scholarly journals A simple promoter containing two Sp1 sites controls the expression of sterol-regulatory-element-binding protein 1a (SREBP-1a)

2005 ◽  
Vol 386 (1) ◽  
pp. 161-168 ◽  
Author(s):  
Chengkang ZHANG ◽  
Dong-Ju SHIN ◽  
Timothy F. OSBORNE
Keyword(s):  
Transcriptional Activation ◽  
Binding Protein ◽  
Regulatory Element ◽  
Animal Experiments ◽  
Proximal Region ◽  
Mrna Levels ◽  
Relative Level ◽  
Transcriptional Activation Domain ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

The mammalian gene for SREBP-1 (sterol-regulatory-element-binding protein 1) contains two promoters that control the production of two proteins, SREBP-1a and -1c, and each contains a unique N-terminal transcriptional activation domain, but they are otherwise identical. The relative level of each mRNA varies from tissue to tissue and they respond differently to regulatory stimuli. SREBP-1c is more abundantly expressed in liver, where its level is also regulated by insulin and liver X receptor activators, and it is also autoregulated by SREBPs. In contrast, SREBP-1a mRNA levels are relatively low and constant in different tissues and few studies have specifically analysed its pattern of expression and regulation. In the present study, we show that the promoter for SREBP-1a is contained in a very small promoter-proximal region containing two Sp1 sites. The small and relatively simple structure for its promoter provides an explanation for the low level of SREBP-1a expression. Additionally, since Sp1 has been implicated in the modest regulation of several genes by insulin, its involvement in the expression of the SREBP-1a promoter provides an explanation for the modest insulin regulation observed in animal experiments.

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.

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

2004 ◽  
Vol 287 (6) ◽  
pp. E1039-E1048 ◽  
Author(s):  
Caroline Améen ◽  
Daniel Lindén ◽  
Britt-Mari Larsson ◽  
Agneta Mode ◽  
Agneta Holmäng ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Continuous Infusion ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
Female Rats ◽  
Mrna Levels ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Secretory Pattern

We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-α (LXRα) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRα mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRα mRNA but is associated with decreased insulin sensitivity.

scholarly journals GH and insulin affect fatty acid synthase activity in isolated porcine adipocytes in culture without any modifications of sterol regulatory element binding protein-1 expression

2004 ◽  
Vol 181 (2) ◽  
pp. 271-280 ◽  
Author(s):  
I Louveau ◽  
F Gondret
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Porcine Adipocytes

The ability of GH to decrease fatness and insulin-regulated events such as lipogenic enzyme activities is well known in pigs. Nevertheless, the precise mechanism underlying these actions has not been elucidated yet. Expression of the transcription factor sterol regulatory element binding protein (SREBP)-1 has been reported as a key mediator of insulin action in rat hepatocytes and adipose cell lines. The present study aimed to determine whether the regulation of lipogenesis by GH and/or insulin in porcine adipocytes also involved SREBP-1. Isolated adipocytes, obtained from perirenal or s.c. adipose tissue samples of female pigs (51+/-0.4 kg; n=17), were cultured in serum-free medium in the absence or presence of these hormones for up to 4 days. Glucose incorporation and fatty acid synthase activity were increased by insulin in a dose-dependent manner in adipocytes of both sites. The increase was maximal at 1.7 and 17 nM in s.c. and perirenal adipocytes respectively, suggesting inter-depot differences in the regulation of lipogenesis by insulin. These insulin-stimulated events were decreased by GH (1 nM). No change in SREBP-1 mRNA levels was observed in response to GH and/or insulin. Taken together, these data indicate that the regulation of lipogenesis by insulin and GH appears to not involve changes in SREBP-1 mRNA levels in porcine adipocytes.

Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice

2003 ◽  
Vol 285 (6) ◽  
pp. E1182-E1195 ◽  
Author(s):  
Kenji Harada ◽  
Wen-Jun Shen ◽  
Shailja Patel ◽  
Vanita Natu ◽  
Jining Wang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Receptor ◽  
Binding Protein ◽  
Regulatory Element ◽  
Mrna Levels ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Adipose Differentiation

To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSL-deficient ( HSL– /–) and wild-type mice were fed normal chow or high-fat diets. HSL– /– mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL– /– mice. Serum insulin levels in the fed state and tumor necrosis factor-α mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL– /– mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-γ, CAAT/enhancer-binding protein-α) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination- and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL– /– mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL– /– mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels.

scholarly journals Sterol Regulatory Element Binding Protein-1a Transactivates 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase Gene Promoter

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3446-3456 ◽  
Author(s):  
Isidoro Metón ◽  
Miriam Egea ◽  
Ida G. Anemaet ◽  
Felipe Fernández ◽  
Isabel V. Baanante
Keyword(s):  
Transcriptional Activation ◽  
Sparus Aurata ◽  
Binding Protein ◽  
Regulatory Element ◽  
Gene Promoter ◽  
Sea Bream ◽  
Proximal Promoter ◽  
Mrna Levels ◽  
Nutritional Regulation ◽  
Sterol Regulatory Element

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) catalyzes the synthesis and degradation of fructose-2,6-bisphosphate, a key modulator of glycolysis-gluconeogenesis. To gain insight into the molecular mechanism behind hormonal and nutritional regulation of PFKFB expression, we have cloned and characterized the proximal promoter region of the liver isoform of PFKFB (PFKFB1) from gilthead sea bream (Sparus aurata). Transient transfection of HepG2 cells with deleted gene promoter constructs and electrophoretic mobility shift assays allowed us to identify a sterol regulatory element (SRE) to which SRE binding protein-1a (SREBP-1a) binds and transactivates PFKFB1 gene transcription. Mutating the SRE box abolished SREBP-1a binding and transactivation. The in vivo binding of SREBP-1a to the SRE box in the S. aurata PFKFB1 promoter was confirmed by chromatin immunoprecipitation assays. There is a great deal of evidence for a postprandial rise of PFKB1 mRNA levels in fish and rats. Consistently, starved-to-fed transition and treatment with glucose or insulin increased SREBP-1 immunodetectable levels, SREBP-1 association to PFKFB1 promoter, and PFKFB1 mRNA levels in the piscine liver. Our findings demonstrate involvement of SREBP-1a in the transcriptional activation of PFKFB1, and we conclude that SREBP-1a may exert a key role mediating postprandial activation of PFKFB1 transcription.

Insulin induced lipogenesis and enhanced mRNA level of sterol regulatory element binding protein-1c in primary porcine adipocyte

2008 ◽  
Vol 88 (3) ◽  
pp. 419-424 ◽  
Author(s):  
Y. Li ◽  
G. S. Yang
Keyword(s):  
Binding Protein ◽  
Regulatory Element ◽  
Mrna Level ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Significant Difference ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Porcine Adipocytes ◽  
Dose Dependent

Little is known about the development and metabolism of the pig adipocyte, and even less is known about regulation of lipogenesis in the pig adipocyte. The objective of this study was to test the effects of insulin on the morphology of cells, the content of triacylglycerols (TG), the activity of fatty acid synthase (FAS) and the mRNA level of sterol regulatory element binding protein-1c (SREBP-1c) in porcine adipocytes in vitro. Morphologically, larger lipid droplets appeared in the presence of insulin for 48 h. Insulin-induced lipogenesis of primary porcine adipocytes was correlated with the TG content and FAS activity. There was a significant difference in the TG content and FAS activity between the insulin-treated cells and the control cells (P < 0.05); insulin increased the content of TG and FAS activity in a dose-dependent manner and the maximum activity occurred at 150 nmol L-1. The TG content and FAS activity were increased in a dose-dependent manner and maximal values were obtained when adipocytes were incubated with 150 nmol L-1 insulin. The mRNA levels of SREBP-1c were also increased by insulin. In summary, lipogenesis of porcine adipocyte could be induced by insulin in a dose-dependent manner and the induced hypertrophy of porcine adipocytes partially due to the increase of TG content, FAS activity and SREBP-1c mRNA level. Key words: Lipogenesis, porcine, adipocyte, insulin, SREBP-1c

scholarly journals Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)

2004 ◽  
Vol 378 (3) ◽  
pp. 769-778 ◽  
Author(s):  
Frédérique DIRAISON ◽  
Laura PARTON ◽  
Pascal FERRÉ ◽  
Fabienne FOUFELLE ◽  
Celia P. BRISCOE ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Binding Protein ◽  
Regulatory Element ◽  
Mrna Levels ◽  
Β Cells ◽  
Over Expression ◽  
Triacylglycerol Content ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Accumulation of intracellular lipid by pancreatic islet β-cells has been proposed to inhibit normal glucose-regulated insulin secretion (‘glucolipotoxicity’). In the present study, we determine whether over-expression in rat islets of the lipogenic transcription factor SREBP1c (sterol-regulatory-element-binding protein-1c) affects insulin release, and whether changes in islet lipid content may be reversed by activation of AMPK (AMP-activated protein kinase). Infection with an adenovirus encoding the constitutively active nuclear fragment of SREBP1c resulted in expression of the protein in approx. 20% of islet cell nuclei, with a preference for β-cells at the islet periphery. Real-time PCR (TaqMan®) analysis showed that SREBP1c up-regulated the expression of FAS (fatty acid synthase; 6-fold), acetyl-CoA carboxylase-1 (2-fold), as well as peroxisomal-proliferator-activated receptor-γ (7-fold), uncoupling protein-2 (1.4-fold) and Bcl2 (B-cell lymphocytic-leukaemia proto-oncogene 2; 1.3-fold). By contrast, levels of pre-proinsulin, pancreatic duodenal homeobox-1, glucokinase and GLUT2 (glucose transporter isoform-2) mRNAs were unaltered. SREBP1c-transduced islets displayed a 3-fold increase in triacylglycerol content, decreased glucose oxidation and ATP levels, and a profound inhibition of glucose-, but not depolarisation-, induced insulin secretion. Culture of islets with the AMPK activator 5-amino-4-imidazolecarboxamide riboside decreased the expression of the endogenous SREBP1c and FAS genes, and reversed the effect of over-expressing active SREBP1c on FAS mRNA levels and cellular triacylglycerol content. We conclude that SREBP1c over-expression, even when confined to a subset of β-cells, leads to defective insulin secretion from islets and may contribute to some forms of Type II diabetes.

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