Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression

Dentin, Renaud; Pégorier, Jean‐Paul; Benhamed, Fadila; Foufelle, Fabienne; Ferré, Pascal; Fauveau, Véronique; Magnuson, Mark A.; Girard, Jean; Postic, Catherine

doi:10.1074/jbc.m312475200

Cited by 400 publications

(380 citation statements)

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“…It has also been proposed that the mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol (PI) 3-kinase pathway are involved in the SREBP-1c-mediated FAS gene expression 41,42 and that hepatic glucokinase (glucose-specific hexokinase) is required for the synergistic action of ChREBP and SREBP-1c in lipogenic gene expression. 39 The high hexokinase activity in the transplantation model has already been demonstrated 5 and we have recently also shown, that insulin signalling via the MAP kinase pathway is strongly increased in the FAH. 7 Thus, our in vivo study confirms the observations made in cultured hepatocytes: high levels of insulin and glucose in conjunction with high glucokinase expression, possibly mediated by the MAP kinase pathway, lead to upregulation of the FAS gene.…”

Section: Discussionmentioning

confidence: 98%

“…FAS gene expression in rat hepatocytes is regulated by both insulin and glucose. It has been suggested that insulin regulation of FAS is at least partly mediated by the basic/helixloop-helix/leucine zipper transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) 38 and that glucose induction of FAS is mediated through a SREBP-1c-distinct transcription factor, designated as either carbohydrate-responsive element-binding protein (ChREBP) 39 or carbohydrateresponsive factor. 40 Interestingly, glucose and insulin stimulate FAS expression synergistically, that is, high glucose levels increase the insulin stimulatory effect, 38 which explains the strong FAS overexpression in our hormonal model.…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Evert

Schneider‐Stock

Dombrowski

2005

Laboratory Investigation

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Fatty acid synthase (FAS) is the key enzyme of de novo fatty acid synthesis and has been shown to be involved in carcinogenesis of numerous human malignancies, including breast, colorectal, and prostate carcinomas, often associated with a worse prognosis. Although FAS is mainly expressed in the liver, an implication of FAS in hepatocarcinogenesis, has not yet been investigated. FAS expression is stimulated by insulin and glucose, and insulin is also the primary trigger of hepatocarcinogenesis in an endocrine experimental model, which is induced by low-number transplantation of islets of Langerhans into the livers of diabetic rats. We therefore investigated, whether FAS is implicated in hepatocarcinogenesis in this model and in comparison to chemically induced hepatocarcinogenesis after N-nitrosomorpholine (NNM) treatment in diabetic and normoglycemic rats. Preneoplastic clear-cell foci of altered hepatocytes (FAH), harvested after laser-microdissection of kryostat sections, showed an overexpression of FAS messenger RNA in gene expression profiles, done by arrayhybridization, and in quantitative RT-PCR (Light-Cycler). Virtually, all (96-98%) of the subsequently investigated FAH and the glycogenotic hepatocellular adenomas and carcinomas showed an additional strong FAS protein overexpression. In the NNM-model, FAS protein was also overexpressed in the vast majority (87%) of glycogenotic FAH and neoplasms, in particular in the diabetic animals. Also two spontaneous glycogenotic FAH in control animals displayed strong FAS overexpression. Basophilic lesions and neoplasms, which occasionally develop out of the primary clear-cell FAH at later stages of carcinogenesis, however, lost FAS overexpression. In conclusion, FAS overexpression is an early phenonemon in spontaneous, hormonally and chemically induced rat hepatocarcinogenesis, demonstrable in early clear-cell (glycogenotic) FAH and hepatocellular neoplasms. Keywords: fatty acid synthase; glucose; hepatocarcinogenesis; insulin; islet transplantatation; N-nitrosomorpholine After low-number transplantation of islets of Langerhans into the livers of diabetic rats, the liver acini draining the blood from the islet grafts show cellular alterations, the foci of altered hepatocytes (FAH). 1 FAH resemble the glycogen-storing or clear-cell phenotype of preneoplastic foci known from experimental and human hepatocarcinogenesis. 2,3 In the transplantation model, these preneoplastic FAH may develop into hepatocellular adenomas (HCA) and carcinomas (HCC) within 6-24 months after islet transplantation. 4 Previous results indicate that insulin is the primary trigger for the development of FAH and hepatocarcinogenesis in this model. 1,[4][5][6][7] In the beginning of the carcinogenic process, however, these FAH can be regarded as purely adaptative in nature. At this stage, insulin effects manifested in several aspects, that is, an increase in glycogen storage and proliferative activity, lipid accumulation, and altered expression of several insulinrelated proteins, including IGF-I a...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Evert

Schneider‐Stock

Dombrowski

2005

Laboratory Investigation

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“…[16][17][18][19][20] In this study, we investigated whether uric acid induced ER stress in liver, and modulation of uric acid-induced ER stress could ameliorate hepatic fat accumulation. We also examined the differential activation of transcription factors responsible for uric acid-induced fat accumulation in hepatocytes with a demonstration of cross-talk between ER stress and oxidative stress.…”

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confidence: 99%

Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes

Choi

Shin

Choi

et al. 2014

Laboratory Investigation

216

172

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Non-alcoholic fatty liver disease (NAFLD) is currently one of the most common types of chronic liver injury. Elevated serum uric acid is a strong predictor of the development of fatty liver as well as metabolic syndrome. Here we demonstrate that uric acid induces triglyceride accumulation by SREBP-1c activation via induction of endoplasmic reticulum (ER) stress in hepatocytes. Uric acid-induced ER stress resulted in an increase of glucose-regulated protein (GRP78/94), splicing of the X-box-binding protein-1 (XBP-1), the phosphorylation of protein kinase RNA-like ER kinase (PERK), and eukaryotic translation initiation factor-2a (eIF-2a) in cultured hepatocytes. Uric acid promoted hepatic lipogenesis through overexpression of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) via activation of SREBP-1c, which was blocked by probenecid, an organic anion transport blocker in HepG2 cells and primary hepatocytes. A blocker of ER stress, tauroursodeoxycholic acid (TUDCA), and an inhibitor of SREBP-1c, metformin, blocked hepatic fat accumulation, suggesting that uric acid promoted fat synthesis in hepatocytes via ER stress-induced activation of SREBP-1c. Uric acid-induced activation of NADPH oxidase preceded ER stress, which further induced mitochondrial ROS production in hepatocytes. These studies provide new insights into the mechanisms by which uric acid stimulates fat accumulation in the liver.

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“…Afin de confirmer le rôle de ChREBP en tant que média-teur majeur de l'action transcriptionnelle du glucose, notre équipe a développé une technique d'ARN interférent (ARNi) permettant d'inhiber sélectivement l'expression de ChREBP. Dans des hépatocytes isolés de souris transfectés avec l'ARNi ChREBP, une forte concentration de glucose (25 mM) n'est plus capable de stimuler l'expression des gènes glycolytiques (L-PK) et lipogéni-ques (ACC, FAS) [16]. De plus, l'accumulation de lipides est fortement diminuée en l'absence de ChREBP dans ces cellules.…”

Section: Identification Du Facteur De Transcription Chrebp Comme Médiunclassified

L’hyperactivité de la lipogenèse peut-elle conduire à la stéatose hépatique ?

2008

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La prévalence de la stéatose hépatique non alcoolique est en augmentation constante dans les pays industrialisés. Cette pathologie, qui se caractérise par une accumulation excessive de lipides dans le foie, est fortement associée au syndrome métabolique, défini par l'existence de troubles tels qu'une obésité abdominale, une résistance à l'insuline avec ou sans hyperglycémie, une dyslipidémie et une hypertension [1]. La stéatose hépatique fait partie d'un large spectre d'atteintes hépatiques regroupées sous le terme de NAFLD (non alcoholic fatty liver disease) ou stéato-hépatopathies non alcooliques. Parmi les NAFLD, on distingue ainsi la simple stéatose et les NASH (non alcoholic steatohepatitis), caractérisées par une stéatose associée à la présence de lésions inflammatoires évolutives responsables de l'apparition d'une fibrose et d'une véritable cirrhose pouvant se compliquer de carcinome hépatocellulaire. Il a été proposé en 1998 un modèle permettant d'expliquer la pathogénie des NAFLD. Selon ce « modèle des 2 attaques » [2], l'accumulation de lipides dans le foie constitue une première phase > L'obésité, la résistance à l'insuline et le diabète de type 2 s'accompagnent fréquemment d'une accumulation excessive de lipides (stéatose) dans des tissus qui, normalement, n'en stockent pas à long terme. C'est en particulier le cas du foie qui joue un rôle central dans le maintien de l'homéostasie énergétique. Ainsi, la prévalence de la stéatose hépatique est en augmentation constante dans nos sociétés industrialisées. La découverte du facteur de transcription ChREBP a permis des avancées considérables dans la compréhension du contrôle du métabolisme glucido-lipidique. Ce facteur de transcription, qui relaie l'action du glucose sur l'expression des gènes, apparaît comme un déterminant central de la physiopathologie de la stéatose hépatique et de la résistance à l'insuline chez la souris. adaptative qui fragilise les cellules, les rendant ainsi plus sensibles aux agressions telles que le stress oxydatif, la peroxydation lipidique et certaines cytokines conduisant à l'inflammation et à la fibrose. Ainsi, bien que chez certains individus, la stéatose demeure béni-gne, elle évolue en stéato-hépatite chez 10 à 20 % des patients obèses et résistants à l'insuline [3]. Lors du développement de la stéatose hépatique, les lipides qui s'accumulent dans le foie sont majoritairement des triglycérides, issus de l'estérification de trois acides gras avec un glycérol-3-phosphate. Les acides gras utilisés pour la synthèse des triglycérides proviennent non seulement du pool plasmatique d'acides gras non estérifiés (issus de la lipolyse du tissu adipeux), mais également des acides gras néosynthétisés à partir du glucose par la voie de la lipogenèse hépatique (Figure 1). Les triglycérides hépatiques sont ensuite stockés dans des gouttelettes lipidiques ou sécrétés dans le sang sous forme de lipoprotéines de très faible densité (VLDL, very low density lipoproteins). Les triglycérides peuvent également être hydrolysés dans l'hépatocyte et...

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Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression

Abstract: Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes.

Cited by 400 publications

References 61 publications

Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes

L’hyperactivité de la lipogenèse peut-elle conduire à la stéatose hépatique ?

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