1952;8:416-23.
(La
fructokinase
du foie.)
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
of the
mation
oxidation
oxidative
glycolysis
activation
nance
ketone
have
in humans,
References
in the
fructose
pool and all pathways
leading
from it, after bypassing
phofructokinase
regulatory
step in glycolysis.
In the
this
there
in
review.
Specific
enzymes
tniokinase-allow
consequent
Nuclear
of
that
to ascertain
sumption
and
tenious
effects
carried
quantities
is required,
It is clear
needed
conclusions
although
metabolism
gations
have been carried
out in laboratory
animals,
particularly
rats. This is inevitable
when
precise
information
about
intracelcedures.
Summary
that
on fructose
METABOLISM
21.
Hers HG. Tniokinase.
in enzymology.
22.
Underwood
nase
In: Colowick
Academic
AH,
from
rat
Newsholme
liver
SP, Kaplan
Press,
and
New
relation
to the
features
24.
in the
of phosphofructoki-
ciency.
control
Cell Regul
Murray
RK,
perfused
effects
44.
of glycolysis
in liver.
livers
I. General
of rats.
J Biol
of fructose
in the liver.
Curr
biochemistry.
DK,
23rd
ed.
Mayes
PA,
Rodwell
Norwalk,
CT:
VW.
Appleton
Harper’s
Sestoff
tose
L, Fleron
Biochim
27.
P. Determination
transport
and
Biophys
Woods
and
in
the
constants
of fruc-
perfused
rat
LV, Krebs
HA. The cause
of fructose-i-phosphate
on
fructose
liver.
of hepatic
loading.
accu-
Biochem
29.
Gunther
Scand
using
assay
with a specific
l-phosphofructokinase.
OH,
L, Max
glycerol
in liver
P, Chyu
KJ.
and glucose
and kidney.
Effect
33.
the
34.
35.
of large
mucosa
galactose.
Acta
Lamers
JMJ,
on metabolites
J Biol Chem
fructose
loads
in different
during
means
Scand
HUlsmann
WC.
of
‘P
Kayc
to
the
acids formed
of fructose,
The
effect
resonance
ML,
Barbero
accumulation
of
LV,
Woods
fructose-i-phosphate.
fructose
on
glycolytic
intermediates.
R. Effects
of fructose
Lancet
l971;1:366-9.
The
HF.
Activation
FEBS
52.
53.
54.
and
the
stores
control
of liver
40.
on
57.
58.
to utilization
and
J Clin Invest
the
Stockholm:
of glycogen
activity
Royal
infusion
on
pyruvate
kinase
on
1978;31:1305-1
and glurat liver.
in man.
varying
various
me-
1.
rate of gluconeogenesis
rat liver. Biochem
from
J 1967;
DL. Effects
metabolism,
heat
Nutr
Diet
effects
2 years
of fructose
production
Biochem
P. Metabolic
Res
2,6-bisphosphate
concentraand
substrate
J 1979:184:501-7.
of high
sucrose
or fructose
1983;42:56-lOi.
Uram J, Friedman
L, Kline 0. Influence
of diet on glucose tolerance. Am J Physiol 1958:192:521-4.
Cohen A, Teitelbaum
A, Balogh M, Green J. Effect of interchanging
bread
diet
on
and
the
sucrose
as main
glucose
tolerance
source
curve
of carbohydrate
of healthy
in a low
volunteer
fat
subjects.
Am J Clin Nutr 1966:19:59-62.
Shafrir E, Teitelbaum
A, Cohen AM. Hyperlipidemia
and impaired
glucose tolerance
in Acomys
cahirinus
maintained
on synthetic
carbohydrate
diets. Isr J Med Sci l972;8:990-2.
Bruckdorfer
KR,
Yudkin
sucrose
in the
pig.
Reaven
GM,
Risser
J. A comparison
Nutr
Metab
of
TR, Chen
YDI,
of dietary-induced
induced
dietary
starch
and
1975;i9:225-32.
Reaven
EP. Characterization
hypertriglycenidemia
obese rats. J Lipid Res i979;20:371-8.
Sleder J, Chen YDI, Cully MD, Reaven
in young,
non-
GM. Hypeninsulinemia
hypertniglycenidemia
Vr#{225}naA, Slabochov#{225} Z, Fabry
in
the
rat.
in
Metabolism
starch
and
or sucrose
insulin
P, Kazdov#{225} L. Influence
content
sensitivity
on glucose
in rats.
tolerance,
Physiol
of diet
serum
Bohemoslov
with
insulin
1974;
liver.
Annu
G, Hers
HG. Effect
phosphorylase
of Sciences,
of frucand
RE.
Decrease
and
62.
63.
Hauhart
EM,
dietary
syn-
1973.
Thurston
Jones
by
liver
inhibition
of
64.
liver glycogen
phosphorylase
after fructose.
An experimental
model for the study of hereditary
fructose
intolerance.
Diabetes
65.
1974;23:597-604.
U, Froesch
ER. Inhibition
a-glycerophosphate
Vr#{225}na
A, Fabry P. Effect of dietary fructose
on free fatty acid
release from adipose tissue and serum free fatty acid concentration
in the rat. Nutr Metab 1974;17:74-83.
Merkens
IS, Tepperman
HM, Tepperman
J. Effects of short-term
tion.
of glycogen
Academy
in the
42.
tose-1-phosphate,
World
level
61.
metabolism
Glycogen
synthesis
in the perfused
rats. Biochem
J 1975;150:153-65.
Kaufmann
Nutr
or sorbitol
rat hepatocytes.
Vr#{225}na
A, Fabry
a high
60.
lactate
Whitton
PD, Hems DA.
of streptozotocin-diabetic
43.
J Clin
OH, Topping
in isolated
of a model
59.
of glucose
41.
JH,
fructose,
Biochem
carbohydrate
fructose
Lett 1970;6:43-5.
Rev Biochem
1976;45:167-89.
Hue L, Stalmans
W, Van den Berghe
thetase.
Am
DG, Filsell
on
cycling
Biochimie
study
with reference
Hers
injection
sucrose,
in blood.
Clark
tion
within
glucose
spectroscopy.
39.
tose
HG.
Munksgaard:
23:305-10.
H, Scalettar
Eggleston
of glucose,
J 1982;206:l-i2.
56.
of
G. Comparative
in infants
and uric acid metabolism.
38.
load
E. Fructose
of the
1942;4:225-48.
magnetic
metabolism
Sahebjami
administration
Copenhagen,
HG, Van Schaftingen
1958:37:752-62.
37.
of the
1980;29:303-5.
R, Williams
and fructose
metabolism.
its discovery.
1991 ;73: 105-8.
36.
of hepatic
after
55.
absorption
Physiol
parts
of energy-rich
phosphate
in rat jejunum
in vivo. Biochim Biophys
Acta 1973;3l3:l-8.
Segebarth
C, Gnivegn#{233}eAR, Longo R, Luyten PR, den Hollander
JA. In vivo monitoring
of fructose metabolism
in the human liver
by
Regulation
intake.
J Biol Chem 1980;255:8239-44.
K. The hexosemonophosphonic
intestinal
Effect
Hers
of
3 1 . Van den Berghe G. Fructose:
metabolism
and short-term
effects on
carbohydrate
and purine metabolic
pathways.
In: Macdonald
I,
Vrana A, eds. Metabolic
effects of dietary carbohydrates.
Prog
Biochem
Pharmacol
1986;21:i-32.
32. Burch HB, Choi 5, Dence CN, Alvey TR, Cole BR, Lowry OH.
effects
HG.
50.
1970;245:2092-102.
rat nephron.
Kjerulf-Jensen
L, Hers
Ross BD, Hems R, Krebs HA. The
various
precursors
in the perfused
51.
Meinhardt
fructose,
dihydroxyacetone,
and related
compounds
Metabolic
G, Hue
49.
Enzymol
1967:8:341-52.
Lowry
defi-
1973;3:407-13.
of phosphorylase-a
and
fructose-
by fruc1 ,6-diphos-
glucose
J Nutr
and
fructose
on rat
serum
triglyceride
concentra-
1980;110:982-8.
Bender AE, Thadini PV. Some metabolic
effects of dietary sucrose.
Nutr Metab i970;i2:22-39.
Tuovinen
CGR, Bender AE. Some metabolic
effects of prolonged
feeding of starch, sucrose,
fructose
and carbohydrate-free
diet in
the rat. Nutr Metab 1975;19:i6i-72.
Freedland
RA, Harper AE. Metabolic
adaptations
in higher animals. I. Dietary
effects
on liver glucose-6-phosphatase.
J Biol
Chem 1957;228:743-5
1.
Vr#{225}na
A, Fabry P. Kazdov#{225}L. Liver glycogen
synthesis
and glucose
tolerance
fructose
in rats
or glucose.
adapted
Nutr
Metab
to diets
with
1978;22:262-8.
a high
proportion
of
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
HB,
Berghe
in heredi-
1,6-diphosphatase
102:942-51.
A, Sols A. Fructokinase
method
Biol Clin (Basel)
Bunch
in the liver tissue
and glycerol. Acta
1942;4:249-58.
MA, Sillero
spectrophotometnic
30.
den
tabolites
Kjerulf-Jensen
K. The phosphate
esters formed
of rats and rabbits during assimilation
of hexoses
Physiol
Eur J Clin Invest
hypoglycemia
fructose-
of fructose,
on the glycogenolytic
action of glucagon.
An investigation of the pathogeny
of hereditary
fructose intolerance.
Biochem
J 1973;l34:637-45.
Hers HG, Stalmans
W, de Wuif H, Laloux M, Hue L. The control
of glycogen
metabolism
in the liver. In: Lundquist
F, Tygstrup
N,
the
J
l970;1 19:501-10.
28.
and
46. Topping
DL, Mayes PA. Comparative
effects of fructose
cose on the lipid and carbohydrate
metabolism
of perfused
BrJ Nutr i976;36:113.-26.
47. Cook GC. Absorption
and metabolism
of D(-)
fructose
Am J Clin Nutr 1971;24:i302-7.
48. Macdonald
I, Keyser A, Pacy D. Some effects in man of
Lange,
1974:345:27-38.
HF, Eggleston
mulation
of the kinetic
phosphorylation
Acta
Van
for fructose-induced
intolerance
1974:237-49.
1993:206-11.
26.
fructose
eds.
1978;13:97-135.
Granner
Explanation
tary
45.
Chem 1967;242:2622-36.
Van den Berghe G. Metabolic
Top
25.
of gluconeogenesis
phate.
l962;5:362-4.
and gluconeogenesis.
Biochem
J 1965;95:868-75.
23. Exton JH, Park CR. Control of gluconeogenesis
763S
FRUCTOSE
NO, eds. Methods
York:
EA. Properties
their
OF
MAYES
764S
66.
Vr#{225}naA,
Fabry
P. Kazdov#{225} L, Zvolankov#{225} K. Effect
and proportion
liver
and
of dietary
muscle
carbohydrate
glycogen
on serum
synthesis
in
of the
glucose
the
rat.
type
levels
Nutr
87.
and
67.
Kelsay
JL,
88.
Behall
KM,
of carbohydrate
tabolism
69.
and
by diaphragm
Metabolism
Vr#{225}na
A, Fabry
Prather
use
ES.
of oral
I. Blood
R, Fabry
cenidemia.
and
The
effect
on me-
lactate,
uric
of rats
with
90.
fructose
and
induced
fatty
acid
P,
Sj#{246}strOm L.
from
in the
adipose
rat.
hypertrigly-
and
Metab
serum
lations
and
some
Carbohydrate
quantitative
storage
in
considerations.
man:
1978;
Ri,
Felts
JM,
cnous
triglycerides
Van
Duyne
in blood
CM.
plasma
Formation
and
fate
of rabbits.
J Lipid
of endogRes
Soling
1962;
isolated
B, Janson
perfused
rat
G. Ketogenic
and
guinea
action
pig
liver.
of fructose
FEBS
Lett
in
Laker
in
1970;
the
Mayes
PA.
perfused
Wieland
rat
OH,
[U-’4C]
liver.
Siess
pyruvate
In: Davies
bridge:
75.
Fructose
Biochem
DD,
ME,
sulin
on
and
Soc
lipid
metabolism
Trans
95.
1979:7:1279-
hepatic
activity.
of biological
Press,
i968;i6i:
96.
Cam-
Biophys
and
effects
Acta
and
97.
pyruvate
adenine
F,
Corte
Stefano
Romsos
in
DR,
vivo
ED,
Bonetti
Leveille
fatty
on protein
98.
synthesis.
DL,
hyperuricaemia.
E,
Abbondanza
Lancet
A,
hyperunicaemia.
Effect
synthesis
of dietary
in
PA.
the
Effects
concentrations
rat liver.
C, Loffler
hydrogenase
99.
Abbati
A,
Lancet
1970;
fructose
rat.
on in vitro
Biochim
and
Biophys
Zakim
in
the
of fructose
and
Biochem
G, Wieland
D, Herman
cose
on
the
Biochim
83.
Bunch
pyruvate
Trans
Soc
OH.
isolated
tone.
84.
concentration
on ad-
dehydrogenase
activ-
1977;5:1001-2.
Interconversion
perfused
rat
Biochem
0,
of pyruvate
liver.
Eur
de-
85.
Exton
given
(Zu
Life
McGarry
amounts
Res
Regulation
metabolism
of hepatic
Annu
Rev
in the
fatty
acid
Biochem
liver.
oxidation
1980:49:395-
PA. The immediate
effects
of the perfused
acid
oxidation
liver.
and
D, Martin
by
and fruc-
in lipoprotein
estenification,
Biochem
Monianity
of insulin
Changes
lipogenesis
and
J 1972:126:295-311.
DB.
Regulation
insulin
and
of hepatic
glucagon.
acetyl
J Biol
Chem
R, Chnistiansen
R, Chnistopherson
in fatty
acid
utilization.
BO,
Bremer
Cinc
Res
J. The
i976;38:I-
Declerecq
PE,
Debeen
Ii,
Mannaerts
and glycerophosphate
of hepatic
GP.
Role
acyltransferase
tniacylglycerol
synthesis.
of glycerol-3-phos-
in the nutritional
Biochem
con-
J 1982:204:247-
and
in the
Metabolic
of fructose
EJ,
effects
tivity,
ketogenesis
fused
liver.
Jourdan
J Biol
DL,
FEBS
MH.
serum
SP,
on glycerol
and
serum
Lett
1977;84:225-8.
A difference
glyceride
fatty
between
acid
male
to
rapid
D,
Mayes
PA.
acyltransferase
ac-
concentration
and
in per-
female
baboons
intravenous
in
injections
of
1969;20l:27P-8P.
P, Shafnir
E. Comparison
glycerol
Saggerson
phosphate
free
response
J Physiol
Rozen
Sooranna
of insulin
and
insulin
of changes
following
in plasma
glucose
and
free
fructose
fatty
loads.
Rawat
AK,
Menahan
and
LA.
sorbitol
Antiketogenic
in the
action
rat in vivo.
of fructose,
Diabetes
glyc-
1975:24:926-
Sestoft
Biol
liver.
Chem
Interrelation
effect
glucagon,
on
gluconeogenic
Chem
and
intermediates
Chem
acid
DW.
synthesis
i978;253:8294-300.
and
role
Acta
rat
and
1974:343:1-16.
in rat liver
tissue
in vitro.
of orally
Metabolism
administered
i97i;20:392-400.
105.
Jourdan MH. The incorporation
of fructose
and glucose,
given intravcnously,
into the serum lipids of baboons.
Nutr Metab 1972:
106.
Heinz F. The enzymes
of carbohydrate
degradation.
Prog Biochem
Pharmacol
1973;8:1-56.
Fitch WH, Chaikoff
IL. Extent and patterns
of adaptation
of enzyme activities
in livers of normal rats fed diets high in glucose
and fructose.
J Biol Chem i960;235:554-7.
Moser PB, Berdamier
CD. Effect of early sucrose
feeding on the
metabolic
patterns of mature rats. J Nutr i974;104:687-94.
Naismith
DJ. Differences
in the metabolism
of dietary carbohy-
1969;i8: 1021-5.
rat.
14:339-48.
und
107.
adeno-
108.
in per-
of malonyl-CoA
oxidation
Biophys
I. Incorporation
body
Gale MM, Crawford
MA. Different
rate of incorporation
of glucose
and fructose into plasma and liver lipids in guinea pig. Metabolism
109.
The
Biochim
Macdonald
ketone
104.
glu-
1969;244:1424-33.
Y, Foster
Y,
in the perfused
glucose,
103.
in liver III. Effects
epinephnine
metabolism.
metabolism
onthophosphate,
glucose-U’4C
and fructose-U’4C
into the triglyceride
of the liver,
plasma and adipose tissue of rats. Metabolism
1973;22: 1205-15.
Pereira JN, Jangaard
NO. Different
rates of glucose and fructose
of glycerol
glycerin
of fructose
with
Mahurama
intermediates
von
1972:247:1788-800.
L. Regulation
102.
or dihydroxyace-
Wirkungen
of gluconeogenesis
of fatty
J Biol
Topping
metabolism
i969;34:6i9-26.
fructose,
JD, Takabayashi
rat hepatocytes.
Bates
Acute
101.
1962;2:49-54.
pyruvate,
in the coordination
OH.
F. On the antiketogenic
den antiketogenen
Sci
fructose
concentration
Commun
JH, Park CR. Control
rat liver.
of intravenous
K, Lowry
sine-3’5’-monophosphate
fused
effect
large
Matschinsky
of L-lactate,
86.
Proc
100.
J Biochem
1968;165:374-9.
P, Chyu
Biophys
fructose.
fructose.)
The
a-glycerophosphate
Acta
Max
of rats
Wieland
and
RH.
hepatic
Biophys
HB,
in liver
perfusion.
Exton JH, Edson NL. The antiketogenic
action of sorbitol. Biochem
J 1964;91:478-83.
Ontko JA. Metabolism
of free fatty acids in isolated liver cells. J
Acta
i973;33: 117-22.
82.
DW.
of fat
production.
A carboxylase
ethanol
Mayes
nucleotide
Patzelt
GA.
acid
ity of perfused
81.
LA,
eraldehyde,
i-i 1.
Topping
enine
by liver
32.
K. Fructose-induced
F. Fructose-induced
1974;360:
80.
studied
Isr J Med Sci 1972:8:838-40.
nucleo-
2:1310-i.
79.
function
Regulation
ofacyltransferases
acids,
i984;795:427-30.
Liver
its effect
of in-
1253-4.
J, Raivio
Stirpe
Dc
acid
hatched
1966;7:16-29.
metabolism.
Borrebach
the
1967;2:528-31.
78.
Foster
body
fatty
fructose.
direct
secretion
Kekom#{228}ki MP.
depletion
processes.
the
lipoprotein
KO,
mam-
1973:371-400.
into
Biochim
Raivio
fructose-induced
Perheentupa
of the
modification.
by covalent
Investigations
ketogenesis,
PH,
Science
77.
PA.
L, et al. Regulation
complex
control
University
Mayes
Maenpaa
tides:
Weiss
ed. Rate
dehydrogenase
76.
EA,
dehydrogenase
Cambridge
Laker
newly
56.
ME,
malian
JM.
DL, Mayes
Witters
trol
81.
74.
Felts
JD,
Liven
on the metabolism
phate
11:324-7.
73.
of fatty
the
in isolated
drates
studied
in the
rat.
Proc
Nutn
Soc
1971;30:259-65.
1 10. Vr#{225}na
A, Roulin J, Loriette
C, Kazdov#{225}L. Basal pyruvate
dehydrogenase
activity in the liver, adipose tissue and brain of rats
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
the
Willms
of
16 to 21.
94.
HD,
1967;215:716-8.
role
3:297-308.
72.
liver
1979;254:6644-9.
93.
Havel
PA,
coenzyme
27:1853-65.
7i.
Mayes
carbohydrate
specu-
Metabolism
JM.
Drug Tox
Nature
McGarny
Stimulation
in the
J 1970;i18:259-63.
Felts
secretion,
l974;i7:7492.
Bjorntorp
PA,
tose
83.
70.
Biochem
Mayes
oflipogenesis.
in vitro
420.
of dietary
tissue
Nutr
and
chick.
91. Topping
release
concentration
Regulation
and ketone
glucose
i978;27:885-8.
acid
89.
acid,
i977;30:2016-22.
P. Kazdov#{225} L. Palmitate
AG.
in vivo
Eur Soc Study
of kind
contraceptives
urinary
P. Slabochov#{225} Z, Kazdov#{225}L. Effect
on free
fatty
PB,
Am J Clin Nutr
oxidation
free
diet
women.
Vr#{225}naA, Poledne
fructose
Moser
in the
of young
and phosphorus.
68.
synthesis
Metab
1978;22:313-20.
Goodnidge
METABOLISM
with
fructose-induced
hypentniglycenidemia.
Nutn
Rep
Int
OF
1983;
124.
E, Benchimol
perlipogenesis
diets;
1 12.
A, Orevi
in spiny
relationship
Isr J Med
Winder
WW,
Sci
Booth
on response
M. Hyperlipidemia
Acomys
mice
to peripheral
release.
1975;
FW,
of liver
Effects
of dietary
1 i4.
and
RH,
in the
liver
Biochem
and
the
pigs
on
and
tissue
126.
of exercise
fructose
diet.
Proc
lipogenic
ER, Leveille
growth,
chicks.
J. Fatty
plasma
Proc
Soc
127.
metabExp
of rats
acid synthetase
fed
1 i8.
Nutr
with
activity
various
carbohy-
Bnindley
DN.
The
involvement
and phospholipase
G,
Rozen
precursors
in rat
bohydrate.
Enzyme
Zakim
D. The
Acta
Med
synthesis.
i 19. Zakim
Biochem
terol
in rats.
Fabry
Biophys
diet on
131.
ad libitum.
in the
Am
and
albino
122.
Teppenman
123.
Chevalier
Acta
J. Influence
J Physiol
type
Dicta
of diet
into
JH,
of fatty
acids.
HE. Mechanism
diets
RS,
fructose
loading
in adipose
I. Some
high
on in vitro
Biochim
changes
fructose
utilization
liven
Proc
GA.
fatty
or
acid
effect
on hepatic
and
Biophys
Acta
in the
glucose
triglyceride
me-
diets.
Metabolism
I. Effects
tissue
Biochem
of acute
on
hepatic
Soc
Trans
Bottiger
of
plasma
SE,
Williams
i972;i
:865-8.
Cnyer
A, Riley
sucrose
and
carbohydrate
on serum
lipids.
Prog
LE.
glucose
Ischaemic
heart
triglycerides
ER,
feeding
Robinson
factor
Effects
insulin
lipase
in relation
cholesterol.
DS.
on plasma
cleaning
disease
and
to
Lancet
of fructose,
concentrations
activity
and
in the rat. Biochem
Reiser
5, Hallfnisch
Raton,
FL: CRC
Henry
RR,
J. Metabolic
Press,
Crapo
PA.
effects
of dietary
fructose.
Boca
1987.
Current
issues
in fructose
metabolism.
Annu
199i;1i:21-39.
Perheentupa
J, Raivio
K. Fructose-induced
hyperunicaemia.
Lancet
RG,
Weisberg
JS,
Meyers
AR.
Effects
of carbohydrates
acid metabolism.
Metabolism
1974:23:455-65.
den Berghe
G, Bnonfman
M, Vanneste
R, Hers
of adenosine
tniphosphate
A kinetic
study
depletion
in the
of liver adenylate
HG.
liver
deaminase.
on
The
mech-
after
a load
Biochem
Van
den
Berghe
rat
G,
Bontemps
hepatocytes.
F, Hers
Influence
HG.
of
Punine
catabolism
coformycin.
in
Biochem
J
1980; 188:913-20.
Vincent
MF,
nucleotide
lipogenesis
and
138.
Van
den
catabolism
subjected
and liven of the rat. J Nutr
diet
1973;8:216-41.
LA,
isolated
choles-
fructose
effects
sucrose
J 1977;162:601-9.
137.
of dietary
combined
secretion.
of dietary
Pharmacol
of fructose.
in
1970;29:1284-93.
and
to a high
127-8.
anism
of feeding
lipogenesis
singular
lipoprotein
values
134.
of glucose
and
The
adaptation
Carlson
Narins
136.
T. The
Effect
PA.
and
fasting
uric
Van
for
on lipogenesis
Gluconeogenesis,
Fed
on
Mayes
Macdonald
i33.
135.
on
carbohydrate
Leveille
fructose
rat.
i967;2:528-31.
car-
1968;i0:81-90.
HM.
metaphor.
Wiley
on fatty acid synthesis
102:337-42.
dietary
1959;197:55-9.
of dietary
Nutr
J, Tepperman
MM,
of the
1967;i44:242-51.
R, Kazdov#{225} L, Braun
rat.
Sherningtonian
132.
of lipogenic
synthesis
carbohydrate
of acetate-i-C’4
P, Poledne
frequency
nature
RH, Sauberlich
of high
J, Mayer
incorporation
1972;
fed
R. Effects
on hepatic
RS, Herman
Biochim
and
to the
of fructose
effects
Chnistophe
the
of rats
1972:542:205-14.
D, Pardini
rat liver.
121.
of a high fructose
organs
B, Lowy
according
the
J i974;i40:56i-3.
J
1974;i7:319-32.
effect
the differential
120.
N. Effects
in some
R, Ardouin
rats
Gardner
Rev Nutr
liver,
Scand
Y, Macdonald
of
on adipose-tissue
A activities
1975;105:1377-83.
Griffaton
of dietary
in
to anoxia.
Murray
RK,
23rd
Bode
Zelder
JC,
adenosine
i973;3:436-41.
DK,
ed. Norwalk,
0,
phosphates
of fructose
and
G, Hers
its
Biochem
Granner
chemistry.
Berghe
or sorbitol
The
pathway
in isolated
of adenine
rat
hepatocytes
J 1982:202:117-23.
Mayes
CT:
Rumpelt
and
HG.
control
PA,
Rodwell
Appleton
HJ,
Wittkamp
metabolic
effects
in man
and
VW.
Lange
Harper’s
bio-
1993:363-77.
U. Depletion
of intravenous
and in the rat. Eur J Clin
of liver
infusion
Invest
Downloaded from ajcn.nutrition.org by guest on July 14, 2014
J
117.
Y, Monita
Effect
1-1 i.
Biochem
Biol
129.
glycerolipid
activities
synthesis
Maruhama
i974;2:1
GA.
130.
enzyme
GA.
acid
very-low-density
1978; 174:667-70.
1 16. Sagawa-Katayama
Leveille
fatty
tabolism
insulin
129:439-46.
hepatic
DR,
1974;360:
i25.
128.
IH, Yudkin
adipose
of
low
Effect
to a high
source
in rats,
J 1972;
control
hy-
vivo
1972:21:835-42.
JO.
154.
AC, Miller
1 15. Sturton
G, Pritchard
PH, Han LY,
of phosphatidate
phosphohydrolase
in
and
Holloszy
enzymes
carbohydrate
Med 1975:150:220-5.
Bruckdorfer
KR, Khan
drates.
hepatic
1 i :738-52.
Fitts
lipogenic
lipogenesis
and
on carbohydrate
cahirinus)
unresponsiveness
Soc Exp Biol Med 1975:148:1150-i
I 13. Waterman
RA, Romsos
DR. Tsai
olites
Romsos
in
28: i437-44.
1 1 1 . Shafnir
765S
FRUCTOSE