scholarly journals A Component Formula of Chinese Medicine for Hypercholesterolemia Based on Virtual Screening and Biology Network

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaoqian Huo ◽  
Fang Lu ◽  
Liansheng Qiao ◽  
Gongyu Li ◽  
Yanling Zhang
Keyword(s):  
Chinese Medicine ◽  
Virtual Screening ◽  
Regulatory Element ◽  
Pharmacophore Model ◽  
Lipid Lowering ◽  
Hmg Coa Reductase ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Coa Reductase

Hypercholesterolemia is a risk factor to atherosclerosis and coronary heart disease II. The abnormal rise of cholesterol in plasma is the main symptom. Cholesterol synthesis pathway is an important pathway of the origin of cholesterol, which is an essential pathway for the therapy of hypercholesterolemia. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), squalene synthase (SQS), and sterol regulatory element binding protein-2 (SREBP-2) are closely connected with the synthesis of cholesterol. The inhibition of these targets can reduce the cholesterol in plasma. This study aimed to build a component formula including three Traditional Chinese Medicines (TCM) components with the inhibition activity of these targets by using virtual screening and biological network. Structure-based pharmacophore models of HMG-CoA reductase and SQS and ligand-based pharmacophore model of SREBP-2 were constructed to screen the Traditional Chinese Medicine Database (TCMD). Molecular docking was used for further screening of components of HMG-CoA reductase and SQS. Then, metabolic network was constructed to elucidate the comprehensive interaction of three targets for lipid metabolism. Finally, three potential active compounds were obtained, which are poncimarin, hexahydrocurcumin, and forsythoside C. The source plants of the compounds were also taken into account, which should have known action of lowering hyperlipidemia. The lipid-lowering effect of hexahydrocurcumin was verified by experiment in vitro. The components that originated from TCMs with lipid-lowering efficacy made up a formula with a synergistic effect through the computer aid drug design methods. The research provides a fast and efficient method to build TCM component formula and it may inspire the study of the explanation of TCM formula mechanism.

scholarly journals Sex-specific effects of in vitro fertilization on adult metabolic phenotypes and hepatic transcriptomic and proteomic pathways in mouse

2020 ◽  
Author(s):  
Laren Narapareddy ◽  
Eric A. Rhon-Calderon ◽  
Lisa A. Vrooman ◽  
Josue Baeza ◽  
Duy K. Nguyen ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Perinatal Outcomes ◽  
Vitro Fertilization ◽  
Specific Effects ◽  
Cholesterol Levels ◽  
Element Binding Protein ◽  
Fat Composition ◽  
Sterol Regulatory Element

AbstractAlthough in vitro fertilization (IVF) is associated with adverse perinatal outcomes, an increasing concern is the long-term health implications. We augmented our IVF mouse model to longitudinally investigate cardiometabolic outcomes in offspring from optimal neonatal litter sizes. We found that IVF-conceived females had higher body weight and cholesterol levels compared to naturally-conceived females, whereas IVF-conceived males had higher levels of triglycerides and insulin, and increased body fat composition. Through transcriptomics and proteomics of adult liver, we identified sexually-dimorphic dysregulation of the sterol regulatory element binding protein (SREBP) pathways that are associated with the sex-specfic phenotypes. We also found that global loss of DNA methylation in placenta was linked to higher cholesterol levels in IVF-conceived females. Our findings indicate that IVF procedures have long-lasting sex-specific effects on metabolic health of offspring and lay the foundation to utilize the placenta as a predictor of long-term outcomes.

scholarly journals A New Role for Sterol Regulatory Element Binding Protein 1 Transcription Factors in the Regulation of Muscle Mass and Muscle Cell Differentiation

2009 ◽  
Vol 30 (5) ◽  
pp. 1182-1198 ◽  
Author(s):  
Virginie Lecomte ◽  
Emmanuelle Meugnier ◽  
Vanessa Euthine ◽  
Christine Durand ◽  
Damien Freyssenet ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Muscle Mass ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Myogenic Program

ABSTRACT The role of the transcription factors sterol regulatory element binding protein 1a (SREBP-1a) and SREBP-1c in the regulation of cholesterol and fatty acid metabolism has been well studied; however, little is known about their specific function in muscle. In the present study, analysis of recent microarray data from muscle cells overexpressing SREBP1 suggested that they may play a role in the regulation of myogenesis. We then demonstrated that SREBP-1a and -1c inhibit myoblast-to-myotube differentiation and also induce in vivo and in vitro muscle atrophy. Furthermore, we have identified the transcriptional repressors BHLHB2 and BHLHB3 as mediators of these effects of SREBP-1a and -1c in muscle. Both repressors are SREBP-1 target genes, and they affect the expression of numerous genes involved in the myogenic program. Our findings identify a new role for SREBP-1 transcription factors in muscle, thus linking the control of muscle mass to metabolic pathways.

Modulation of human Niemann-Pick C1-like 1 gene expression by sterol: role of sterol regulatory element binding protein 2

2007 ◽  
Vol 292 (1) ◽  
pp. G369-G376 ◽  
Author(s):  
Waddah A. Alrefai ◽  
Fadi Annaba ◽  
Zaheer Sarwar ◽  
Alka Dwivedi ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Absorption ◽  
Cholesterol Depletion ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Niemann Pick ◽  
Coa Reductase

Niemann-Pick C1-like 1 (NPC1L1) is an essential intestinal component of cholesterol absorption. However, little is known about the molecular regulation of intestinal NPC1L1 expression and promoter activity. We demonstrated that human NPC1L1 mRNA expression was significantly decreased by 25-hydroxycholesterol but increased in response to cellular cholesterol depletion achieved by incubation with Mevinolin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) in human intestinal Caco-2 cells. We also showed that a −1741/+56 fragment of the NPC1L1 gene demonstrated high promoter activity in Caco-2 cells that was reduced by 25-hydroxycholesterol and stimulated by cholesterol depletion. Interestingly, we showed that the NPC1L1 promoter is remarkably transactivated by the overexpression of sterol regulatory element (SRE) binding protein (SREBP)-2, suggesting its involvement in the sterol-induced alteration in NPC1L1 promoter activity. Finally, we identified two putative SREs in the human NPC1L1 promoter and established their essential roles in mediating the effects of cholesterol on promoter activity. Our study demonstrated the modulation of human NPC1L1 expression and promoter activity by cholesterol in a SREBP-2-dependent mechanism.

scholarly journals Functional antagonism between inhibitor of DNA binding (Id) and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1c (ADD1/SREBP-1c) trans-factors for the regulation of fatty acid synthase promoter in adipocytes

1999 ◽  
Vol 344 (3) ◽  
pp. 873-880 ◽  
Author(s):  
Marthe MOLDES ◽  
Muriel BOIZARD ◽  
Xavier LE LIEPVRE ◽  
Bruno FÈVE ◽  
Isabelle DUGAIL ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Dna Binding ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Expression Vectors ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Inhibitor Of Dna Binding ◽  
Isolated Rat

We show that Id (inhibitor of DNA binding) 2 and Id3, dominant negative members of the helix-loop-helix (HLH) family, interact with the adipocyte determination and differentiation factor 1 (ADD1)/sterol regulatory element-binding protein (SREBP) 1c, a transcription factor of the basic HLH-leucine zipper family that controls the expression of several key genes of adipose metabolism. Gel mobility-shift assays performed with in vitro-translated ADD1, Id2 or Id3 proteins and a fatty acid synthase (FAS) promoter oligonucleotide showed evidence for a marked inhibition of the formation of DNA-ADD1 complexes by Id2 or Id3 proteins. Co-immunoprecipitation studies using in vitro-translated proteins demonstrated further the physical interaction of Id and ADD1/SREBP-1c proteins in the absence of DNA. Using the FAS gene as a model of an ADD1-regulated promoter in transiently transfected isolated rat adipocytes or mature 3T3-L1 adipocytes, a potent inhibition of the activity of the FAS-chloramphenicol acetyltransferase reporter gene was observed by overexpression of Id2 or Id3. Reciprocally, co-transfection of Id3 antisense and ADD1 expression vectors in preadipocytes potentiated the ADD1/SREBP-1c effect on the FAS promoter activity. Finally, in the non adipogenic NIH-3T3 cell line, most of the ADD1-mediated trans-activation of the FAS promoter was counteracted by co-transfection of Id2 or Id3 expression vectors. Previous studies have indicated Id gene expression to be down-regulated during adipogenesis [Moldes, Lasnier, Fève, Pairault and Djian (1997) Mol. Cell. Biol. 17, 1796-1804]. We here demonstrated that there was a dramatic rise of Id2 and Id3 mRNA levels when 3T3-L1 adipocytes or isolated rat fat cells were exposed to lipolytic and anti-lipogenic agents, forskolin and isoproterenol. Taken together, our data show that Id products are functionally involved in modulating ADD1/SREBP-1c transcriptional activity, and thus lipogenesis in adipocytes.

scholarly journals Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements

2004 ◽  
Vol 385 (1) ◽  
pp. 207-216 ◽  
Author(s):  
Lauren M. CAGEN ◽  
Xiong DENG ◽  
Henry G. WILCOX ◽  
Edwards A. PARK ◽  
Rajendra RAGHOW ◽  
...  
Keyword(s):  
Binding Protein ◽  
Regulatory Element ◽  
Ectopic Expression ◽  
Rat Hepatocytes ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Cis Acting ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

The enhanced synthesis of fatty acids in the liver and adipose tissue in response to insulin is critically dependent on the transcription factor SREBP-1c (sterol-regulatory-element-binding protein 1c). Insulin increases the expression of the SREBP-1c gene in intact liver and in hepatocytes cultured in vitro. To learn the mechanism of this stimulation, we analysed the activation of the rat SREBP-1c promoter and its truncated or mutated congeners driving a luciferase reporter gene in transiently transfected rat hepatocytes. The rat SREBP-1c promoter contains binding sites for LXR (liver X receptor), Sp1, NF-Y (nuclear factor-Y) and SREBP itself. We have found that each of these sites is required for the full stimulatory response of the SREBP-1c promoter to insulin. Mutation of either the putative LXREs (LXR response elements) or the SRE (sterol response element) in the proximal SREBP-1c promoter reduced the stimulatory effect of insulin by about 50%. Insulin and the LXR agonist TO901317 increased the association of SREBP-1 with the SREBP-1c promoter. Ectopic expression of LXRα or SREBP-1c increased activity of the SREBP-1c promoter, and this effect is further enhanced by insulin. The Sp1 and NF-Y sites adjacent to the SRE are also required for full activation of the SREBP-1c promoter by insulin. We propose that the combined actions of the SRE, LXREs, Sp1 and NF-Y elements constitute an insulin-responsive cis-acting unit of the SREBP-1c gene in the liver.

scholarly journals Importin beta1 mediates the glucose-stimulated nuclear import of pancreatic and duodenal homeobox-1 in pancreatic islet beta-cells (MIN6)

2004 ◽  
Vol 378 (1) ◽  
pp. 219-227 ◽  
Author(s):  
Ghislaine GUILLEMAIN ◽  
Gabriela da SILVA XAVIER ◽  
Imran RAFIQ ◽  
Armelle LETURQUE ◽  
Guy A. RUTTER
Keyword(s):  
Nuclear Membrane ◽  
Nuclear Import ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Regulatory Element ◽  
Pancreatic Islet Beta Cells ◽  
Element Binding Protein ◽  
Elevated Glucose ◽  
Sterol Regulatory Element

The transcription factor PDX-1 (pancreatic and duodenal homeobox-1) is essential for pancreatic development and the maintainence of expression of islet β-cell-specific genes. In an previous study [Rafiq, Kennedy and Rutter (1998) J. Biol. Chem. 273, 23241–23247] we demonstrated that PDX-1 may be activated at elevated glucose concentrations by translocation from undefined binding sites in the cytosol and nuclear membrane into the nucleoplasm. In the present study, we show that PDX-1 interacts directly and specifically in vitro with the nuclear import receptor family member, importin β1, and that this interaction is mediated by the PDX-1 homeodomain (amino acids 146–206). Demonstrating the functional importance of the PDX-1–importin β1 interaction, microinjection of MIN6 β-cells with anti-(importin β1) antibodies blocked both the nuclear translocation of PDX-1, and the activation by glucose (30 mM versus 3 mM) of the pre-proinsulin promoter. However, treatment with extracts from pancreatic islets incubated at either low or high glucose concentrations had no impact on the ability of PDX-1 to interact with importin β1 in vitro. Furthermore, importin β1 also interacted with SREBP1c (sterol-regulatory-element-binding protein 1c) in vitro, and microinjection of importin β1 antibodies blocked the activation by glucose of SREBP1c target genes. Since the subcellular distribution of SREBP1c is unaffected by glucose, these findings suggest that a redistribution of importin β1 is unlikely to explain the glucose-stimulated nuclear uptake of PDX-1. Instead, we conclude that the uptake of PDX-1 into the nucleoplasm, as glucose concentrations increase, may be mediated by release of the factor both from sites of retention in the cytosol and from non-productive complexes with importin β1 at the nuclear membrane.

scholarly journals Caspase-2, a Novel Lipid Sensor under the Control of Sterol Regulatory Element Binding Protein 2

2005 ◽  
Vol 25 (21) ◽  
pp. 9621-9631 ◽  
Author(s):  
E. Logette ◽  
C. Le Jossic-Corcos ◽  
D. Masson ◽  
S. Solier ◽  
A. Sequeira-Legrand ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Apoptotic Cell ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
Lipid Lowering ◽  
Proteolytic Activation ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Caspase 2 ◽  
Interfering Rna

ABSTRACT Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5′-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels.

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