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

Fructose induces synthesis and reduces oxidation of
liver fatty acids through CHREBP activation
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.
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
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
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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- 290 - | VOLUMEN 10 Nº 4 | DICIEMBRE 2012
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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DI, Kang DH , et al. Potential role of sugar (fructo -
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tose, weight gain, and the insulin res istance syndro-
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Kikkawa R, Kashiwagi A. Amelioration of high fruc-
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Ma y ;2 8 2( 5) :E 118 0 - E119 0 .
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Am J Hypertens 2008 Sep;21(9):1018-22.
6. Roglans N, Vila L, Farre M, Alegret M, Sanchez RM,
Vazquez-Carrera M, et al. Impairment of hepatic
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in fructose-fed rats. Hepatology 2007 Mar;45(3):778-
7. Vila L, Roglans N, Alegret M, Sanchez RM, Vazquez-
Carrera M, Laguna JC. Suppressor of cytokine sig-
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Carrera M, Alegret M, et al. Liver A MP/ATP ratio
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in mice. J Cli n Invest 2010 Dec 1;120(12):4316-31.
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- 292 - | VOLUMEN 10 Nº 4 | DICIEMBRE 2012
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Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic β-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor α (PPARα) is an important regulator of genes involved in fatty acid metabolism and has been shown to protect against lipid-induced β-cell dysfunction. We and others have previously shown that expression of the PPARα gene in β-cells is rapidly repressed by glucose. Here we show that the PPARα gene is transcribed from five alternative transcription start sites, resulting in three alternative first exons that are spliced to exon 2. Expression of all PPARα transcripts is repressed by glucose both in insulinoma cells and in isolated pancreatic islets. The observation that the dynamics of glucose repression of PPARα transcription are very similar to those of glucose activation of target genes by the carbohydrate response element-binding protein (ChREBP) prompted us to investigate the potential role of ChREBP in the regulation of PPARα expression. We show that a constitutively active ChREBP lacking the N-terminal domain efficiently represses PPARα expression in insulinoma cells and in rodent and human islets. In addition, we demonstrate that siRNA-mediated knockdown of ChREBP abrogates glucose repression of PPARα expression as well as induction of well established ChREBP target genes in insulinoma cells. In conclusion, this work shows that ChREBP is a critical and direct mediator of glucose repression of PPARα gene expression in pancreatic β-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of β-cells.
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Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide, and is commonly associated with the metabolic syndrome. Secular trends in the prevalence of these diseases may be associated with the increased fructose consumption observed in the Western diet. NAFLD is characterized by two steps of liver injury: intrahepatic lipid accumulation (hepatic steatosis), and inflammatory progression to nonalcoholic steatohepatitis (NASH) (the 'two-hit' theory). In the first 'hit', hepatic metabolism of fructose promotes de novo lipogenesis and intrahepatic lipid, inhibition of mitochondrial beta-oxidation of long-chain fatty acids, triglyceride formation and steatosis, hepatic and skeletal muscle insulin resistance, and hyperglycemia. In the second 'hit', owing to the molecular instability of its five-membered furanose ring, fructose promotes protein fructosylation and formation of reactive oxygen species (ROS), which require quenching by hepatic antioxidants. Many patients with NASH also have micronutrient deficiencies and do not have enough antioxidant capacity to prevent synthesis of ROS, resulting in necroinflammation. We postulate that excessive dietary fructose consumption may underlie the development of NAFLD and the metabolic syndrome. Furthermore, we postulate that NAFLD and alcoholic fatty liver disease share the same pathogenesis.
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To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-alpha (PPARalpha) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARalpha as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARalpha protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARalpha protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to beta-oxidation and the enhancement of mitochondrial gene expression.
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This review explores whether fructose consumption might be a contributing factor to the development of obesity and the accompanying metabolic abnormalities observed in the insulin resistance syndrome. The per capita disappearance data for fructose from the combined consumption of sucrose and high-fructose corn syrup have increased by 26%, from 64 g/d in 1970 to 81 g/d in 1997. Both plasma insulin and leptin act in the central nervous system in the long-term regulation of energy homeostasis. Because fructose does not stimulate insulin secretion from pancreatic beta cells, the consumption of foods and beverages containing fructose produces smaller postprandial insulin excursions than does consumption of glucose-containing carbohydrate. Because leptin production is regulated by insulin responses to meals, fructose consumption also reduces circulating leptin concentrations. The combined effects of lowered circulating leptin and insulin in individuals who consume diets that are high in dietary fructose could therefore increase the likelihood of weight gain and its associated metabolic sequelae. In addition, fructose, compared with glucose, is preferentially metabolized to lipid in the liver. Fructose consumption induces insulin resistance, impaired glucose tolerance, hyperinsulinemia, hypertriacylglycerolemia, and hypertension in animal models. The data in humans are less clear. Although there are existing data on the metabolic and endocrine effects of dietary fructose that suggest that increased consumption of fructose may be detrimental in terms of body weight and adiposity and the metabolic indexes associated with the insulin resistance syndrome, much more research is needed to fully understand the metabolic effect of dietary fructose in humans.
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Currently, we are experiencing an epidemic of cardiorenal disease characterized by increasing rates of obesity, hypertension, the metabolic syndrome, type 2 diabetes, and kidney disease. Whereas excessive caloric intake and physical inactivity are likely important factors driving the obesity epidemic, it is important to consider additional mechanisms. We revisit an old hypothesis that sugar, particularly excessive fructose intake, has a critical role in the epidemic of cardiorenal disease. We also present evidence that the unique ability of fructose to induce an increase in uric acid may be a major mechanism by which fructose can cause cardiorenal disease. Finally, we suggest that high intakes of fructose in African Americans may explain their greater predisposition to develop cardiorenal disease, and we provide a list of testable predictions to evaluate this hypothesis.
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The etiology of the metabolic syndrome (MS) includes both genetic and environmental factors. The two most commonly studied animal models of the MS are the high-sucrose diet given to spontaneously hypertensive rats (SHRs) and high-fructose diet given to Sprague Dawley rats (SDRs). This study compares between these two models. The two rat strains were examined; within each group, the rats were assigned to either the high-sugar diet (SDRs with fructose-enriched diet and SHRs with sucrose-enriched diet) or standard rat chow (control group). The rats were followed for 7 weeks. The main MS components (obesity, hypertension, impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia) were measured. At baseline systolic blood pressure (SBP), fasting blood levels of triglycerides and insulin, as well as glucose intolerance, were significantly higher among the SHRs compared to SDRs. Following fructose enrichment, SDRs became hyperinsulinemic, hypertriglyceridemic, hypercholesterolemic, hypertensive, and insulin resistant, whereas SHRs responded to sucrose supplementation by a significant elevation in blood pressure and mild worsening of insulin resistance. Endpoint results revealed superiority of sucrose--SHR model in terms of hypertension and superiority of fructose--SDR model in terms of hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia. Both models showed similar postintervention degree of glucose tolerance. The fructose-fed SDR model represents a predominantly environmentally acquired MS, whereas the SHR model is less affected by dietary intervention and better displays the predominantly genetic spontaneous appearance of the syndrome. This fundamental difference should be taken into consideration when choosing an animal model to study the MS.
Women, but not men, show an association between fructose consumption and an increased risk of Type 2 diabetes mellitus. As rats are considered a model for human fructose metabolism, we sought to determine whether such a gender-related difference is present in Sprague-Dawley rats and to analyze the molecular mechanism behind. Male and female Sprague-Dawley rats had free access to water or to a 10% w/v fructose solution for 14 days. Plasma analytes, liver triglycerides and enzyme activities and the expression of enzymes and transcription factors related to fatty acid metabolism, insulin signaling and glucose tolerance were determined. Fructose-fed rats had hypertriglyceridemia, steatosis and reduced fatty acid oxidation activity, although the metabolic pattern of fructose-fed female rats was different to that observed for male rats. Fructose-fed female, but not male rats, showed no change in plasma leptin; they had hyperinsulinemia, an altered glucose tolerance test and less liver insulin receptor substrate-2. Further, only fructose-fed female rats had increased adenosine 5'-monophosphate (AMP)-activated protein kinase activity, resulting in a decreased expression of hepatic nuclear factor 4 and sterol response element binding protein 1. These differences were related to the fact that liver expression of the enzyme fructokinase, controlling fructose metabolism, was markedly induced by fructose ingestion in female, but not in male rats, resulting in a significant increase in the AMP/adenosine 5'-triphosphate (ATP) ratio and, thus, AMP-activated protein kinase activation, in female rats only. The difference in fructokinase induction could explain the higher metabolic burden produced by fructose ingestion in the livers of female Sprague-Dawley rats.
The ability of an organism to sense and store nutrients is vital to survival. The liver is the major organ responsible for converting excess dietary carbohydrate to lipid for storage. An elegant molecular pathway has evolved that allows increased glucose flux into hepatocytes to generate a signaling molecule, xylulose 5-phosphate, that triggers rapid changes in glycolytic enzyme activities and nuclear import of a transcription factor, ChREBP, which coordinates the transcriptional regulation of enzymes that channel the glycolytic end-products into lipogenesis. Further understanding of this metabolic cascade should provide insights on conditions such as fatty liver, obesity, and the metabolic syndrome.
Unlabelled: Fructose makes up a significant proportion of energy intake in westernized diets; its increased consumption has paralleled the growing prevalence of obesity and metabolic syndrome over the past two decades. In the current study, we demonstrate that fructose administration (10% wt/vol) in the drinking water of rats reduces the trans-activating and trans-repressing activity of the hepatic peroxisome proliferator-activated receptor alpha (PPARalpha). As a consequence, fructose decreases hepatic fatty oxidation and increases pro-inflammatory transcription factor nuclear factor kappaB (NF-kappaB) activity. These changes were not observed in glucose-administered rats (10% wt/vol), although both carbohydrates produced similar changes in plasma adiponectin and in the hepatic expression of transcription factors and enzymes involved in fatty acid synthesis. Fructose-fed, but not glucose-fed, rats were hyperleptinemic and exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) transcription factor, although they did not present a similar increase in the serine phosphorylation of nuclear STAT3. Thus, an impairment in the hepatic transduction of the leptin signal could be responsible for the observed alterations in PPARalpha activity in fructose-fed rats. Because PPARalpha activity is lower in human than in rodent liver, fructose ingestion in humans should cause even worse effects, which would partly explain the link between increased consumption of fructose and widening epidemics of obesity and metabolic syndrome. Conclusion: Hypertriglyceridemia and hepatic steatosis induced by fructose ingestion result from a reduction in the hepatic catabolism of fatty acids driven by a state of leptin resistance.