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Fructose induces synthesis and reduces oxidation of liver fatty acids through ChREBP activation

Authors:
Fructose induces synthesis and reduces oxidation of
liver fatty acids through CHREBP activation
INTRODUCTION AND AIMS
During last few decades, the prevalence
of obesity, metabolic syndrome and
insulin resistance, among other metabolic
disturbances, has raised considerably in
many countries worldwide. Environmental
factors (diet, physical activity), in tandem
with predisposing genetic factors, may
be responsible for this trend1. Along with
an increase in total energy consumption
during recent decades, there has also been
a shift in the type of nutrients, with an
increased consumption of fructose, largely
attributable to a greater intake of beverages
containing high levels of fructose2,3.
It has been accepted the rat as a good
model for the study of fructose metabolism
in humans4. A high-fructose diet in rats
induces metabolic alterations similar to
those found in the metabolic syndrome5.
In fact, in previous studies, our research
group showed that fructose administration
(10% w/v) into drinking water during 14
days causes hypertriglyceridemia and fatty
liver as a result of an induced synthesis and
a reduced oxidation of liver fatty acids6,7,8.
These metabolic disturbances caused by
liquid fructose consumption were observed
both in male and in female rats. However,
only in male rats they were caused by a state
of hepatic leptin resistance7,8. Therefore,
the aim of this work was to determine the
molecular mechanisms involved in the
hypertriglyceridemia and hepatic steatosis
induced by fructose supplementation in
female rats.
METHODS
Female Sprague-Dawley rats had
free access to water (n=8) or to a 10 %
(w/v) fructose solution (n=12). After 7
and 14 days, animals were sacrificed by
decapitation under isoflurane anesthesia
and plasma and liver samples were
obtained for determining plasma
analytes, liver triglycerides, liver enzyme
activities and expression of enzymes and
transcription factors related to fatty acid
metabolism. To confirm possible molecular
mechanisms, FaO rat hepatoma cells, and
a primary culture of human hepatocytes
were incubated for 24 hours in absence or
presence of 25 mM fructose (n=4 for each
treatment).
RESULTS AND DISCUSSION
As it can be observed in table 1, fructose-
supplemented female rats, had increased
plasma and liver triglyceride concentrations
after 14 days but not at 7 days of treatment.
The hepatic expression of lipogenic genes
such as Liver Pyruvate Kinase (L-PK) and
Stearoyl-CoA Desaturase 1 (SCD1) was
induced by fructose consumption both
at 7 and 14 days, but the nuclear content
of the transcription factor Carbohydrate
Response Element Binding Protein
(ChREBP), which induces liver lipogenesis
after carbohydrate ingestion9, was only
increased in the liver of those animals
which had consumed fructose for 14 days.
In regard to fatty acid -oxidation activity,
it was reduced by fructose consumption
both at 7 and 14 days, but the expression of
Peroxisome Proliferator Activated Receptor
(PPAR ) and its target genes Acyl-CoA
Oxidase (ACO) and Liver Carnitine
Palmitoyl Transferase I (L-CPT-I), enzymes
that strictly control fatty acid -oxidation
activity, was only decreased after 2 weeks of
fructose treatment, showing an important
role of PPAR down-regulation in the
A Rebolloa,b, M Baenaab, N Roglansa,b,c, M Alegreta,b,c, JC Lagunaa,b,c
a Unitat de Farma-
cologia, Facultat de
Farmàcia, Universitat
de Barcelona, Barce-
lona, Spain. b Institut
de Biomedicina de la
Universitat de Barce-
lona (IBUB), Barce-
lona, Spain. c CIBER
Fisiopatología de la
Obesidad y Nutrición
(CIBERobn), Insti-
tuto de Salud Carlos
III, Spain
VI CONGRESO EPHAR
PREMIO A LA MEJOR COMUNICACIÓN ORAL
ACTUALIDAD EN FARMACOLOGÍA Y TERAPÉUTICA | VOLUMEN 10 Nº 4 | DICIEMBRE 2012 - 289 -
LA SEF INFORMA
onset of hypertriglyceridemia and hepatic
steatosis induced by fructose.
On the other hand, incubation of FaO
cells, a well-known rat hepatoma cell
line, with 25 mM fructose also increased
the nuclear content of ChREBP and the
expression of its main target gene, L-PK.
Moreover, fructose treatment to FaO cells
reduced the expression of the nuclear
receptor PPAR and its target genes, CYP4A1
and ACO. Furthermore, in a primary culture
of human hepatocytes, fructose treatment
also increased L-PK gene expression,
indicating the activation of ChREBP
transcription factor, and down-regulated
PPAR and L-CPT-I expression (Table 2).
Concerning the cause of PPAR down-
regulation, Boergesen et al. have recently
described that glucose can repress PPAR
expression through the activation of ChREBP
in -pancreatic cells10. Interestingly, when we
treated FaO cells in presence of glucose or
fructose at 25 mM concentration during 24
h, we observed a down-regulation of PPAR
expression only in those cells incubated with
fructose and not with glucose (Figure 1A).
Similarly, L-PK gene expression was only
induced by fructose treatment, indicating
that only fructose and not glucose was
capable of activating ChREBP in FaO cells
(Figure 1B).
Moreover, as Bricambert et al. showed that
ChREBP acetylation leads to an increased
binding activity of this transcription factor11,
we determined the acetylation degree
of ChREBP. We observed an increase of
the acetylation of this protein only in the
livers of 14 days-fructose fed rats (Figure
2), occurring at the same time as down-
regulation of PPAR expression.
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ACTUALIDAD EN FARMACOLOGÍA Y TERAPÉUTICA
- 290 - | VOLUMEN 10 Nº 4 | DICIEMBRE 2012
LA SEF INFORMA
In summary, our results suggest that fructose can
reduce fatty acid catabolism through the increase of
the nuclear content and hyperactivation of ChREBP.
We are now transfecting FaO cells with a siRNA
against ChREBP in order to confi rm the involvement
of ChREBP activation by fructose in the reduction of
PPAR expression.
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2. Elliot t SS, Keim NL , Stern JS, Teff K, Havel PJ. Fruc-
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Bibliografía
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ACTUALIDAD EN FARMACOLOGÍA Y TERAPÉUTICA | VOLUMEN 10 Nº 4 | DICIEMBRE 2012 - 291 -
ACTUALIDAD EN FARMACOLOGÍA Y TERAPÉUTICA
- 292 - | VOLUMEN 10 Nº 4 | DICIEMBRE 2012
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Los artículos con referencias al tratamiento de enfermedades con-
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ta-hemolytic streptococci utilizing a two-disk technique. Journal
of Clinical Microbiology, 1979; 10: 80-84.
Las referencias de libros incluirán: apellidos e inicial del nombre/s
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Sabath, L.D.; Masten, J.M.: Análisis de los agentes antimicrobia-
nos. En: Lennette, E. H.; Spaulding, E. H.; Truant, J. (ed.): Manual
de Microbiología Clínica. Salvat, Barcelona, 1981, pp. 437-440.
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diagramas, fotografías, etc., deben numerarse con números or-
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uno de estos materiales iconográficos se remitirá en formato digi-
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Nota importante: no pegar las imágenes en un documento de
word, puesto que reduce notablemente su calidad . Enviar siem-
pre en los formatos anteriormente especificados.
Contacto:
Luis Gandía Juan.
Redactor Jefe.
Instituto Teófilo Hernando
Facultad de Medicina. UAM.
Avda. Arzobispo Morcillo, 4
28029-Madrid
Tlfo.: 91 497 53 96 Fax: 91 497 31 20
c.e.: luis.gandia@uam.es
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