Partenaires et organisations internationales
(Anglais)
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INSERM U465 (F), Tiense Suikraffinaderij (B), Univ. of Bristol (UK), Univ. Catholique de Louvain (B), Univ. Claude Bernard (F)
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Résumé des résultats (Abstract)
(Anglais)
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Obesity is the storage of an excessive amount of triglycerides in adipose tissue. Triglycerides can originate from the diet but can also be synthetized from carbohydrates ingested in excess of the energy needs, in the liver and adipose tissue by a metabolic pathway called lipogenesis. The overall objective of this program was to study the efficiency of various carbohydrates to modulate the lipogenic capacity and relevant gene expression in rat and human species and to understand the underlying mechanisms involved in the regulation of lipogenic genes by carbohydrates. Due to the absence of relevant human cellular models, most of the knowledge on the molecular regulation of hepatic lipogenic activity were generated on rodent cells. For this purpose we developed SV40-Tantigen immortalized human liver cells lines (THLE cells) and used these cell lines for studying the regulation of hepatic lipogenesis. The influence of non digestible carbohydrate metabolites (i.e., short chain fatty acids) as well as leptin on lipogenic activity was also evaluated. As previously described in rat hepatocytes, glucose, in presence of insulin, induced lipogenic genes, such as fatty acid synthase (FAS) and acetyl CoA carboxylase (ACC), and stimulated triacylglycerol (TAG) accumulation in THLE cells. Increased cellular glucose 6-phosphate levels, due to the disappearance of GLUT2 gene expression, led to the dysregulation of the FAS gene expression. In comparison with GLUT2-positive THLE cells, GLUT2-negative cells showed high levels of TAG accumulation due to a up-regulation of the FAS gene expression, even in low glucose conditions. Sterol Regulatory Element Binding Protein-1c (SREBP-1c) is a transcriptional factor described as essential for the expression of FAS gene in response to glucose and insulin. SREBP-1c expression was strongly reduced in GLUT2-negative cells, in comparison with -positive cells, indicating that this transcriptional factor could play a role in glucose-transporter gene expression. The effects of physiologic concentrations of different SCFAs on the lipogenic capacity of GLUT2-positive THLE cells were examined. Butyrate (145 µM) and acetate (1.3 mM) treatments do not modify glucose-induced FAS expression, while propionate (440 µM) and a mixture of the 3 SCFAs tend to decrease FAS expression but without reaching significance. Moreover, no significant effects of leptin on glucose-induced TAG synthesis were observed in GLUT2-positive cells while a significant increase was obtained in GLUT2 negative cells.
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