scholarly journals The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Motohiro Sekiya ◽  
Kenta Kainoh ◽  
Takehito Sugasawa ◽  
Ryunosuke Yoshino ◽  
Takatsugu Hirokawa ◽  
...  
Keyword(s):  
Binding Protein ◽  
Regulatory Element ◽  
Structural Domain ◽  
Transcriptional Corepressor ◽  
Hepatic Gluconeogenesis ◽  
Hepatic Glucose ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Sense And Respond ◽  
Glucose And Lipid Homeostasis

AbstractBiological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches.

scholarly journals New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c

2002 ◽  
Vol 366 (2) ◽  
pp. 377-391 ◽  
Author(s):  
Fabienne FOUFELLE ◽  
Pascal FERRÉ
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Binding Protein ◽  
Regulatory Element ◽  
Fine Tuning ◽  
Whole Body ◽  
Transcriptional Level ◽  
Hepatic Glucose ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

The regulation of hepatic glucose metabolism has a key role in whole-body energy metabolism, since the liver is able to store (glycogen synthesis, lipogenesis) and to produce (glycogenolysis, gluconeogenesis) glucose. These pathways are regulated at several levels, including a transcriptional level, since many of the metabolism-related genes are expressed according to the quantity and quality of nutrients. Recent advances have been made in the understanding of the regulation of hepatic glycolytic, lipogenic and gluconeogenic gene expression by pancreatic hormones, insulin and glucagon and glucose. Here we review the role of the transcription factors forkhead and sterol regulatory element binding protein-1c in the inductive and repressive effects of insulin on hepatic gene expression, and the pathway that leads from glucose to gene regulation with the recently discovered carbohydrate response element binding protein. We discuss how these transcription factors are integrated in a regulatory network that allows a fine tuning of hepatic glucose storage or production, and their potential importance in metabolic diseases.

scholarly journals Hairpin Orientation of Sterol Regulatory Element-binding Protein-2 in Cell Membranes as Determined by Protease Protection

1995 ◽  
Vol 270 (49) ◽  
pp. 29422-29427 ◽  
Author(s):  
Xianxin Hua ◽  
Juro Sakai ◽  
Ho Y. K. ◽  
Joseph L. Goldstein ◽  
Michael S. Brown
Keyword(s):  
Cell Membranes ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

scholarly journals Sterol Regulatory Element Binding Protein 1a Regulates Hepatic Fatty Acid Partitioning by Activating Acetyl Coenzyme A Carboxylase 2

2009 ◽  
Vol 29 (17) ◽  
pp. 4864-4872 ◽  
Author(s):  
Seung-Soon Im ◽  
Linda E. Hammond ◽  
Leyla Yousef ◽  
Cherryl Nugas-Selby ◽  
Dong-Ju Shin ◽  
...  
Keyword(s):  
Insertional Mutagenesis ◽  
Coenzyme A ◽  
Binding Protein ◽  
Regulatory Element ◽  
Fatty Acyl ◽  
Acetyl Coenzyme A ◽  
Acetyl Coenzyme ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Microarray Expression

ABSTRACT We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5% of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.

scholarly journals Analysis of the role of protein kinase B (cAKT) in insulin-dependent induction of glucokinase and sterol regulatory element-binding protein 1 (SREBP1) mRNAs in hepatocytes

2003 ◽  
Vol 376 (3) ◽  
pp. 697-705 ◽  
Author(s):  
Pascale G. RIBAUX ◽  
Patrick B. IYNEDJIAN
Keyword(s):  
Protein Kinase ◽  
Protein Kinase B ◽  
Binding Protein ◽  
Regulatory Element ◽  
Necessary Condition ◽  
Insulin Effect ◽  
Element Binding Protein ◽  
Insulin Dependent ◽  
Sterol Regulatory Element ◽  
Stimulation Of

Previous work showed that acute stimulation of a conditionally active protein kinase B (PKB or cAKT) was sufficient to elicit insulin-like induction of GCK (glucokinase) and SREBP1 (sterol regulatory element-binding protein 1) in hepatocytes [Iynedjian, Roth, Fleischmann and Gjinovci (2000) Biochem. J. 351, 621–627; Fleischmann and Iynedjian (2000) Biochem. J. 349, 13–17]. The objective of the present study was to determine whether activation of PKB during insulin stimulation of hepatocytes was a necessary condition for the induction of the two genes. Activation of PKB by insulin was inhibited by pretreatment of the hepatocytes with C2 ceramide. This resulted in the inhibition of insulin-dependent increases in GCK and SREBP1 mRNAs. A triple mutant of PKB failed to interfere with insulin activation of PKB in hepatocytes even at high overexpression levels achieved after adenovirus transduction. A PKB–CaaX fusion protein, which can act as a dominant-negative inhibitor of PKB activation in other cells, was shown to be constitutively activated in hepatocytes and to trigger insulin-like induction of GCK and SREBP1. In addition, constitutive PKB–CaaX activity caused refractoriness of the hepatocytes to insulin signalling at an upstream step resulting in the inhibition of both extracellular-signal-regulated kinase 1/2 and endogenous PKB activation. The stimulation of gene expression by constitutively active PKB–CaaX and inhibition of the insulin effect by ceramide are compatible with a role for PKB in the insulin-dependent induction of GCK and SREBP1.

scholarly journals Central Leptin Regulates Total Ceramide Content and Sterol Regulatory Element Binding Protein-1C Proteolytic Maturation in Rat White Adipose Tissue

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 169-178 ◽  
Author(s):  
Elena Bonzón-Kulichenko ◽  
Dominik Schwudke ◽  
Nilda Gallardo ◽  
Eduardo Moltó ◽  
Teresa Fernández-Agulló ◽  
...  
Keyword(s):  
Nervous System ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
White Adipose Tissue ◽  
Binding Protein ◽  
Regulatory Element ◽  
Mrna Levels ◽  
Element Binding Protein ◽  
Ceramide Content ◽  
Sterol Regulatory Element

Obesity and type 2 diabetes are associated with insulin and leptin resistance, and increased ceramide contents in target tissues. Because the adipose tissue has become a central focus in these diseases, and leptin-induced increases in insulin sensitivity may be related to effects of leptin on lipid metabolism, we investigated herein whether central leptin was able to regulate total ceramide levels and the expression of enzymes involved in ceramide metabolism in rat white adipose tissue (WAT). After 7 d central leptin treatment, the total content of ceramides was analyzed by quantitative shotgun lipidomics mass spectrometry. The effects of leptin on the expression of several enzymes of the sphingolipid metabolism, sterol regulatory element binding protein (SREBP)-1c, and insulin-induced gene 1 (INSIG-1) in this tissue were studied. Total ceramide levels were also determined after surgical WAT denervation. Central leptin infusion significantly decreased both total ceramide content and the long-chain fatty acid ceramide species in WAT. Concomitant with these results, leptin decreased the mRNA levels of enzymes involved in de novo ceramide synthesis (SPT-1, LASS2, LASS4) and ceramide production from sphingomyelin (SMPD-1/2). The mRNA levels of enzymes of ceramide degradation (Asah1/2) and utilization (sphingomyelin synthase, ceramide kinase, glycosyl-ceramide synthase, GM3 synthase) were also down-regulated. Ceramide-lowering effects of central leptin were prevented by local autonomic nervous system denervation of WAT. Finally, central leptin treatment markedly increased INSIG-1 mRNA expression and impaired SREBP-1c activation in epididymal WAT. These observations indicate that in vivo central leptin, acting through the autonomic nervous system, regulates total ceramide levels and SREBP-1c proteolytic maturation in WAT, probably contributing to improve the overall insulin sensitivity. Central leptin decreases total ceramide levels and prevents sterol regulatory element binding protein (SREBP-1C) proteolytic maturation in white adipose tissue, and probably, in this way, contributes to improve the overall insulin sensitivity.

Analysis of Sterol-Regulatory Element-Binding Protein 1c Target Genes in Mouse Liver during Aging and High-Fat Diet

2013 ◽  
Vol 6 (2) ◽  
pp. 107-122 ◽  
Author(s):  
Frédéric Capel ◽  
Gaëlle Rolland-Valognes ◽  
Catherine Dacquet ◽  
Manuel Brun ◽  
Michel Lonchampt ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Mouse Liver ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
High Fat ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c

2003 ◽  
Vol 282 (2) ◽  
pp. 132-137 ◽  
Author(s):  
Y.u-A.n Yang ◽  
Patrice J. Morin ◽  
Wan Fang Han ◽  
Tinghua Chen ◽  
Daniel M. Bornman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element
Sign in / Sign up

Export Citation Format

Share Document