ADD1/SREBP-1c Mediates Insulin-Induced Gene Expression Linked to the MAP Kinase Pathway

Kotzka, Jörg; Müller‐Wieland, Dirk; Koponen, Anni; Njamen, Dieudonné; Kremer, L.; Roth, Günther E.; Munck, Martina; Knebel, Birgit; Krone, Wilhelm

doi:10.1006/bbrc.1998.9161

Cited by 81 publications

(84 citation statements)

References 16 publications

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“…The promoter of the SREBP-1c gene contains both the SREBP response element and the liver X receptor response element (37,54). Transcription of the SREBP-1c gene can be auto-stimulated by SREBP proteins through the SREBP response element (55)(56)(57) or stimulated by the LXR agonists through the liver X receptor response element (37,54). Because PGC-1␤ possesses the domains for mediating its interactions with both SREBP and LXR (19), it is possible that PGC-1␤ regulates the transcription of SREBP-1c and other SRE-and liver X receptor response element-containing genes through assembling the SREBP and LXR complexes, and p38 regulates transcription of key lipogenic genes (SREBP-1c) through expression of the PGC-1␤ gene.…”

Section: Discussionmentioning

confidence: 99%

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Xiong

Collins

et al. 2007

Journal of Biological Chemistry

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Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1␤ gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1␤ gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1␤ and hepatic lipogenesis.Hepatic lipogenesis is essential for maintaining energy balance (1). Disorders of hepatic lipogenesis may lead to fatty liver, dyslipidemia, type II diabetes mellitus, and complications such as atherosclerosis (2). Lipogenesis in liver includes de novo synthesis of fatty acids and cholesterols. As a major site for synthesis of fatty acids, the liver converts excess carbohydrates into fat storage in the fed state. Fatty acids synthesized in the liver are converted into triglycerides and secreted as very low density lipoproteins, which transport fatty acids to the storage sites in adipocytes. Cholesterols synthesized in the liver are also transported to other tissues via very low density lipoproteins as essential building materials for steroid hormones and cellular membranes. However, excess production of fatty acids and cholesterols from the liver may contribute to a variety of lipid disorders. The lipogenic process in the liver is primarily regulated by central lipogenic transcription factors, sterol regulatory element-binding proteins (SREBPs) 2 (reviewed in Refs. 3 and 4).The SREBPs are basic helix-loop-helix-leucine zipper-containing transcription factors (5). Among three known SREBPs, SREBP-1a and -1c are encoded by the same gene; SREBP-1c lacks the N-terminal exon compared with SREBP-1a (6). SREBP-2 is encoded by a separate gene (7). Although SREBPs share similar lip...

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Section: Discussionmentioning

confidence: 99%

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Xiong

Collins

et al. 2007

Journal of Biological Chemistry

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“…There it binds sterol regulatory elements (SRE) in the promoters of many genes involved in fatty acid and triglyceride synthesis (Wang et al, 1994). Transcription of the SREBP1c gene is induced by insulin (Kotzka et al, 1998;Ducluzeau et al, 2001) and oxysterols through LXR (Repa et al, 2000). Much of the insulin action on lipogenic gene transcription has been ascribed to the insulinmediated induction of SREBP-1c (Kotzka et al, 1998;Matsumoto et al, 2002).…”

Section: From Fatty Acids To Oxidative Stressmentioning

confidence: 99%

“…Transcription of the SREBP1c gene is induced by insulin (Kotzka et al, 1998;Ducluzeau et al, 2001) and oxysterols through LXR (Repa et al, 2000). Much of the insulin action on lipogenic gene transcription has been ascribed to the insulinmediated induction of SREBP-1c (Kotzka et al, 1998;Matsumoto et al, 2002). In contrast, unsaturated fatty acids suppress the nuclear SREBP-1c levels and when nSREBP-1c is over-expressed in primary hepatocytes it eliminates the effects of polyunsaturated fatty acids (PUFA) on several lipogenic genes.…”

Section: From Fatty Acids To Oxidative Stressmentioning

confidence: 99%

Nutrient-gene interactions: a single nutrient and hundreds of target genes

Daniel¹,

Dieck²

2004

Biological Chemistry

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Based on the effects of a selective experimental zinc deficiency in a rodent model we explore the use of transcriptome profiling for assessing nutrient-gene interactions in the liver at the molecular and cellular levels. Zinc deficiency caused pleiotropic alterations in mRNA/protein levels of hundreds of genes. In the context of observed metabolic alterations in hepatic metabolism, possible mechanisms are discussed for how a low zinc status may be sensed and transmitted into changes in various metabolic pathways. However, it also becomes obvious that analysis of such complex nutrient-gene interactions beyond the descriptional level is a real challenge for systems biology.

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“…SREBP-2 is a transcription factor that is a major regulator of cholesterol homeostasis and that is activated by cellular cholesterol depletion. It was recently demonstrated that SREBP-2 was linked to p44/42 6 mitogen-activated protein (MAP) kinase signaling cascade [17,18]. On the other hand, statins regulate the induction of various proteins or genes through an activation of MAP kinase signaling cascades [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Pitavastatin induces PON1 expression through p44/42 mitogen-activated protein kinase signaling cascade in Huh7 cells

et al. 2009

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ADD1/SREBP-1c Mediates Insulin-Induced Gene Expression Linked to the MAP Kinase Pathway

Cited by 81 publications

References 16 publications

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Nutrient-gene interactions: a single nutrient and hundreds of target genes

Pitavastatin induces PON1 expression through p44/42 mitogen-activated protein kinase signaling cascade in Huh7 cells

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