![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
3
*
Unité de Nutrition Lipidique, Institut National de la Recherche Agronomique, 21034 Dijon Cédex, France;
Laboratoire de Physiologie de la Nutrition, Université de Paris-Sud, 91405 Orsay, France; and
**
Laboratoire de Toxicologie Nutritionnelle, Institut National de la Recherche Agronomique, 21034 Dijon Cédex, France.
3To whom correspondence should be addressed.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
- but also (-1)-laurate
hydroxylase (CYP4A1 and CYP2E1, respectively). The dietary cyclic fatty
acids induced a coordinated regulation between the activities of the
lipogenic enzymes studied (
9-desaturase, phosphatidate
phosphohydrolase) and peroxisomal oxidation, but not with mitochondrial
ß-oxidation. The dose-dependent decrease of 9-desaturase
activity (P < 0.05) with cyclic fatty acid monomer
intake was accompanied by a similar decrease of the monounsaturated
fatty acid level in liver. The increase in the 
-linolenic acid level
also suggested an increase in 6-desaturase activity with cyclic
fatty acid intake (P < 0.05). In addition, our
results strongly suggested that the altered liver levels of
eicosapentaenoic and arachidonic acids were due to the peroxisomal
retroconversion process in rats fed cyclic acids. Finally, an effect of
these cyclic compounds on the carbohydrate metabolism cannot be
disregarded because they decreased liver glycogen concentration. We
conclude that cyclic fatty acid monomers affect different aspects of
lipid metabolism, including a phenotypic peroxisome proliferator
response. This provides the ground for further studies investigating
the biochemical pathways that underlie the nutritional effect of such
molecules.
KEY WORDS: • rats • liver • cyclic fatty acid monomer • lipogenic enzymes • peroxisome proliferator
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). CFAM generated from
18:1(n-9) are composed of at least eight different saturated cyclic
fatty acids with a C5- or a C6-membered ring (Dobson et al. 1996
). Thirteen identified different monoenoic CFAM are formed
from 18:2(n-6), containing mostly a C5-membered ring (Christie et al. 1993b
, Sébédio et al. 1989
).
Finally, 18:3(n-3) gives rise to 16 identified dienoic CFAM, with a
mixture of C5- and C6-membered rings with some bicyclic acids
(Dobson and Christie, 1996
, Mossoba et al. 1995
, Sébédio et al. 1989
)
(Fig. 1
). Although they are usually present at low levels in oils (from 0.01 to
0.66 g/100 g of the total fatty acids) (Frankel et al. 1984
, Sébédio et al. 1991
), some
investigators, using a purified preparation of CFAM, suggested that
they might have adverse effects in animal models. However, these
studies are scarce; when CFAM were administered orally to mice, a
higher death rate was observed (Saito and Kaneda 1976
).
Weight gain in weaning rats was decreased and the liver weight
(Iwaoka and Perkins, 1976
, Sébédio and Grandgirard, 1989
) and death rate increased in rat pups
from mothers fed CFAM. CFAM feeding also reduced the number of pups per
litter (Sébédio and Grandgirard 1989
,
Sébédio et al. 1995
). CFAM are also
incorporated into cultured heart cells (Ribot et al. 1992
) where they alter the electrophysiologic properties
(Athias et al. 1992
). However, they do have a positive
effect on prostacyclin release by cultured pig endothelial cells
(Flickinger et al. 1997
). Few studies have addressed the
effect of CFAM on the major biochemical pathways of the intermediary
metabolism. Recently, several investigators described the effect of
CFAM on some rat liver enzyme activities (Lamboni et al. 1998
). In that instance, they restricted their observations to
only a few enzymes involved in lipid metabolism (carnitine
palmitoyltransferase-I, in particular). Therefore, our first goal
was to identify which important lipid-related biochemical pathways
could be modified by CFAM ingestion.
|
9-desaturase,
carnitine palmitoyltransferase, acyl-CoA oxidase, and
(-1)-laurate hydroxylase] were assayed after CFAM administration.
The data suggest that CFAM acted as peroxisome proliferator analogs. |
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Solvents were from SDS (Peypin, France) and were distilled before use. Scintillation solutions Ecoscint A and Ecoscint BD were purchased from National Diagnostic (Atlanta, GA), and Floscint II and Ultima Flo were obtained from Packard Bioscience (Groningen, The Netherlands). [1-14C]-lauric acid (2 GBq/mmol), [1-14C]-palmitic acid (2 GBq/mmol) and [1-14C]-stearic acid (2 GBq/mmol) were purchased from Amersham (Amersham, Courtaboeuf, France). All the other chemicals were from Sigma-Aldrich (Sigma, L’Isle d’Abeau-Chêne, France). Soybean oil with no CFAM was a generous gift of Lesieur (Coudekerque, France).
Animals and diet.
Official French regulations (n° 87848) for care and use of laboratory
animals were followed (n° 03056). Weanling male Wistar rats
(n = 18), weighing 266–300 g, were obtained from
the Center d’élevage DEPRE (Saint Doulchard, France). They were
housed at a constant humidity and temperature, with a 12-h light:dark
cycle. They had free access to water and received the same amount of a
purified diet daily (Table 1
). Rats were divided into three groups (n = 6/group)
and were fed for 2 wk a 10 g/100 g fat diet (by weight) containing
either 0.1 or 1 g/100 g CFAM isolated from heated linseed oil
(Sébédio et al. 1987
) and in the form of
triacylglycerols [TG; synthesized as described by Martin et al. (1997)
]. The control group received the same soybean oil
based–diet (10 g/100 g by weight) but without CFAM-TG. At the end
of the feeding period, the rats were killed by exsanguination, livers
were excised, blotted, weighed and immediately used for subcellular
fractionation. Aliquots of 2 and 0.5 g were stored at -80°C for
subsequent lipid and glycogen analyses, respectively.
|
The following procedures were conducted at 0°C except the centrifugation steps, which were at 4°C. The excised liver samples were finely chopped and homogenized in 3 vol of a Tris (0.05 mol/L) buffer (pH 7.5), containing sucrose (0.25 mol/L) and EDTA (1 mmol/L). The homogenate was first centrifuged at 400 x g to pellet the cell debris. The supernatant was subsequently centrifuged at 15,000 x g for 15 min, and the peroxisomal + mitochondrial pellet was recovered, divided into aliquots and stored at -80°C for further analysis, or used immediately to assess the mitochondrial oxidation of [14C]-palmitic acid (see below). The supernatants were ultracentrifuged (1 h at 105,000 x g in the same sucrose buffer, and an additional hour in a 0.15 mol/L Tris buffer, pH 8.0) to yield the microsomal pellet and the cytosolic fraction (supernatant of the first ultracentrifugation for this latter fraction). All liver fractions were then stored at -80°C.
Enzyme activity.
The peroxisomal acyl-CoA oxidase (ACO) and mitochondrial carnitine
palmitoyltransferase (CPT) activities were both assessed in the
peroxisomal + mitochondrial fractions. The ACO activity was determined
according to Lazarow (1976)
and the CPT activity
according to the method of Bieber et al. (1972)
.
The - and (-1)-laurate hydroxylation was determined as a marker
of the cytochrome P4504A1 and cytochrome P4502E1 activities,
respectively (Amet et al. 1994
, Pacot et al. 1993
). Measurements were determined in the microsomal fraction
according to Orton and Parker (1982)
as modified by
Laignelet et al. (1989)
. The reaction products were
extracted with diethyl ether, separated by reversed-phase HPLC and
quantified with a radiochromatographic detector Flo-one ß (serie
A-100, Radiomatic Instruments, Tampa, FL) by peak integration (HPLC
conditions: ODS column 25 cm length x 4.6 mm i.d., scintillation
solution of Floscint II, 2:1, v/v). The mobile phase was made up of
ammonium acetate (A, 270 g/L), acetonitrile (B, 320 g/L and
H2O (C, 410 g/L); the samples were eluted with this mixture
for 4 min. The mobile phase was then changed within a 2-min gradient to
A (100 g/L) and B (900 g/L) and held for a further 4.5 min.
The phosphatidate phosphohydrolase (PAP) total activity (i.e.,
Mg2+-dependent and Mg2+-independent) was
assessed in both the microsomal fraction and the cytosol, essentially
as described by Walton and Possmayer (1985)
and modified
by Surette et al. (1992)
.
The 9-desaturase activity was determined by adding 1.6 MBq of
[1-14C]-18:0 dissolved in 3 µL of
ethanol (30 nmol/assay) to the microsome preparation (0.4 mL, 4–5 mg
protein), incubated with 0.3 mL of cytosol (4–5 mg protein) for 15 min
at 37°C under gentle shaking in a pH 7.4 phosphate buffer made up of
0.15 mol/L Na2HPO4, 0.15mol/L
KH2PO4, 7.2 mmol/L ATP, 6 mmol/L
MgCl2, 1.2 mmol/L NADPH and 0.54 mmol/L CoA. The reaction
was terminated by saponification of the fatty acid esters while adding
1 mL of 2 mol/L KOH and heating at 70°C for 30 min. After
acidification with HCl, the free fatty acids released were extracted
with 2 x 4 mL of diethyl ether. The solvent was removed under a
stream of nitrogen and the fatty acids were methylated with boron
trifluoride (140 g/L) in methanol as described by Morrison and Smith (1964)
. After hexane extraction, the residue was
redissolved in 100 µL of acetonitrile and analyzed by
radiodetection. The fatty acid methyl esters (FAME) (0.5–1 mg) were
separated by HPLC (model 600, Waters, Saint Quentin en Yvelines,
France) using a reversed-phase column (Nucleosil C18, 5
µm particle size, 250 mm length x 4.6 mm i.d.)
(Interchim, Montluçon, France) and isocratic elution with pure
acetonitrile at 1 mL/min. The radioactivity was detected using a
radiochromatographic detector Flo-one ß (serie A-100, Radiomatic
Instruments) after addition of Ultima Flo (2:1, v/v). The results were
expressed as the percentage of conversion of
[1-14C]-stearic acid to [1-14C]-oleic acid.
Fatty acid oxidation.
The total fatty acid oxidation was measured in the peroxisomal +
mitochondrial fraction as adapted from Anderson (1968)
and Clouet et al. (1989)
, using albumin-bonded
[1-14C]-palmitate (1:2, mol/mol; 50
µmol/L with a specific activity of 0.34 GBq/mmol).
Lipid analysis.
The total lipids of a portion aliquot of the liver were extracted with
chloroform/methanol (2:1; v/v) according to Folch et al. (1957)
and weighed after removal of the solvent under reduced
pressure. Total FAME of 5 mg of the lipid residue were then prepared
using boron trifluoride in 140 g/L methanol, as described by
Morrison and Smith (1964)
, before gas-liquid
chromatographic (GLC) analysis. FAME analysis from the total fatty
acids was carried out on a Hewlett-Packard gas chromatograph (model
5890, Les Ulis, France) fitted with a flame-ionization detector and
a split-splitless injector both set at 250°C. Carrier gas was
helium (1.1 mL/min) and elution was performed with a BPX 70 column
(SGE, Villeneuve-Saint-Georges, France) (50 m length, 0.33 mm i.d. and
0.25 µm film thickness) in programmed mode. The column
was operated at 60°C for 1.1 min; the temperature was increased to
170°C at a rate of 20°C/min, held for 5 min, then increased at
2.5°C/min to 220°C and held for 15 min.
FAME from the above lipid extract were further fractionated by HPLC to
concentrate CFAM for a better analytical accuracy. FAME were dissolved
in 100 µL of acetone, injected onto a
reversed-phase column Nucleosil C18, 250 mm length, 10
µm i.d. and 5 µm particle size
(Shandon, Cergy-Pontoise, France) connected to a
Spectra-physics 8810 HPLC system (Spectra-Physics, La
Verpillière, France). CFAM were detected with a Waters 410
differential refractometer (Waters). Acetonitrile was the mobile phase
(4 mL/min). CFAM were found to coelute with 18:2(n-6), 14:0, 15:0 and
16:1. The collected fractions were then dried at reduced pressure,
dissolved in a minimum of solvent and stored at -20°C before GLC
analysis under the same conditions as above. Linoleic acid contained in
samples served as an internal standard in both the total fatty acid
profile and the CFAM fraction to recalculate the relative content of
the CFAM in the total lipid. CFAM identification was performed by
comparison with a heated linseed oil CFAM standard whose peak
characterization has been detailed elsewhere (Christie et al. 1993a
).
Other determinations.
The protein content of the total liver homogenate as well as of each
subfraction was determined according to Lowry et al. (1951)
and the glycogen content as described by Lo et al. (1970)
.
Statistics.
Results were computed and analyzed with the use of SigmaStat sofware
(Jandel Scientific, San Rafael, CA). Comparisons were made using
one-way ANOVA or ANOVA on Ranks when the normality test failed.
Student-Newman-Keuls test was used when heterogeneity among groups was
demonstrated. Regressions were established using the
linear-regression fit model. The level of significance was set at
P 
0.05.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
) and no significant weight differences were observed at the end of the
feeding period (data not shown). Relative liver weight was higher in
the rats fed 1 g/100 g CFAM than in the other two groups (P
< 0.05) (Table 2)
. The rats fed both levels of CFAM had liver
glycogen concentrations 30–40% lower than those in the control group,
whereas the protein and lipid concentrations did not differ (Table 2)
.
In contrast, microsomal and cytosolic PAP activities (a
rate-limiting enzyme in the glycerolipid synthesis) were lower
(P 0.05) in rats fed 1 g/100 g CFAM than in controls
(Table 3
).
|
|
. The peroxisomal ACO activity was accompanied by
a similar rise of microsomal - and (-1)-laurate hydroxylases
(CYP4A1 and CYP2E1, respectively) (Table 3
and Table 4
). Conversely, no effects of CFAM intake on mitochondrial ß-oxidation
were detected, as evaluated by measurements of the CPT-I activity
and the radioactive oxidation products arising from
[1-14C]-palmitate (Table 3)
. It is interesting
to note that enzymes involved in peroxisomal lipid oxidation (ACO,
CYP2E1 and CYP4A1) were negatively correlated with enzymes involved in
lipid synthesis (PAP and 9-desaturase) after CFAM consumption (Table 4)
. This was not the case between the enzyme associated with
mitochondrial oxidation (CPT-I) and the above lipogenic enzymes (Table 4)
.
|
). There was a 10-fold difference in CFAM intake between the 0.1 and the
1 g/100 g CFAM groups, whereas the CFAM content in the total liver
lipids was only 75% lower in the former group than in the latter
group. The sum of the monounsaturated fatty acids originating primarily
from a 9-desaturation was significantly lower in the 1 g/100 g CFAM
group than in the 0.1 g/100 g CFAM group or in the control group (Table 5)
. Although not significant (P = 0.25), the 0.1 g/100
g CFAM group had slightly more monounsaturates than the control group.
This was also true for 9-desaturase (Table 3)
; this activity was
closely associated with the monounsaturated fatty acid content in liver
of rats from either dietary group (r = 0.714;
P 0.05; Fig. 2
).
|
|
. Additionally, an inverse relationship was
found between ACO activity and the same group of selected fatty acids,
i.e., 22:6(n-3) (r = -0.55; P 0.05,
Fig. 3A
) and 22:4n-6 (r = -0.57; P 0.05;
Fig. 3B
). CFAM intake was also accompanied by increases in
the liver content of both 20:5(n-3) and 20:4(n-6) (Table 5)
. The
increases of these two fatty acids were positively correlated with the
peroxisomal ACO activity [r = 0.77; P
0.05, and r = 0.57; P 0.05
for 20:5(n-3) and 20:4(n-6), Figure 4
and
B, respectively]. The decrease in 22:6(n-3) fatty acid level with
increased CFAM intake was inversely related to an increase in the
20:5(n-3) content of liver lipids (Table 4)
(r = -0.55; P 0.05; data not shown for the linear
regression fit). The same trend for the (n-6) fatty acids homologs
[i.e., 22:4(n-6) and 20:4(n-6)] was also observed, but was not
significant for the relationship between adrenic acid [22:4(n-6)] and
arachidonic acid [20:4(n-6)] (r = -0.34;
P = 0.18; data not shown). Interestingly, the level of
18:3(n-6), the 6-desaturated product of linoleic acid, increased
steadily with CFAM consumption (P 0.05, Table 5
),
with no change in the 18:2(n-6) level.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, Sébédio et al. 1987
). 18:3(n-3)-derived CFAM are representative of all
CFAM in terms of the ring (contain either a C5- or a C6-membered ring)
and they can be analyzed easily in their nonhydrogenated form. Rats
were fed these fatty acids as TG because this is the natural form of
dietary fat and also because it has been demonstrated that this is a
bioavailable form of CFAM (Martin et al. 1997
).
Recently, Lamboni et al. (1998)
studied the relationship
between intake of CFAM purified from a heated linseed oil and liver
enzyme activity in rats. Some differences exist between their results
and ours, such as a decrease in CPT-I activity in vitro due to CFAM
intake that was not observed in our study, as well as an increase in
the total liver lipids and proteins in their study but not in ours
(Table 2)
. It is noteworthy that variations in the feeding conditions
could explain the discrepancies between these studies. In the former
study, CFAM were administrated as methyl esters (0.15 g/100 g), in
their hydrogenated form for 7 wk to rats weighing 50–60 g at the onset
of the experiment. In our study, CFAM were ingested as triacylglycerol
(0.1 and 1 g/100 g), in nonhydrogenated form for 2 wk to rats weighing
200–220 g. Nonetheless, we observed a decrease in the glycogen content
in the liver, which was also noted in the earlier study (Lamboni et al. 1998
). This decrease was maximal with as little as 0.1
g/100g CFAM intake.
In this study, indirect evidence of a peroxisome proliferation effect
was observed in rats consuming CFAM, such as hepatomegaly (increase in
the relative liver weight) (Bentley et al. 1993
,
Hawkins et al. 1987
), and an increase of the liver
microsomal CYP4A1, (Bentley et al. 1993
,
Intrasuksri et al. 1998
) and peroxisomal ACO activities
(Bardot et al. 1995
, Bentley et al. 1993
)
(Tables 3
and 4)
. It is noteworthy that CFAM seemed to be as potent as
the classical peroxisome proliferators because they induced their
effect in the same dose range (1–10 mg/g) (Bentley et al. 1993
). Nonetheless, this apparent peroxisome proliferation due
to CFAM demonstrated differences from the common peroxisome
proliferator agents such as fibrates. For example, we did not measure
smooth endoplasmic reticulum membrane proliferation (Bentley et al. 1993
), which was observed as shown by the absence of
microsomal protein increase with CFAM consumption (Table 2)
.
Additionally, in our study, dietary CFAM were strong enough to induce
CYP4A1 (-laurate hydroxylation) and CYP2E1 [(-1)-laurate
hydroxylation] activities equally (Table 3)
. In addition, no induction
of CPT-I and 9-desaturase activities was observed after CFAM
consumption (Table 3)
, as is usually the case with common peroxisome
proliferator drugs such as fibrates (Schoonjans et al. 1996
). On the contrary, the 9-desaturase activity was even
decreased at the 1 g/100 g CFAM dose (Table 3)
. Some PUFA such as
arachidonic acid and eicosapentaenoic acid (EPA) (Miller and Ntambi 1996
), as well as conjugated linoleic acids
(Belury et al. 1997
), can also acutely induce both ACO
and CYP4A1 mRNA, and decrease 9-desaturase mRNA levels with no
effect on CPT-I activity (Park et al. 1997
) in the
liver of mice. It should not be surprising that CFAM, which are also
PUFA, would also be able to induce both the liver ACO and CYP4A1
activities and decrease the 9-desaturase activity without affecting
CPT-I. Also, the decrease in 9-desaturase activity observed in
our study may be the result of a direct inhibition by CFAM, as occurs
with other cyclic fatty acids such as sterculic acid (a cyclopropenoic
acid) (Jeffcoat, 1977
, Legrand et al. 1997
). This effect on the desaturase is important because liver
9-desaturase activity varies in parallel with hepatic TG secretion,
as assessed in vitro in chickens (Legrand et al. 1997
)
or in vivo in mice (de Antueno et al. 1993
). Additionally, the decrease
of the 9-desaturase activity was associated with a similar lowering
of the microsomal-bound PAP activity (Table 4)
. In rats, this
microsome-bound enzyme is rate limiting for the synthesis of TG in
the liver (Cha et al. 1998
) and in turn, modulates the
plasma TG concentration (Cha et al. 1998
, Marsh et al. 1987
). It is therefore highly conceivable that dietary
CFAM, which activate peroxisomal oxidation and seem to be potent as
peroxisome proliferators, as 9-desaturase activity inhibitors and as
microsome-bound PAP regulators, may also impair
VLDL-TG secretion by the liver. It is interesting to note also that
in lymph-canulated rats (Martin et al. 1997
), the
same CFAM generated from heated linseed oil are also efficient
modulators of lipoprotein secretion rate by the intestine, which is the
other important organ for lipoprotein production.
However, in spite of the above effects on both the peroxisomal
ß-oxidation and the lipogenic activities measured in this study,
there was no modification of the overall lipid content of liver (Table 2)
. One explanation is that only the TG would be lowered, whereas the
phospholipids would be increased, as was already demonstrated in rat
liver with tetradecylthioacetic acid, a sulfur-substituted
peroxisome proliferator fatty acid (Skorve et al. 1990
).
From that viewpoint, a detailed analysis of the lipid composition could
have been informative.
In addition to the effect of CFAM on liver 9-desaturase and
downstream on the monounsaturated fatty acid level (Tables 3
and 5
,
Fig. 2
), other modifications of the fatty acid profile due to the CFAM
consumption were also found. In particular, the content of the C-22
PUFA decreased in a dose-dependent manner with increasing CFAM
intake (Table 4)
. This decrease was particularly pronounced with
22:6(n-3) and 22:4(n-6), the two main C-22 PUFA, and was accompanied by
a similar rise of their biosynthetic precursors, 20:5(n-3) and
20:4(n-6), respectively. Because the decrease of both 22:6(n-3) and
22:4(n-6) and the rise of 20:5(n-3) and 20:4(n-6) were closely
associated with peroxisomal ACO activity (Figs. 3
and 4)
, it is
plausible that the levels of both EPA and arachidonic acid in our
experimental conditions were dictated by the peroxisomal
retroconversion activity of their longer-chain homologs, i.e.,
docosahexaenoic acid (DHA) and adrenic acid, respectively (Hagve and Christophersen 1986
, Sprecher et al. 1995
).
However, a precursor-product relationship between adrenic acid
[22:4(n-6)] and arachidonic acid [20:4(n-6)] was not significant
(r = -0.34; P = 0.18). The
relationship between DHA [22:6:(n-3)] and EPA [20:5:(n-3)] was
significant (r = -0.55; P 0.05). A
possible explanation could be that the retroconversion effect of the
C-22 metabolites to 20:4n-6 would be somewhat counterbalanced by the
contribution of the chain elongation and desaturation system from the
abundant precursors [i.e.,18:2(n-6) and 20:3(n-6)], which operate
downstream. Under those conditions, a possible enhancement of the
6-desaturation of linoleic acid due to CFAM intake cannot be
disregarded, as suggested by the increase in -linolenic acid, the
6-desaturation product of 18:2(n-6), and the resulting rise in the
18:3(n-6)/18:2(n-6) ratio (Table 4)
.
In conclusion, purified CFAM generated from heated linseed oil and
given as TG elicited a phenotypic peroxisome proliferator response in
rats in dose ranges used commonly for drug-induced peroxisome
proliferation. CFAM exerted specific effects on the metabolism of a
complex carbohydrate (glycogen) and on the metabolism of unsaturated
fatty acids. They regulated some aspects of both lipogenesis and
peroxisomal ß-oxidation in a coordinate manner, although
mitochondrial ß-oxidation was unaffected. The effect on the
unsaturated fatty acids would be due to a modulation of the desaturase
(9 and possibly 6) and of the peroxisomal retroconversion
activities. On the basis of the effects of CFAM on apparent peroxisomal
proliferation, 9-desaturase activity and PAP activity, the
possibility that CFAM would also reduce the secretion of VLDL-TG by
the liver is likely and merits further investigation. It would be
interesting to address whether the phenotypic effects observed are
supported by a genotypic response, such as a peroxisome
proliferator-activated receptor (PPAR)-mediated induction.
|
FOOTNOTES |
|---|
2 F. J. is a recipient of a INRA and Nestlé fellowship.
4 ACO, acyl-CoA oxidase; CFAM, cyclic fatty acid monomers; CPT, carnitine palmitoyltransferase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FAME, fatty acid methyl esters; GLC, gas-liquid chromatography, PAP, phosphatidate phosphohydrolase; PUFA, polyunsaturated fatty acids; TG, triacylglycerol.
Manuscript received June 23, 1999. Initial review completed August 13, 1999. Revision accepted January 20, 2000.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1.
Amet Y., Berthou F., Goasduff T., Salaun J. P., Le Breton L., Menez J. F. Evidence that cytochrome P450 2E1 is involved in the (-1)-hydroxylation of lauric acid in rat liver microsomes. Biochem. Biophys. Res. Commun. 1994;203:1168-1174[Medline]
2.
Anderson R. L. Oxidation of the geometric isomers of 9,12-octadecadienoic acid by rat liver mitochondria. Biochim. Biophys. Acta 1968;152:531-538[Medline]
3. Athias P., Ribot E., Grynberg A., Sébédio J.-L., Grandgirard A. Effects of cyclic fatty acid monomers on the function of cultured rat cardiac myocytes in normoxia and hypoxia. Nutr. Res. 1992;12:737-745
4. Bardot O., Clemencet M. C., Cherkaoui Malki M., Latruffe N. Delayed effects of ciprofibrate on rat liver peroxisomal properties and proto-oncogene expression. Biochem. Pharmacol. 1995;50:1001-1006[Medline]
5. Belury M. A., Moya-Camarena S. Y., Liu K. L., Heuvel J.P.V. Dietary conjugated linoleic acid induces peroxisome-specific enzyme accumulation and ornithine decarboxylase activity in mouse liver. J. Nutr. Biochem. 1997;8:579-584
6. Bentley P., Calder I., Elcombe C., Grasso D., Stringer D., Wiegand H.-J. Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem. Toxicol. 1993;31:857-907[Medline]
7. Bieber L. L., Abraham T., Helmrath T. A rapid spectrometric assay for carnitine palmitoyltransferase. Anal. Biochem. 1972;50:509-518[Medline]
8. Cha J. Y., Mameda Y., Yamamoto K., Oogami K., Yanagita T. Association between hepatic triacylglycerol accumulation induced by administering orotic acid and enhanced phosphatidate phosphohydrolase activity in rats. Biosci. Biotechnol. Biochem. 1998;62:508-513[Medline]
9. Christie W. W., Brechany E. Y., Sébédio J. L., LeQueré J. L. Silver ion chromatography and gas chromatography-mass spectrometry in the structural analysis of cyclic dienoic acids formed in frying oils. Chem. Phys. Lipids 1993a;66:143-153
10. Christie W. W., Brechany E. Y., Sébédio J.-L., LeQueré J.-L. Silver ion chromatography and gas chromatography-mass spectrometry in the structural analysis of cyclic monoenoic acids formed in frying oils. Chem. Phys. Lipids 1993b;66:143-153
11.
Clouet P., Niot I., Bézard J. Pathway of 
-linolenic acid through the mitochondrial outer membrane in the rat liver and influence on the rate of oxidation. Biochem. J. 1989;263:867-873[Medline]
12.
de Antueno R. J., Cantrill R. C., Huang Y.-S., Elliot M., Horrobin D. F. Relationship between mouse liver -9 desaturase activity and plasma lipids. Lipids 1993;28:285-290[Medline]
13. Dobson G., Christie W. W. Structural analysis of fatty acids by mass spectrometry of picolinyl esters and dimethyloxazoline derivatives. Trends Anal. Chem. 1996;15:130-137
14. Dobson G., Christie W. W., Sébédio J. L. Monocyclic saturated fatty acids formed from oleic acid in heated sunflower oils. Chem. Phys. Lipids 1996;82:101-110
15. Flickinger B. D., McCusker R. H., Perkins E. G. The effects of cyclic fatty acid monomers on cultured porcine endothelial cells. Lipids 1997;32:925-933[Medline]
16.
Folch J., Lees M., Sloane-Stanley G. H. A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 1957;226:497-509
17. Frankel E. N., Smith L. M., Hamblin C. L., Creveling R. K., Clifford A. J. Occurrence of cyclic fatty acid monomers in frying oils used for fast foods. J. Am. Oil Chem. Soc. 1984;61:87-90
18. Hagve T. A., Christophersen B. O. Evidence for peroxisomal retroconversion of adrenic acid [22:4(n-6)] and docosahexaenoic acid [22:6(n-3)] in isolated liver cells. Biochim. Biophys. Acta 1986;6:165-173
19. Hawkins J. M., Jones W. E., Bonner F. W., Gibson G. G. The effect of peroxisome proliferators on microsomal, peroxisomal, and mitochondrial enzyme activities in the liver and kidney. Drug Metab. Rev 1987;18:441-515[Medline]
20. Intrasuksri U., Rangwala S. M., Obrien M., Noonan D. J., Feller D. R. Mechanisms of peroxisome proliferation by perfluorooctanoic acid and endogenous fatty acids. Gen. Pharmacol. 1998;31:187-197[Medline]
21. Iwaoka W. T., Perkins E. G. Nutritional effects of the cyclic monomers of methyl linolenate in the rat. Lipids 1976;11:349-353[Medline]
22. Jeffcoat R. Studies on the inhibition of the desaturases by cyclopropenoid fatty acids. Lipids 1977;12:480-485[Medline]
23. Laignelet L., Narbonne J. F., Lhuguenot J. C., Riviere J. L. Induction and inhibition of rat liver cytochrome(s) P-450 by an imidazole fungicide (prochloraz). Toxicology 1989;59:271-284[Medline]
24. Lamboni C., Sébédio J. L., Perkins E. G. Cyclic fatty acid monomers from dietary heated fats affect rat liver enzyme activity. Lipids 1998;33:675-681[Medline]
25. Lazarow P. B. Assay of peroxisomal beta-oxidation of fatty acids. Methods Enzymol.. 1976;72:315-319
26.
Legrand P., Catheline D., Fichot M. C., Lemarchal P. Inhibiting -9 desaturase activity impairs triacylglycerol secretion in cultured chicken hepatocytes. J. Nutr. 1997;127:249-256
27.
Lo S., Russell J. C., Taylor A. W. Determination of glycogen in small tissue samples. J. Appl. Physiol. 1970;28:234-236
28.
Lowry O. H., Rosebrough N. J., Farr A. L., Randall R. J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951;193:265-275
29. Marsh J. B., Topping D. L., Nestel P. J. Comparative effects of dietary fish oil and carbohydrate on plasma lipids and hepatic activities of phosphatidate phosphohydrolase, diacylglycerol acyltransferase and neutral lipase activities in the rat. Biochim. Biophys. Acta 1987;922:239-243[Medline]
30. Martin J. C., Caselli C., Broquet S., Juanéda P., Nour M., Sébédio J. L., Bernard A. Effect of cyclic fatty acid monomers on fat absorption and transport depends on their positioning within the ingested triacylglycerols. J. Lipid Res. 1997;38:1666-1679[Abstract]
31. Martin J. C., Lavillonnière F., Nour M., Sébédio J. L. Effect of fatty acid positional distribution and triacylglycerol composition on lipid by-products formation during heat-treatment: III-Cyclic fatty acid monomers study. J. Am. Oil Chem. Soc. 1998;75:1691-1697
32.
Miller C. W., Ntambi J. M. Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression. Proc. Natl. Acad. Sci. U.S.A. 1996;93:9443-9448
33. Morrison W. R., Smith L. M. Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol. J. Lipid Res. 1964;5:600-608[Abstract]
34. Mossoba M., Yurawecz M. P., Roach J.A.G., Lin H. S., MacDonald R. E., Flickinger B. D., Perkins E. G. Elucidation of cyclic fatty acid monomer structures. Cyclic and bicyclic ring sizes and double bond position and configuration. J. Am. Oil Chem. Soc. 1995;72:721-727
35. Orton T. C., Parker G. L. The effect of hypolipidemic agents on the hepatic microsomal drug-metabolizing enzyme system of the rat. Induction of cytochrome(s) P-450 with specificity toward terminal hydroxylation of lauric acid. Drug Metab. Dispos. 1982;10:10110-10115
36. Pacot C., Petit M., Caira F., Rollin M., Behechti N., Grégoire S., Cherkaoui Malki M., Cavatz C., Moisant M., Moreau C., Thomas C., Descotes G., Gallas J. F., Deslex P., Althoff J., Zahnd J. P., Lhuguenot J. C., Latruffe N. Response of genetically obese Zucker rats to ciprofibrate, a hypolipidemic agent, with peroxisome proliferation activity as compared to Zucker lean and Sprague-Dawley rats. Biol. Cell 1993;77:27-35[Medline]
37. Park Y., Albright K. J., Liu W., Storkson J. M., Cook M. E., Pariza M. W. Effect of conjugated linoleic acid on body composition in mice. Lipids 1997;32:853-858[Medline]
38. Ribot E., Grandgirard A., Sébédio J. L., Grynberg A., Athias P. Incorporation of cyclic fatty acid monomers in lipids of rat heart cell cultures. Lipids 1992;27:79-81[Medline]
39. Saito M., Kaneda T. Studies on the relationship between the nutritive value and the structure of polymerized oils. Jpn. J. Oil Chem. Soc. 1976;25:13-20
40. Schoonjans K., Staels B., Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J. Lipid Res. 1996;37:907-925[Abstract]
41. Sébédio J. L., Chardigny J. M., Juaneda P., Giraud M. C., Nour M., Christie W. W., Dobson G. Nutrional impact and selective incorporation of cyclic fatty acid monomers in rats during reproduction. Castenmiller W.A.M. eds. 21st World Congress of the International Society for Fat Research Oils-Fats-Lipids 1995;vol. 2:307-310 Barnes PJ, The Hague The Netherlands
42. Sébédio J. L., Grandgirard A. Cyclic fatty acids: natural sources, formation during heat treatment, synthesis and biological properties. Prog. Lipid Res. 1989;28:303-336[Medline]
43. Sébédio J. L., Kaitaranta J., Grandgirard A., Malkki Y. Quality assessment of industrial prefried french fries. J. Am. Oil Chem. Soc. 1991;68:299-302
44. Sébédio J. L., LeQueré J. L., Morin O., Grandgirard A. Heat treatment of vegetable oils. III. GC-MS characterization of cyclic fatty acid monomers in heated sunflower and linseed oils after total hydrogenation. J. Am. Oil Chem. Soc. 1989;66:704-709
45. Sébédio J. L., Prévost J., Grandgirard A. Heat treatment of vegetable oils. I. Isolation of the cyclic fatty acid monomers from heated sunflower and linseed oils. J. Am. Oil Chem. Soc. 1987;64:1026-1032
46. Skorve J., Asiedu D., Rustan A. C., Drevon C. A., Al-Shurbaji A., Berge R. K. Regulation of fatty acid oxidation and triglyceride and phospholipid metabolism by hypolipidemic sulfur-substituted fatty acid analogues. J. Lipid Res. 1990;31:1627-1635[Abstract]
47. Sprecher H., Luthria D. L., Mohammed B. S., Baykousheva S. P. Reevaluation of the pathways for the biosynthesis of polyunsaturated fatty acids. J. Lipid Res. 1995;36:2471-2477[Abstract]
48. Surette M. E., Whelan J., Lu G. P., Broughton K. S., Kinsella J. E. Dependence on dietary cholesterol for n-3 polyunsaturated fatty acid-induced changes in plasma cholesterol in the syrian hamster. J. Lipid Res. 1992;33:236-271
49. Walton P. A., Possmayer F. Mg2+-dependent phosphatidate phosphohydrolase of rat lung: development of an assay employing a defined chemical substrate which reflects the phosphohydrolase activity measured using membrane-bound substrate. Anal. Biochem. 1985;151:479-486[Medline]
This article has been cited by other articles:
|
|
 |
|
  A. Koch, B. Konig, J. Spielmann, A. Leitner, G. I. Stangl, and K. Eder Thermally Oxidized Oil Increases the Expression of Insulin-Induced Genes and Inhibits Activation of Sterol Regulatory Element-Binding Protein-2 in Rat Liver J. Nutr., September 1, 2007; 137(9): 2018 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sulzle, F. Hirche, and K. Eder Thermally Oxidized Dietary Fat Upregulates the Expression of Target Genes of PPAR{alpha} in Rat Liver J. Nutr., June 1, 2004; 134(6): 1375 - 1383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-M. Chao, C.-Y. Chao, F.-J. Lin, and C.-j. Huang Oxidized Frying Oil Up-Regulates Hepatic Acyl-CoA Oxidase and Cytochrome P450 4 A1 Genes in Rats and Activates PPAR{alpha} J. Nutr., December 1, 2001; 131(12): 3166 - 3174. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
