scholarly journals Dual Effect of the Adapter Growth Factor Receptor-Bound Protein 14 (Grb14) on Insulin Action in Primary Hepatocytes

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 3109-3117 ◽  
Author(s):  
Nadège Carré ◽  
Michèle Caüzac ◽  
Jean Girard ◽  
Anne-Françoise Burnol
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Binding Protein ◽  
Regulatory Element ◽  
Growth Factor Receptor ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Growth Factor Receptor Bound

Tight control of insulin action in liver is a crucial determinant for the regulation of energy homeostasis. Growth factor receptor-bound protein 14 (Grb14) is a molecular adapter, highly expressed in liver, which binds to the activated insulin receptor and inhibits its tyrosine kinase activity. The physiological role of Grb14 in liver metabolism was unexplored. In this study we used RNA interference to investigate the consequences of Grb14 decrease on insulin-regulated intracellular signaling, and on glucose and lipid metabolism in mouse primary cultured hepatocytes. In Grb14-depleted hepatocytes, insulin-induced phosphorylation of Akt, and of its substrates glycogen synthase kinase 3 and fork-head box protein 1, was increased. These effects on insulin signaling are in agreement with the selective inhibitory effect of Grb14 on the receptor kinase. However, the metabolic and genic effects of insulin were differentially regulated after Grb14 down-regulation. Indeed, the insulin-mediated inhibition of hepatic glucose production and gluconeogenic gene expression was slightly increased. Surprisingly, despite the improved Akt pathway, the induction by insulin of sterol regulatory element binding protein-1c maturation was totally blunted. As a result, in the absence of Grb14, glycogen synthesis as well as glycolytic and lipogenic gene expression were not responsive to the stimulatory effect of insulin. This study provides evidence that Grb14 exerts a dual role on the regulation by insulin of hepatic metabolism. It inhibits insulin receptor catalytic activity, and acts also at a more distal step, i.e. sterol regulatory element binding protein-1c maturation, which effect is predominant under short-term inhibition of Grb14 expression.

scholarly journals Sterol Regulatory Element-binding Protein-2- and Liver X Receptor-driven Dual Promoter Regulation of Hepatic ABC Transporter A1 Gene Expression

2007 ◽  
Vol 282 (29) ◽  
pp. 21090-21099 ◽  
Author(s):  
Norimasa Tamehiro ◽  
Yukari Shigemoto-Mogami ◽  
Tomoshi Kakeya ◽  
Kei-ichiro Okuhira ◽  
Kazuhiro Suzuki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Abc Transporter ◽  
Binding Protein ◽  
Regulatory Element ◽  
Liver X Receptor ◽  
Promoter Regulation ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Dual Promoter

scholarly journals Transcription Factor Sterol Regulatory Element Binding Protein 2 Regulates Scavenger Receptor Cla-1 Gene Expression

2004 ◽  
Vol 24 (12) ◽  
pp. 2358-2364 ◽  
Author(s):  
Morgan Tréguier ◽  
Chantal Doucet ◽  
Martine Moreau ◽  
Christiane Dachet ◽  
Joëlle Thillet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Binding Protein ◽  
Regulatory Element ◽  
Scavenger Receptor ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

scholarly journals Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression

2015 ◽  
Vol 35 (2) ◽  
pp. 803-815 ◽  
Author(s):  
Andreas Bitter ◽  
Andreas K. Nüssler ◽  
Wolfgang E. Thasler ◽  
Kathrin Klein ◽  
Ulrich M. Zanger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Liver ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
Lipogenic Gene ◽  
Knock Down ◽  
Lipogenic Gene Expression ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Background/Aims: Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. Methods: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. Results: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. Conclusion: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.

scholarly journals FoxO1 Inhibits Sterol Regulatory Element-binding Protein-1c (SREBP-1c) Gene Expression via Transcription Factors Sp1 and SREBP-1c

2012 ◽  
Vol 287 (24) ◽  
pp. 20132-20143 ◽  
Author(s):  
Xiong Deng ◽  
Wenwei Zhang ◽  
InSug O-Sullivan ◽  
J. Bradley Williams ◽  
Qingming Dong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

scholarly journals Calpain System Regulates the Differentiation of Adult Primitive Mesenchymal ST-13 Adipocytes

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4811-4819 ◽  
Author(s):  
Yukiko Yajima ◽  
Mayumi Sato ◽  
Hiroyuki Sorimachi ◽  
Mitsushi Inomata ◽  
Masatoshi Maki ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Binding Protein ◽  
Regulatory Element ◽  
Clonal Expansion ◽  
Dominant Negative ◽  
Nuclear Fraction ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Mitotic Clonal Expansion ◽  
Calpain System

The activity of calpain, a calcium-activated protease, is required during the mitotic clonal expansion phase of 3T3-L1 embryonic preadipocyte differentiation. Here we examined the role of calpain in the adipogenesis of ST-13 preadipocytes established from adult primitive mesenchymal cells, which do not require mitotic clonal expansion. After exposure to the calpain inhibitor, N-benzyloxycarbonyl-l-leucyl-l-leucinal or overexpression of calpastatin, a specific endogenous inhibitor of calpain, ST-13 preadipocytes acquired the adipocyte phenotype. Overexpression of calpastatin in ST-13 adipocytes stimulated the expression of adipocyte-specific CCAAT/enhancer-binding protein-α (C/EBPα), peroxisome proliferator-activated receptor (PPAR)-γ, sterol regulatory element-binding protein 1, and the insulin signaling molecules, insulin receptor α, insulin-receptor substrates, and GLUT4. However, insulin-stimulated glucose uptake was reduced by approximately 52%. The addition of calpain to the nuclear fraction of ST-13 adipocytes resulted in the Ca2+-dependent degradation of PPARγ and C/EBPα but not sterol regulatory element-binding protein 1. Exposing ST-13 adipocytes to A23187 also led to losses of endogenous PPARγ and C/EBPα. Under both conditions, calpain inhibitors almost completely prevented C/EBPα cleavage but partially blocked the decrease of PPARγ. Two ubiquitous forms of calpain, μ- and m-calpain, localized to the cytosol and the nucleus, whereas the activated form of μ- but not m-calpain was found in the nucleus. Finally, stable dominant-negative μ-calpain transfectants showed accelerated adipogenesis and increase in the levels of PPARγ and C/EBPα during adipocyte program. These results support evidence that the calpain system is involved in regulating the differentiation of adult primitive mesenchymal ST-13 preadipocytes.

Abstract 148: Sterol Regulatory Element-Binding Protein-1 Is Involved in the Development of Angiotensin II-Induced Cardiac Fibrosis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Satoshi Sakai ◽  
Yoshimi Nakagawa ◽  
Nobutake Shimojo ◽  
Taizo Kimura ◽  
Kazuko Tajiri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Binding Protein ◽  
Regulatory Element ◽  
Antioxidant Genes ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Sterol Regulatory Element Binding Protein (SREBP)-1 is a transcription factor for triglyceride synthesis. SREBP-1 is shown to contribute to the organ damages such as pancreatic beta cell, liver, and kidney; however, it is unclear whether SREBP-1 also contributes to the cardiac pathogenesis. We made cardiac dysfunction and fibrosis model by 2-week infusion of angiotensin II (A-II, 1.44 mg/kg BW/day). Mice were divided into followings (n=5∼6 in each group): wild with vehicle (WC), wild with A-II (WA), SREBP-1 knockout mice (SREBP-KO) with vehicle (SC), and SREBP-KO with A-II (SA). WA clearly demonstrated cardiac dysfunction and severe perivascular fibrosis compared to WC; however, these findings were not observed in SA compared to SC. We analyzed gene expression by DNA microarray using the software DAVID and quantitative RT-PCR to find gene clusters mostly illustrative for these phenotypes. Gene expression of extracellular matrix (Col1a, 3a, periostin) was increased in WA. Highly scored annotations in WA were chemokines (CCL5, CXCL10) and their receptors (CCR5, CXCR3), and Th2 cytokines (IL-13 and TGFb), suggesting that chronic inflammatory and repairing responses occurred. These changes were normalized in SA compared to SC. Expression of NOX4, a component of NADPH oxidase, was significantly increased in WA and SA compared to each control in a similar extent, suggesting that the Ang II-induced oxidative stress to the heart did not differ. To elucidate why the cardiac fibrosis differed between WA and SA, we analyzed the expression of transcription factors. Nrf2, a transcription factor for detoxification and anti-oxidant gene against to reactive oxygen species (ROS), was significantly decreased in WA compared to WC; however, it did not differ between in SA and SC. Furthermore, expression of the Nrf2-inducible genes HO-1 and NQO1, antioxidant genes, was significantly decreased in WA compared to WC; meanwhile, there were no differences between in SA and SC. [Conclusion] SREBP-1 may positively contribute to the A-II-induced cardiac fibrosis via the involvement of chronic inflammatory responses, which is induced partly by the reduction of antioxidant activity.

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