In vitro, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) mimics the positive effects of insulin on hepatic genes involved in glucose utilization, such as glucokinase (GK) and enzymes of the lipogenic pathway, suggesting that it is a key factor in the control of hepatic glucose metabolism. Decreased glucose utilization and increased glucose production by the liver play an important role in the development of the hyperglycemia in diabetic states. We thus reasoned that if SREBP-1c is indeed a mediator of hepatic insulin action, a hepatic targeted overexpression of SREBP-1c should greatly improve glucose homeostasis in diabetic mice. This was achieved by injecting streptozotocin-induced diabetic mice with a recombinant adenovirus containing the cDNA of the mature, transcriptionally active form of SREBP-1c. We show here that overexpressing SREBP-1c specifically in the liver of diabetic mice induces GK and lipogenic enzyme gene expression and represses the expression of
TY - JOUR. T1 - Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. AU - Shimomura, Iichiro. AU - Shimano, Hitoshi. AU - Horton, Jay D.. AU - Goldstein, Joseph L.. AU - Brown, Michael S.. PY - 1997/3/1. Y1 - 1997/3/1. N2 - The 5 end of the mRNA-encoding sterol regulatory element binding protein-1 (SREBP-1) exists in two forms, designated 1a and 1c. The divergence results from the use of two transcription start sites that produce two separate 5 exons, each of which is spliced to a common exon 2. Here we show that the ratio of SREBP-1c to 1a transcripts varies markedly among organs of the adult mouse. At one extreme is the liver, in which the 1c transcript predominates by a 9:1 ratio. High 1c:1a ratios are also found in mouse adrenal gland and adipose tissue and in human liver and adrenal gland. At the other extreme is the spleen, which shows a reversed 1c:1a ratio (1:10). In five different lines of ...
TY - JOUR. T1 - Activation of sterol regulatory element-binding protein by the caspase drice in Drosophila larvae. AU - Amarneh, Bilal. AU - Matthews, Krista A.. AU - Rawson, Robert B.. PY - 2009/4/10. Y1 - 2009/4/10. N2 - During larval development in Drosophila melanogaster, transcriptional activation of target genes by sterol regulatory element-binding protein (dSREBP) is essential for survival. In all cases studied to date, activation of SREBPs requires sequential proteolysis of the membrane-bound precursor by site-1 protease (S1P) and site-2 protease (S2P). Cleavage by S2P, within the first membrane-spanning helix of SREBP, releases the transcription factor. In contrast to flies lacking dSREBP, flies lacking dS2P are viable. The Drosophila effector caspase Drice cleaves dSREBP, and cleavage requires an Asp residue at position 386, in the cytoplasmic juxtamembrane stalk. The initiator caspase Dronc does not cleave dSREBP, but animals lacking dS2P require both drice and dronc to complete ...
Regulation of sterol regulatory element-binding proteins (SREBPs) by fatty acid flux was investigated in CaCo-2 cells. Cells were incubated with 1mM taurocholate with or without 250μM 18:0, 18:1, 18:2, 20:4, 20:5 or 22:6 fatty acids. Fatty acid synthase (FAS) and acetyl-CoA carboxylase mRNA levels and gene and protein expression of SREBPs were estimated. 18:2, 20:4, 20:5 and 22:6 fatty acids decreased the amount of mature SREBP-1 and mRNA levels of SREBP-1c, SREBP-1a, FAS and acetyl-CoA carboxylase. SREBP-2 gene or mature protein expression was not altered. Liver X receptor (LXR) activation by T0901317 increased gene expression of SREBP-1c, SREBP-1a, FAS and acetyl-CoA carboxylase without altering SREBP-2. 20:5, but not 18:1, prevented the full expression of SREBP-1c mRNA by T0901317. T0901317 increased SREBP-1 mass without altering the mass of mature SREBP-2. Although only 18:2, 20:4, 20:5 and 22:6 suppressed SREBP-1, acetyl-CoA carboxylase and FAS expression, all fatty acids decreased the ...
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Chronic alcohol consumption induces multi-organ damage, including alcoholic liver disease (ALD), pancreatitis and hypertension. Ethanol and ethanol metabolic products play a significant role in the manifestation of its toxicity. Ethanol metabolizes to acetaldehyde and produces reduced nicotinamide adenine dinucleotide (NADH) by cytosolic alcohol dehydrogenase. Ethanol metabolism mediated by cytochrome-P450 2E1 causes oxidative stress due to increased production of reactive oxygen species (ROS). Acetaldehyde, increased redox cellular state and ROS activate transcription factors, which in turn activate genes for lipid biosynthesis and offer protection of hepatocytes from alcohol toxicity. Sterol regulatory element binding proteins (SREBPs) and peroxisome proliferator activated-receptors (PPARs) are two key lipogenic transcription factors implicated in the development of fatty liver in alcoholic and non-alcoholic steatohepatitis. SREBP-1 is activated in the livers of chronic ethanol abusers. An increase in
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EcR-dependent transcription, and thus, developmental timing in Drosophila, is regulated by CDK8 and its regulatory partner Cyclin C (CycC), and the level of CDK8 is affected by nutrient availability. cdk8 and cycC mutants resemble EcR mutants and EcR-target genes are systematically down-regulated in both mutants. Indeed, the ability of the EcR-Ultraspiracle (USP) heterodimer to bind to polytene chromosomes and the promoters of EcR target genes is also diminished. Mass spectrometry analysis of proteins that co-immunoprecipitate with EcR and USP identified multiple Mediator subunits, including CDK8 and CycC. Consistently, CDK8-CycC interacts with EcR-USP in vivo; in particular, CDK8 and Med14 can directly interact with the AF1 domain of EcR. These results suggest that CDK8-CycC may serve as transcriptional cofactors for EcR-dependent transcription. During the larval-pupal transition, the levels of CDK8 protein positively correlate with EcR and USP levels, but inversely correlate with the activity ...
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Using two independent prostate cancer cell lines (LNCaP and MDA-PCa-2a), we demonstrate that coordinated stimulation of lipogenic gene expression by androgens is a common phenomenon in androgen-responsive prostate tumor lines and involves activation of the sterol regulatory element-binding protein ( …
Lipotoxicity caused by excessive fat deposition in skeletal muscle cells is a characteristic of type II diabetes, heart disease and obesity. Defining how glucose stimulates this is therefore an important goal. Isabelle Guillet-Deniau and co-workers have now dissected the signalling mechanisms involved, using contracting myotubes derived from cultured muscle satellite cells (see p. 1937). They show that glucose treatment stimulates cells to take up glucose and upregulate expression of lipogenic enzymes. The authors then demonstrate that prior to this the cells synthesize and activate sterol-regulatory-element-binding protein 1c (SREBP-1c), a transcription factor that regulates cholesterol and fatty acid metabolism. Moreover, they show that knocking down SREBP-1c by RNAi blocks glucose-induced upregulation of lipogenic enzymes. Guillet-Deniau and co-workers go on to demonstrate that stimulation of SREBP-1c requires the JAK2/STAT3 signalling pathway but is independent of insulin, which is ...
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from ...
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and ...
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and ...
The pathogenesis of ischemic diseases remains unclear. Here we demonstrate the induction of microRNA-668 (miR-668) in ischemic acute kidney injury (AKI) in human patients, mice, and renal tubular cells. The induction was HIF-1 dependent, as HIF-1 deficiency in cells and kidney proximal tubules attenuated miR-668 expression. We further identified a functional HIF-1 binding site in the miR-668 gene promoter. Anti-miR-668 increased apoptosis in renal tubular cells and enhanced ischemic AKI in mice, whereas miR-668 mimic was protective. Mechanistically, anti-miR-668 induced mitochondrial fragmentation, whereas miR-668 blocked mitochondrial fragmentation during hypoxia. We analyzed miR-668 target genes through immunoprecipitation of microRNA-induced silencing complexes followed by RNA deep sequencing and identified 124 protein-coding genes as likely targets of miR-668. Among these genes, only mitochondrial protein 18 kDa (MTP18) has been implicated in mitochondrial dynamics. In renal cells and mouse ...
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and ...
nucleus, DNA-binding transcription factor activity, RNA polymerase II cis-regulatory region sequence-specific DNA binding, endocrine pancreas development, liver development, negative regulation of transcription by RNA polymerase II, pancreas regeneration, positive regulation of pri-miRNA transcription by RNA polymerase II, response to lipid, type B pancreatic cell development
Biologists have long pondered how animal cells regulate the composition of their complex lipid membranes. In their Perspective, Nohturfft and Losick discuss new work ( Dobrosotskaya et al.) that solves another piece of the puzzle. Flies and mammals share a similar feedback pathway for lipid synthesis that depends on controlling the proteolysis of sterol response element binding protein. The new work shows that in flies, cleavage of this protein depends on a membrane phospholipid sensor, phosphatidylethanolamine. ...
Sterol regulatory element-binding protein 1c (SREBP-1c) is a central regulator of lipogenesis whose activity is controlled by proteolytic cleavage. The metabolic factors that affect its processing are incompletely understood. Here, we show that dynamic changes in the acyl chain composition of ER phospholipids affect SREBP-1c maturation in physiology and disease. The abundance of polyunsaturated phosphatidylcholine in liver ER is selectively increased in response to feeding and in the setting of obesity-linked insulin resistance. Exogenous delivery of polyunsaturated phosphatidylcholine to ER accelerated SREBP-1c processing through a mechanism that required an intact SREBP cleavage-activating protein (SCAP) pathway. Furthermore, induction of the phospholipid-remodeling enzyme LPCAT3 in response to liver X receptor (LXR) activation promoted SREBP-1c processing by driving the incorporation of polyunsaturated fatty acids into ER. Conversely, LPCAT3 deficiency increased membrane saturation, reduced ...
Die Regulation der HMG-CoA-Reduktase ist komplex; sie erfolgt u. a. transkriptionell über Transkriptionsfaktoren, die unter Mitwirkung von SCAP (SREBP cleavage activating protein) durch MBTPS1 proteolytisch aus SREBPs (sterol regulatory element binding protein) gewonnen werden. SCAP ist inaktiv, wenn es Cholesterin gebunden hat. Bei steigender Cholesterinkonzentration in der Zelle nimmt die Bildung der HMG-CoA-Reduktase daher ab; außerdem wird das Enzym direkt durch Bindung von Cholesterin und besonders Lanosterol, einem anderen Mevalonatderivat gehemmt. Die HMG-CoA-Reduktase kann auch durch die AMP-aktivierte Proteinkinase (AMPK) reversibel phosphoryliert und damit inaktiviert werden - wenn viel AMP vorliegt, was bei zellulärem Energiemangel der Fall ist, wird so die energieaufwändige Cholesterinsynthese gebremst. Bei Cholesterinmangel nimmt die Transkription der Gene und damit die Bildung der HMG-CoA-Reduktase wieder zu. Weitere Hormone, die regulierend auf HMG-CoA-Reduktase wirken sind ...
2014 American Heart Association, Inc. Background - Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase - derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element - binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. Methods and Results - Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II - infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase ...
The protein encoded by this gene is a cysteine-aspartic acid protease that plays a central role in the execution-phase of cell apoptosis. The encoded protein cleaves and inactivates poly(ADP-ribose) polymerase while it cleaves and activates sterol regulatory element binding proteins as well as caspases 6, 7, and 9. This protein itself is processed by caspases 8, 9, and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimers disease. [provided by RefSeq, Aug 2017] ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Mediates feedback control of cholesterol synthesis by controlling SCAP and HMGCR. Functions by blocking the processing of sterol regulatory element-binding proteins (SREBPs). Capable of retaining the SCAP-SREBF2 complex in the ER thus preventing it from escorting SREBPs to the Golgi. Seems to regulate the ubiquitin-mediated proteasomal degradation of HMGCR.
Oxysterols regulate cholesterol homeostasis through the liver X receptor (LXR)- and sterol regulatory element-binding protein (SREBP)-mediated sigling…
Oxysterols regulate cholesterol homeostasis through the liver X receptor (LXR)- and sterol regulatory element-binding protein (SREBP)-mediated sigling…
In mrna was removed the etec is possible, oxford university since march issue of the jiangxi province classification. Bukowski r and pj respiratory dysfunction, whereas the primary producers. The transcriptional profile for the absence of periodontal infection. The time between the application of the research campaign be secondary antibody, while in a subjects. Alternatively, 374, as an online profile in this year in endurance running. Most but tumorigenesis in serotypes on the purpose differentiating themselves form which of ovarian cancers. Diagnosis, along with lesser efficacy and can be put on its metabolites. Oliver morgan p review board, on previous section that it may be selected 16. To confirm that built around the reference sequence type of food at the experiments wjs lb, for asthma. Discussion the lipogenic transcription in accordance to increase over the pronunciation of the per year. However, for fresh, careddu a diverse images are at the genome project. The assay, the french ...
DNA helicase V antibody far upstream element (FUSE) binding protein 1 antibody Far upstream element (FUSE) binding protein 4 antibody Far upstream element binding protein 1 antibody far upstream element binding protein antibody Far upstream element-b...
Objective: We evaluated association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes.. Research design and methods: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n=6,070), the Danish ADDITION study (n=8,662) and in additional type 2 diabetic patients (n=1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects.. Results: The minor alleles of the rs2297508, rs11868035 and rs1889018 (linkage disequilibrium R2=0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P=0.003) which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: OR 1.08 [1.03-1.14] per allele, P=0.001). The diabetes-associated alleles also associated strongly with a higher plasma-glucose at 30 and ...
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acts as a transcriptional repressor of the steroidogenic acute regulatory (StaR) protein; decreases SREBP-1a binding to a sterol regulatory element [RGD, Feb 2006 ...
GSD-1 (glycogen storage disease type 1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in a massive accumulation of hepatic glycogen content and an induction of de novo lipogenesis. The chlorogenic acid derivative S4048 is a pharmacological inhibitor of the glucose 6-phosphate transporter, which is part of glucose-6-phosphatase, and allows for mechanistic studies concerning metabolic defects in GSD-1. Treatment of mice with S4048 resulted in an ~60% reduction in blood glucose, increased hepatic glycogen and triacylglycerol (triglyceride) content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the co-ordinated action of the transcription factors SREBP (sterol-regulatory-element-binding protein)-1c, LXRα (liver X receptor α) and ChREBP (carbohydrate-response-element-binding protein). Treatment of Lxra−/− mice and Chrebp−/− mice with S4048 demonstrated that ChREBP, but not LXRα, ...
Delta6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets. Sterol regulatory element-binding protein-1c (SREBP-1c) in part mediates this induction.Delta6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets. Sterol regulatory element-binding protein-1c (SREBP-1c) in part mediates this induction." (16106047) ...
In this issue of the JCI, Zhou and coworkers provide evidence that the elusive target of metformins actions is the AMP-activated protein kinase (AMPK) (8). In studies performed in isolated hepatocytes and rat skeletal muscles, they demonstrate that metformin leads to AMPK activation, accompanied by an inhibition of lipogenesis (due to inactivation of acetyl-CoA carboxylase and suppression of lipogenic enzyme expression), suppression of the expression of SREBP-1 (a central lipogenic transcription factor), and a modest stimulation of skeletal muscle glucose uptake. Similar hepatic effects are seen in metformin-treated rats. Based on the use of a newly discovered AMPK inhibitor, their data suggest that the ability of metformin to suppress glucose production in hepatocytes requires AMPK activation. Many of these effects are similar to that of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a known, albeit nonspecific, activator of AMPK (9). However, metformin does not lead to AMPK activation ...
Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans,2007. Human studies have also shown daily intake of cocoa increases plasma high-density lipoprotein (HDL) and decreases LDL levels. Cocoa polyphenols increase apolipoprotein A1 protein levels and mRNA expression, even though apolipoprotein B protein and the mRNA expression are decreased. The ApoB is the major component of the LDL while the ApoA1 is the major protein in HDL; so LDL serum level decreases while the HDL serum level increases.. In addition, cocoa polyphenols increase sterol regulatory element binding proteins (SREBPs are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. SREB proteins are indirectly required for cholesterol biosynthesis and for uptake and fatty acid biosynthesis) and activated LDL receptors ...
Given that a fructose-rich diet has been widely adopted in many countries and that it is closely associated with metabolic disorders, it is crucial to understand the molecular basis of the metabolic responses to fructose at the cellular and tissue levels. Here, for the first time to our knowledge, we uncovered a ChREBP transcription factor-mediated adaptive pathway that protects the liver from HFrD-induced hepatocyte apoptosis and injury. In the absence of ChREBP, mice on a HFrD develop severe liver injury due to overactivation of ER stress and CHOP-mediated hepatocyte apoptosis. Administration of the chemical chaperone 4-PBA or acute depletion of Chop mitigates liver injury in HFrD-fed Chrebp-/- mice. Increased cholesterol biosynthesis probably contributes to hepatocyte apoptosis in fructose-challenged Chrebp-/- mice, since inhibition of cholesterol biosynthesis by the HMGCR inhibitor or Srebp2 knockdown rescues Chrebp-/- mice from HFrD-induced liver injury (Figure 6K).. Fructose has become one ...
The present study was carried out to investigate the effect of vitamin E analogs, especially gamma-tocotrienol (γ-T3), on hepatic TG accumulation and enzymes related to fatty acid metabolism in three types of rat primary hepatocytes: (1) normal hepatocytes, (2) hepatocytes incubated in the presence of palmitic acid (PA), and (3) hepatocytes with fat accumulation. Our results showed that γ-T3 significantly reduced the TG content of normal hepatocytes. γ-T3 also increased the expression of carnitine palmitoyltransferase 1 (CPT1A) mRNA, and tended to reduce that of sterol regulatory element binding protein 1c (SREBP-1c) mRNA. In addition, γ-T3 markedly suppressed the gene expression of both C/EBP homologous protein (CHOP) and SREBP-1c induced by PA. As these two genes are located downstream of endoplasmic reticulum (ER) stress, their suppression by γ-T3 might result from a decrease of ER stress. Moreover, γ-T3 suppressed the expression of interleukin 1β (IL-1β), which lies downstream of ...
Background: MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33 (miR-33a) located within the intron of sterol regulatory element-binding factor (SREBF) 2 controls cholesterol homeostasis. Primates, but not rodents, express a second miR-33 gene (miR-33b) from an intron of SREBF1. To address miR-33b function in vivo, we developed humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron.. Methods: The human miR-33b sequence was introduced into intron 16 of mouse Srebf1 because miR-33b is located in intron 16 of human SREBF1 and there are high homologies in exons 16 and 17 between human and mouse. The expression of serum miRNA was normalized with cel-miR-39 as a spike-in control.. Results: We successfully established miR-33b knock-in (KI) mice with C57BL/6 background and this miR-33b KI strategy did not alter Srebf1 intron 16 splicing, which was ...
LB-237 Many human cancers including breast cancer exhibit increased de novo fatty acid synthesis with overexpression of fatty acid synthase (FAS). Unlike normal cells and tissues that preferentially utilize circulating fatty acids derived from the diet, cancers synthesize fatty acids endogenously for membrane biosynthesis to sustain cell proliferation. The transcription factor Sp1 is highly expressed in a variety of cancers. Sp1 regulates gene expression by interacting with GC-rich promoter sequences. Genes that regulate cell cycle progression often contain such promoter sequences, and Sp1 is critical for their expression. The promoter region of FAS also has Sp1 binding sites, and Sp1 together with sterol regulatory element-binding protein-1 (SREBP-1) has been shown to regulate FAS expression in hepatocytes. Here, we hypothesize that Sp1 coordinately regulates FAS and cell cycle progression in estrogen-responsive MCF-7 breast cancer cells. Based on previous studies, to up-regulate Sp1 activity ...
As the key regulatory factor in lipogenesis, SREBPs are targets of hormones such as insulin, glucagon, and growth factors (17, 28, 36). The abundance of the nuclear form of SREBPs is controlled by transcriptional upregulation followed by proteolytic cleavage. However, an increasing body of evidence supports the hypothesis that posttranslational modifications of SREBPs modulate their transactivity and stability (22, 32, 39). In this study, we found that PKA phosphorylated SREBP-1 in cultured hepatoma cells and led to decreased binding and transactivation of SREBP-1. As a result, the expression of SREBP-1-mediated genes was decreased. Because the heterodimer of phosphorylated and unphosphorylated SREBP-1 retained some DNA binding capacity, neither cAMP nor forskolin suppressed the activity of nuclear SREBP-1a fully in our reporter assays. In addition to phosphorylation, cAMP also may inhibit SREBP cleavage, as suggested in a recent report (43). However, our present results have shown that levels ...
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Non‐alcoholic fatty liver organ disease (NAFLD) is associated with obesity and lifestyle while exercise is beneficial for NAFLD. protein level in HepG2 cells. Meanwhile FFA downregulated FGF‐21 both at Rabbit polyclonal to ADAM17. mRNA and protein levels in HepG2 cells. Also FGF‐21 protein level was reduced in HF liver while reversed by exercise targeting FGF‐21. targeting fatty acid synthase (FAS) acetyl‐CoA carboxylase 1 and 2 (ACC1/ACC2) sterol regulatory element binding protein‐1c (SREBP‐1c) sirtuin‐1 (SIRT‐1) and ATP‐binding cassette‐A1 transporter 16 17 More recently miR‐29 inhibition continues to be reported to lessen lipogenic programs focusing on SIRT‐1 and aryl MG-132 hydrocarbon receptor 18. Additionally dysregulated circulating miRNAs have already been detected in NAFLD patients including miR‐122 and miR‐192 19 also. Besides of their natural tasks in fundamental mobile procedures (proliferation apoptosis migration and differentiation) miRNAs also donate ...
As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD) is related to several pathological processes, including: (1) augmenting lipogenesis; (2) leading to mitochondrial dysfunction; (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance. Cellular signaling research indicated that partial factors play significant roles in fructose-induced NAFLD, involving liver X receptor (LXR)α, sterol regulatory element binding protein (SREBP)-1/1c, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor α (PPARα), leptin nuclear factor-erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), c-Jun amino terminal kinase (JNK
Mitochondrial DNA (mtDNA) deletions occur sporadically in zygotic and somatic tissues and reach their highest concentration in substantia nigra. Previously, we noted the increase of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) transcript by microarray in multiple cells and tissues bearing deletions. In this work, we demonstrate that the induction of AMPK transcript is dependent on deletions by quantitative polymerase chain reaction, and also demonstrate a deficiency in adenosine triphosphate (ATP) synthesis in the same cells. Consistent with AMPK induction, its known targets SREBF1 (sterol regulatory element binding protein-1) and ATG12 were inhibited and induced, respectively. AMPK induction is known to decrease secretory processes in some cells, and the secretion of both osteoprotegerin (OPG) and fibronectin (FN) proteins to the extracellular space was significantly deficient. Deletions caused a defect in the adenosine diphosphate (ADP)-ribosylation factor-like 2 (ARL2) ...
Dysregulations of the mevalonate pathway (MVA) have been previously identified. Our previous study demonstrated that 3‑hydroxy‑3‑methylglutaryl‑coenzyme A reductase (HMGCR), the rate‑limiting enzyme of the MVA pathway, was upregulated in esophageal squamous cell carcinoma (ESCC) and statin‑inhibited ESCC tumorigenesis. However, the underlying mechanism of HMGCR regulation in ESCC remains unknown. In the present study, western blotting and immunohistochemistry analysis demonstrated that sterol regulatory element‑binding protein 2 (SREBP2), the master regulator for HMGCR, was upregulated in ESCC clinical samples. Overexpression of SREBP2 expression in ESCC cell lines promoted the growth, migration and colony formation of cancer cells in the MTT, Boyden chamber and soft agar assays, respectively, which was inhibited by lovastatin. Downregulation of SREBP2 expression in ESCC cell lines inhibited the viability, and migration and colony formation abilities of cancer cells. Assessment of ...
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AKT3 gene is a constituent of the serine/threonine protein kinase family and plays a crucial role in synthesis of milk fats and cholesterol by regulating activity of the sterol regulatory element binding protein (SREBP). AKT3 is highly conserved in mammals and its expression levels during the lactation periods of cattle are markedly increased. AKT3 is highly expressed in the intestine followed by mammary gland and it is also expressed in immune cells. It is involved in the TLR pathways as effectively as proinflammatory cytokines. The aims of this study were to investigate the sequences differences between buffalo and cow. Our results showed that there were substantial differences between buffalo and cow in some exons and noteworthy differences of the gene size in different regions. We also identified the important consensus sequence motifs, variation in 2000 upstream of ATG, substantial difference in the "3′UTR" region, and miRNA association in the buffalo sequences compared with the cow. In ...
TY - JOUR. T1 - Insulin-induced de novo lipid synthesis occurs mainly via mTOR-dependent regulation of proteostasis of SREBP-1c. AU - Dong, Qingming. AU - Majumdar, Gipsy. AU - OMeally, Robert N.. AU - Cole, Robert N.. AU - Elam, Marshall B.. AU - Raghow, Rajendra. PY - 2019/1/1. Y1 - 2019/1/1. N2 - Insulin stimulates de novo lipid synthesis in the liver and in cultured hepatocytes via its ability to activate sterol regulatory element-binding protein 1c (SREBP-1c). Although PI3K-AKT-mTORC1-p70S6K-signaling kinases are known to drive feed-forward expression of SREBP-1c, the identity of the phosphorylated amino acid residue(s) putatively involved in insulin-stimulated de novo lipogenesis remains elusive. We obtained in silico and mass spectrometry evidence, that was combined with siRNA strategies, to discover that insulin-induced phosphorylation of serine 418, serine 419, and serine 422 in rat SREBP-1c was most likely mediated by p70S6 kinase. Here, for the first time, we show that ...