Hepatic fatty acid metabolism
in pigs and rats: major
differences in endproducts,
02 uptake, and P-oxidation
SEAN H. ADAMS1
XI LIN,2 XING XIAN YIJ,l JACK ODLE,ly2 AND JAMES
lDivision
of Nutritional
Sciences and 2Department
of Animal Sciences,
University
of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
Adams, Sean H., Xi Lin, Xing Xian Yu, Jack Odle, and
James K. Drackley.
Hepatic fatty acid metabolism
in pigs
and rats: major differences in end products, O2 uptake, and
P-oxidation. Am. J. Physiol. 272 (Regulatory Integrative Comp.
Physiol. 41): R1641-R1646,
1997. -Models
of mammalian
hepatic lipid metabolism
are based largely on observations
made in adult rats, emphasizing
ketogenesis
as a primary
adjunct to mitochondrial
p-oxidation.
Studies using piglets
have illustrated
the divergent nature of intermediary
metabolism in this model, wherein ketogenesis
and p-oxidation
are
small and acetogenesis
is an important
route of fuel carbon
flux. To clarify potential
species differences in hepatic lipid
metabolism
and its control, we compared 02 consumption
and
metabolic
end products in fasted pig and rat liver homogenates treated with l-[14C]C16:0.
Carboxyl carbon accumulation in acid-soluble
products (ASP) plus CO2 was threefold
greater
and 02 consumption
was twofold greater
in rats
(P < 0.05). Unlike rats, pigs showed negligible
carboxyl carbon accumulation
in ketone bodies (3-7% of ASP), whereas
acetate was a carboxyl
carbon reservoir
in both animals
(17-31%
of ASP in pigs). Malonate
increased (-2-fold)
and
antimycin/rotenone
decreased (40-60%) radiolabel
accumulation in acetate. These data concur with the hypotheses that
comparatively
low hepatic P-oxidative flux in piglets is partially related to a smaller metabolic rate and that substantial
acetogenesis
occurs intramitochondrially
in both pigs and
rats.
acetate; ketone bodies; metabolic
rate; piglets
HAS BECOME
increasingly clear that hepatic lipid
metabolism in pigs is not adequately described by
traditional models of P-oxidation that emphasize accelerated ketogenesis concurrent with enhanced mitochondrial flux of fatty acids. For instance, the onset of
suckling in rats induces upregulation of liver enzymes
supporting ketogenesis, including mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) synthase (EC 4.1.3 5) (3 1,35) and carnitine palmitoyltransferase I (CPT-I; EC 23.121) (4, 36). Elevated ketone
body production thus results in a neonatal hyperketonemia in some species (see Ref. 12). However, in piglets,
low blood ketone bodies are observed (5, 26), and a
negligible ketogenic capacity has been reported in vitro
(10, 19, 25, 28) and after a medium-chain fatty acid
(MCFA) challenge in vivo (1). Furthermore, reported
rates of P-oxidation in liver preparations from neonatal
rabbits (9, 27) or mature rats (7, 10) are markedly
higher than liver from newborn pigs (10, 24, 28). This
phenomenon has been ascribed to a propensity for fatty
acid esterification vs. oxidation in piglets (28). The
etiology of attenuated fatty acid oxidation in piglet liver
relative to other species is not clear, but could be
related to metabolic enzyme activities (see above) and/or
IT
0363-6119/97
$5.00
Copyright
o 1997
K. DRACKLEY1y2
other phenomena such as metabolic rate. Low rates of
P-oxidation and a limited capacity for ketogenesis bring
up the possibility that alternative, nonketogenic routes
of carbon flow may predominate in swine liver (24), an
idea supported by recent observations. First, application of radio-high-performance
liquid chromatography
(HPLC) methodology to characterize organic acid end
products of radiolabeled MCFA and long-chain fatty
acid (LCFA) metabolism in piglet liver has revealed a
substantial accumulation of fatty acid carbon in acetate
and not ketone bodies (19, 25). Second, on the basis of
residual P-oxidation in the presence of respiratory
chain inhibitors (7) or O2 consumption of isolated
organelles administered LCFA substrate (37), the relative capacity of peroxisomes to carry at least the first
cycle of LCFA P-oxidation might be elevated in pigs
compared with rats.
Currently accepted principles of P-oxidation and its
control have been derived primarily from studies of
mature rats. The piglet’s apparent departure from
these well-established paradigms raises some intriguing questions addressed in the present study. What is
the basis for relatively low P-oxidation in swine? VVhat
impact would limited ketogenesis and inhibition of
P-oxidation have on cellular carbon trafficking? What is
the organellar origin of acetogenesis in liver? The
possible contribution of tissue metabolic rate in modulating P-oxidative flux was explored through measurement of O2 consumption in liver homogenates oxidizing
fatty acids. Differences in C16:O carboxyl carbon accumulation in metabolic end products were examined
after mitochondrial P-oxidation inhibition by antimycin/
rotenone (AR), and mitochondrial acetogenesis/ketogenesis in the presence of the Krebs cycle inhibitor malonate was determined. Because traditional formulations
of mammalian fat metabolism are fashioned primarily
from the exhaustively studied adult rat system and
because direct comparisons of P-oxidation between pigs
and other species are rare (1, 7, lo), metabolism in
piglet liver was compared with that in ketogenic adult
fasted rats under identical conditions. The data support prior reports of relatively low P-oxidation (7, 10)
and predominance of acetogenesis rather than ketogenesis (19, 25) in piglet liver. These observations are
extended further by results consistent with the hypothesesthat the relatively low rate of P-oxidation in piglets
is partially explained by a lower overall metabolism
and that mitochondria contribute significantly to acetogenesis.
MATERIALS
AND METHODS
Animals and liver sampling. All procedures were approved
by the University
of Illinois Laboratory Animal Care Advisory
the American
Physiological
Society
R1641
R1642
HEPATIC
FATTY
ACID
METABOLISM
Committee.
Commercial
cross-bred piglets collected within
12 h of birth (mass, 1,690 t 33 g; n = 3) and mature SpragueDawley rats (284 k 8 g, n = 3) were fasted for 24 h before
experimentation.
After pentobarbital
sodium (20 mg/kg) administration
(pigs) or ether anesthesia
and cervical dislocation (rats), livers were removed and placed in ice-cold homogenization
buffer [(in mM) 220 mannitol,
70 sucrose, 2 N-2hydroxyethylpiperazine-N
‘-2-ethanesulfonic
acid, and 0.1
EDTA, pH 7.21, and portions were homogenized
manually in
10 volumes of buffer using a Potter-Elvehjem
apparatus. Protein
yield (in mg protein/g wet wt by biuret analysis) averaged 420 ?
33 and 238 5 66 for rats and pigs, respectively Liver mass was
2.4% (rats) and 1.8% (pigs) of body weight.
Incubations.
Homogenate
incubations
to measure LCFA
P-oxidation
were performed
at 37°C as follows: 450+1 aliquots of homogenate
(-40
mg liver) were incubated
in
medium
(pH 7.4) containing
the following
(in mM): 1.0
L-carnitine
(Lonza, Basel, Switzerland),
0.5 Na-Cl6:O ([fatty
acid/bovine serum albumin ratio, 5: 1; containing
[ 1-14C]C 16:O
tracer; (ICN Biochemicals,
Irvine, CA) at 2.6-3.7 &i/pmol],
13.1 sucrose, 78.1 tris(hydroxymethyl)aminomethane
HCl,
10.5 K2HP04, 31.5 KCl, 5.0 ATP, and 1.0 NAD+, as well as
850 PM EDTA and 100 PM CoA in a final volume of 3 ml. Some
flasks contained
A/R (50 and 10 PM, respectively)
or Nazmalonate
(10 mM), which inhibit
mitochondrial
electron
transport
and succinate dehydrogenase,
respectively.
Selection of A/R concentrations
was based on previous research
(13) documenting
maximal inhibition.
Incubations
were initiated by addition of fatty acid after 5-min preincubation,
and
terminated
30 min later by addition of 250 ~160% trichloroacetic acid. Unless otherwise
stated, chemicals were purchased
from Sigma Chemical (St. Louis, MO). Radioactivity
in acidsoluble products (ASP) and CO2 (corrected for time 0 acidkilled blanks) and homogenate
O2 consumption
were determined using methods described previously (24).
Organic acid anaZysis. The ASP samples were subjected to
reversed-phase
ion-pairing
HPLC to characterize
radioactivity associated with ketone bodies and acetate (19). Separation
was achieved using a mobile phase of 0.3% H3P04 (pH 2.1,
0.65 ml/min) with a Beckman Ultrasphere
IP column (5 pm;
4.6 X 250 mm), and volumes of eluent with retention
times
corresponding
to radioactive
peaks of interest (peaks l-6,
Fig. 1) were retrieved by a fraction collector (19). Radioactivity in these samples was quantified
using liquid scintillation
spectrometry
and accounted for 80-90% (rats) to 92-100%
(pigs) of ASP radioactivity.
Not shown are similar analyses of
ASP samples using an ion-exchange
HPLC separation method
(25), which revealed
that Krebs cycle intermediates
accounted for a minimal
fraction (l-5%)
of radiolabeled
carboxy1 carbon accumulated
in ASP of rats and pigs. Real-time
characterization
of radioactive
metabolites
(see Fig. 1) was
achieved using a Radiomatics
Flo-One p-flowmonitor
(Packard Instruments,
Meridien,
CT).
Statistics. Data were subjected to analysis of variance for a
split-plot design with species as the main plot and treatments
as the subplot (Statistical
Analysis System, Cary, NC). Values
are means 2 SE and are considered significantly
different at
IN PIGS
A
AND
RATS
23f
5
RAT
PIGLET
B
2
RAT
IGLET
l
P < 0.05.
RESULTS
P-Oxidation and oxygen consumption. Accumulation
of Cl6:O carboxyl carbon in oxidative end products
(ASP and C02) is shown in Table 1. Malonate, an
inhibitor of succinate dehydrogenase, did not significantly affect the total P-oxidative flux, but, as expected,
0
5
IO
15
20
25
RETENTIONTIME (min)
Fig. 1. Example
of reverse-phase
high-performance
liquid chromatography radiochromatograms
of the acid-soluble
fraction
derived
from
l-day-old
fasted newborn
pig and mature
fasted rat liver homogenates incubated
with [1-14C3C16:0
(see MATERIALS
AND METHODS
for
details).
Incubations
were carried
out in the presence
of antimycin/
rotenone
(A/R; A) or malonate
(B) or in the absence of malonate
and
A/R (control;
C). Radioactivity
peaks l-6 correspond
to unknown A,
acetate, acetoacetate,
P-hydroxybutyrate,
unknown B, and unknown
C, respectively.
Note minimal
carboxyl
carbon radioactivity
accumulated in ketone bodies in piglet samples, the lowered
accumulation
in
ketone
bodies
with
a high proportion
of P-hydroxybutyrate
vs.
acetoacetate
in A/R-treated
rat samples,
and increased
acetate
accumulation
with malonate
treatment.
depressed the accumulation of carboxyl carbon in CO2
by 60% in rats and fivefold in pigs. Carboxyl carbon
accumulation in ASP plus CO2 in piglet homogenates
was just 35% (control and malonate) to 61% (A/R) of
that in rat preparations. Oxygen consumption in control piglet homogenates was only one-half that observed in rat preparations.
Inclusion of A/R slowed mitochondrial metabolism/poxidation in both species (Table 1). Liver O2 consumption decreased significantly in the presence of these
electron-transport inhibitors to levels just 45% of controls, whereas carboxyl carbon accumulation in CO2
was lowered by 85 and 95% in pigs and rats, respectively (Table 1).
ASP analysis. Example radiochromatographs from
HPLC separation of ASP samples derived from C16:O
HEPATIC
FATTY
ACID
METABOLISM
Table 1. Oxygen consumption
and carboxyl carbon
accumulation
in ASP and CO2 from incubations
of rat
or pig liver homogenates with [1 J4C]C1 6:0 t additions
Ofmalonate
or antimycin / rotenone (see MATERIALS AND
METHODS for details)
Treatment
Adult rats
Control
MaIonate
Antimycin/rotenone
Piglets
Control
MaIonate
Antimycin/rotenone
ASP
co2
166 + 20**
1612 16**
50 + gb*
115 1”
7+0.!jb*
0.6 + 0.03”
lO+l*
2:0.3b
51+6*
5829
30 t 2b
1+0.2b
02
Consumption
177?21**
168+16”*
51+ sbt
744 + 141$
6795223
34156
61k7"
60 5 lO*
379224
4165 10
16829
31+2b
-
Values are means + SE for n = 3 replicates/treatment
in nmol . min-’
l g liver?
ASP, acid-soluble
product.
Different
letters
within
a
column
denote
significant
difference
within
a species (PC 0.05).
* Significantly
different
versus
treatment-matched
piglet
value
(P C 0.05); “r P = 0.07. $02 consumption
was lower in piglets (P < O.Ol),
and an effect of treatment
was observed
(control
= malonate
> antimycin/rotenone,
P < 0.01).
oxidation are shown in Fig. 1. Six distinct radioactive
peaks were observed, but only acetate, acetoacetate
(AcAc), and P-hydroxybutyrate
(P-OHB) could be positively identified. Quantification of the carboxyl carbon
accumulated in these metabolites yielded a number of
important observations.
First, acetate was the predominant identifiable end
product of Cl6:O oxidation in the 24-h fasted l-day-old
pig liver, constituting 17 t 1,31? 2, and 17 t 2% ofthe
total carboxyl carbon accumulation in ASP under control, malonate, and A/R treatments, respectively (see
Fig. 2). Second, the addition of malonate doubled C16:O
carboxyl carbon accumulation (in nmol min-l g liver-l)
l
70 -
AND
Malonate
RATS
R1643
in acetate for rats (to 14.2 t 2.3) and piglets (to
18.2 t 3.8) (Fig. 2). Third, piglet liver produced minimal ketone bodies (3-7% of ASP carboxyl carbon),
which is in stark contrast to rats (Fig. 2).
l
These data provide direct evidence in support of
previous suggestions that P-oxidation is lower in pigs
compared with other species (7, 9, 10, 23, 27, 28). The
basis for comparatively
low fatty acid oxidation in
piglet hepatic tissue is not clear, but might be related to
a lower tissue-specific metabolic rate (0, consumption
per unit mass) and thus a diminished demand for
P-oxidation to meet cellular ATP requirements (23). In
fact, O2 consumption in control piglet liver preparations was only 50% that determined in rats (Table l),
indicating that differences in the metabolic rate can at
least partially account for the relatively low P-oxidation
observed in piglets. Piglet body mass was sixfold greater
than rats (see MATERIALS AND METHODS), and it is well
established that, across a wide range of adult mammalian species, the mass-specific basal metabolic rate
decreases with increasing body size (15). Furthermore,
this whole animal relationship between body mass and
O2 consumption holds for liver, such that pig hepatocytes consume O2 at -50% the rate of rats (29,30). The
limitation of this explanation when comparing tissues
from neonates of one species to adults of another is
recognized, and it is likely that factors in addition to
metabolic rate (i.e., metabolic enzyme activities; see
Perspectives) also contribute to differences in P-oxidation across species. Comparisons of in vitro metabolic
rate based on O2 consumption could be confounded by
the potential impact of extramitochondrial
metabolic
pathways that consume O2 but are not directly linked
*
Control
RATS
DISCUSSION
ntal
Oxidation
(ASP + C02)
IN PIGS
Control
Malonate
PIGS
A/R
Fig. 2. Accumulation
of carboxyl
carbon
in the major identifiable
organic acids in
acid-soluble
products
(ASP) derived
from
from
incubation
of liver
homogenates
fasted adult rats (Left) and fasted 1.-dayold piglets
(right) -and incubated
with
[1-14C3C16:0
(see MATERIALS
AND METHODS for details).
For each species, bars
represent
control incubations
and incubations containing
malonate
or A/R treatments. Pooled SE are shown in the first
set of bars. Treatment
had no effect on
accumulation
in ketone bodies in piglets
(P > 0.1). However, in the rat, accumulation in acetoacetate
(crosshatched
bars)
rose
in the
presence
of malonate
(*P < 0.05 vs. control) but fell with A/R
(**P < 0.0001 vs. control and malonate).
Carboxyl
carbon
in P-hydroxybutyrate
(hatched
bars) dropped
with malonate
(*P < 0.0001 vs. control) and with A/R
(**P < 0.01 vs. control and malonate).
Malonate
elicited
a rise (*P < 0.01 vs.
control)
whereas
A/R caused
a fall
(**P < 0.05 vs. control and malonate)
in
accumulation
in acetate
(solid bars) in
both species.
R1644
HEPATIC
FATTY
ACID
METABOLISM
to ATP production
[i.e., peroxisomal
acyl-CoA oxidase
(EC 1.3.3.6) and catalase (EC 1.11.1.6) utilize and
liberate Og, respectively].
Nevertheless,
O2 consumption (Table 1) reflected true differences
in mitochondrial ATP production
because peroxisomal
pathways
of
O2 utilization
could account for only a fraction
of
measured O2 uptake.l
The addition of A/R in liver homogenate incubations
inhibited mitochondrial
metabolism
(Table 1 and Fig.
2), but did not completely
abolish O2 consumption
(Table 1). Diminished
but continued O2 consumption
in
the presence of respiratory
poisons (also see Refs. 5 and
29) may be explained
by a drop in mitochondrial
metabolism
concurrent
with continued
activities
of
extramitochondrial
02-consuming
enzymes
that are
A/R insensitive
(29). The large drop in carboxyl carbon
accumulation
in ketone bodies and COB in the rat
(Table 1 and Fig. 2) supports this assertion.
Incomplete
inhibition
of mitochondrial
respiration
could also explain O2 consumption
in the presence of A/R. This was
signaled by the following
observations:
1) C16:O carboxy1 carbon accumulation
in ketone bodies (Fig. 2)
remained at -30% of control values in rat homogenates
exposed to A/R; and 2) in both species, only a portion of
observed O2 consumption
in the presence ofA/R (Table
1) could be attributed
to peroxisomes
under the assumption that ASP in the presence of A/R is peroxisomally
derived. The lack of total A/R inhibition
indicates that
common estimates
of peroxisomal
metabolism
(cyanide- or AR-insensitive
P-oxidation)
could overestimate the true rate. Nevertheless,
the results
in no
manner discount the assertion that significant
speciesrelated differences
exist with regard to the relative
contribution
of peroxisomes
to total hepatic P-oxidation
(6, 7,13,37).
ASP analysis. ASP generated from radiolabeled
fatty
acids have been primarily
associated with ketone bodies in adult fasted rat liver (20-22).
However,
piglets
represent
an animal model with minimal
ketogenic
potential
(2, 10, 28), which suggested that fatty acid
carbon must flow via alternative
pathways
in this
species (24). Development
of radio-HPLC
methods that
characterize
acid-soluble
end products
of metabolism
have confirmed
that, in piglets, ketogenesis
is negligible (19,25), with acetogenesis and production of other
unknown
compounds
being more predominant
(19).
The present work illustrates
further that, in the liver,
major differences
in the pattern
of carboxyl
carbon
accumulation
in acetate, ketone bodies, and various
metabolites
exist across species and in the presence of
l A hypothetical
maximal
peroxisomal
capacity
for 02 consumption
under control conditions
in the rat (330 nmol min-l
g liver-l)
can be
calculated
assuming
that 100% of ASP is peroxisomally
generated
and C16:O undergoes
four cycles
of peroxisomal
P-oxidation
at
one-half
02 consumed
per cycle. This maximal value, which greatly
overestimates
the peroxisomal
contribution
to ASP, accounts
for just
-40% of the observed
02 uptake
(Table 1). At more realistic
estimates
of peroxisomal
P-oxidation
in fasted rats (520%),
theoretical
peroxisomal
02 uptake
falls to only -2-10%
of total
02 consumed,
consistent
with prior determinations
of nonmitochondrialO2
consumption (29).
l
l
IN PIGS
AND
RATS
mitochondrial inhibitors (Figs. 1 and 2). Similar results
were obtained with fasted piglet hepatocytes administered the substrates C7:O and C&O radiolabeled in the
carboxyl carbon position (19). Acetogenesis has long
been recognized as an alternative route of fatty acid
catabolism (16,32,33), but it operates at a rate (in nmol
C2 equivalents min1 mg mitochondrial protein)
just
2-6% of ketogenesis in liver mitochondrial preparations from adult rats (33), consistent with our control
rat homogenates (i.e., carboxyl carbon accumulation in
acetate was 9% of that in ketone bodies). Under control
conditions, the absolute accumulation of Cl6:O carboxy1 carbon in acetate was not different across species
(Fig. 2). Overall metabolism, P-oxidation, and ketogenesis are less in piglets compared with rats (Table 1 and
Fig. 2), and it follows that, in relative terms, acetogenesis has a substantial impact on the fate of fatty acid
carbon in the neonatal pig liver.
A significant portion of acetate production appears to
occur intramitochondrially
in both species, as indicated
by the following observations. First, addition of malonate doubled carboxyl carbon accumulation in acetate
(Fig. 2). Thus a mitochondrial acetyl-CoA pool provided
acetate precursors when Krebs cycle disposal was
slowed. It is notable that Krebs cycle blockage by
malonate has been associated with exclusive flux of
C16:0-carnitine to AcAc in newborn piglet mitochondria (10, 11). However, this assumption based on measured vs. theoretical O2 consumption is readily explained if the primary end products include acetate or
acetylcarnitine.
Second, the mitochondrial inhibitors
A/R markedly dampened carboxyl carbon accumulation
in acetate in both species (Fig. 2). Third, in the piglet
liver, there was a substantial attenuation of in vitro
MCFA carboxyl-carbon accumulation in acetate brought
about by inclusion of valproate (19), a P-oxidation
inhibitor that is a poor peroxisomal substrate (8,38). In
addition, MCFAof eight or fewer carbons serve as weak
peroxisomal substrates (17), yet contribute to acetogenesis in piglets (19) and adult rats (18, 32, 33). Peroxisomes also have acetogenic capacity (14, 18) and may
have contributed to acetate production in our study
because inclusion of A/R did not abolish LCFA carboxyl
carbon accumulation in acetate (Fig. 2). Similarly,
valproate did not completely block acetogenesis from
MCFA in piglet liver (19).
The data underscoring poor ketogenic potential in
piglets (Figs. 1 and 2) are consistent with previous
reports (10, 19, 25) and indicate that ketone bodies
should not be assumed to compose the majority of
acid-soluble end products of liver fatty acid p-oxidation
in all mammalian species. It should be noted that,
under the conditions used, ketone bodies accounted for
only 50% of ASP radiolabel in rats [% of ASP label in
AcAc and p-OHB were as follows: 22 t 2 and 33 t 2%
(controls), 9 t 0.3 and 41 t 1% (malonate), and 45 2 3
and 8 t 0.2% (AR)]. The remaining radioactivity was
largely found in unknowns A and B (see MATERIALS AND
METHODS and Fig. 1). Unknown A accumulated little
radiolabel in malonate or A/R incubations, which is
suggestive of a mitochondrial origin. Under control
l
l
HEPATIC
FATTY
ACID
METABOLISM
conditions, unknown B contained between 16 (rats) and
44% (pigs) of the ASP radioactivity
(data not shown).
This peak might represent
acetylcarnitine,
an end
product observed in adult rat liver preparations
oxidizing LCFA in the presence of exogenous carnitine
(20,
21)
F’inally, LCFA carboxyl carbon accumulation
in ketone bodies in the presence of respiratory
inhibitors
in
rat liver has been observed (Figs. 1 and 2) (5a, 20).
Although
accumulation
of C16:O carboxyl in AcAc and
p-OHB in rats fell to 7 and 64% of controls (controls:
55 2 6 and 35 5 2 nmolmin-l
‘g liver-l, respectively)
(Fig. 2) and radiolabeled
CO2 production
dropped 95%
in the presence of A/R (Table l), ketone bodies accounted for 53% of ASP under this condition. As discussed previously, this result is likely due to incomplete
mitochondrial
inhibition
by AIR. Nevertheless,
AJR
successfully
slowed mitochondrial
metabolism
(Table 1
and Fig. 2) and decreased matrix NADH disposal; the
latter was reflected in the dramatic shift of the P-OHBI
AcAc ratio toward P-OHB in rats (Figs. 1 and 2) (also
see Ref. 5a).
Perspectives
The physiological
ramifications
of species differences
in hepatic fatty acid metabolism
are currently
being
clarified. Ketogenic capacity is trivial in neonatal piglets (2,10,19), and oxidation of P-OHB under physiological conditions
meets less than 3% of the metabolic
requirements
of a typical piglet (34). In contrast, whole
animal turnover
of endogenously
produced acetate in
piglets indicates that up to 20% of their energy budget
could potentially
be derived from this fuel source (3).
The etiologic basis for attenuated
ketogenesis
and
comparatively
low hepatic P-oxidation
in piglets remains an active area of research. Modulation
of CPT-I
by malonyl-CoA
inhibition (22) is generally accepted as
the predominant
control site for ketogenesis
and fatty
acid oxidation in liver. This system may be important
in
neonatal swine because pig CPT-I is particularly
sensitive to malonyl-CoA
inhibition
(lo), and oxidation of
[ 1-14C]C8:0 to ASP and CO2 surpasses that of [1-14C]C16:
0 by fourfold in piglet hepatocytes
(25). An intramitochondrial
site of ketogenic control has also been suggested (1), which is an idea strongly
supported
by
reports of negligible activity of the ketogenic enzyme
mitochondrial
HMG-CoA
synthase
in pig liver (l,lO).
Comparatively
low activity of this enzyme results from
suppressed
gene expression
in neonatal pigs and may
be related to posttranscriptional
modification
and/or
specific differences
in enzyme kinetics
(1). It remains
plausible that low mitochondrial
HMG-CoA
synthase
activity
in pigs exerts some degree of control over
hepatic P-oxidation
in this species. Clearly, comparative analyses of intermediary
metabolism
and its regulation promise to yield new insight into common or
unique mechanisms
controlling P-oxidation across taxonomic boundaries.
This material
is based on work
of Illinois
Agricultural
Experiment
supported
Station
in part by the University
and by the Cooperative
IN PIGS
AND
R1645
RATS
State Research,
Education,
and Extension
Service, U.S. Department
ofAgriculture,
under Agreement
92-37203-7993
(Project
350525).
Present
addresses:
S. H. Adams, Dept. of Internal
Medicine,
Univ.
of Texas Southwestern
Medical
Center,
Dallas,
TX 75235-9135;
X.
Lin and J. Odle, Dept. of Animal
Sciences,
North
Carolina
State
University,
Raleigh,
NC 27695-7621;
and X. X. Yu, Dept. of Biochemistry, Emory University,
Atlanta,
GA 30322.
Address
for reprint
requests:
J. Odle, PO Box 7621, Raleigh,
NC
27695-7621.
Received
19 August
1996;
accepted
in final
form
10 December
1996.
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