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《Cell reports》2020,30(6):1835-1847.e9
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《Cell cycle (Georgetown, Tex.)》2013,12(12):2348-2358
The aberrantly increased lipogenesis is a universal metabolic feature of proliferating tumor cells. Although most normal cells acquire the bulk of their fatty acids from circulation, tumor cells synthesize more than 90% of required lipids de novo. The sterol regulatory element-binding protein 1 (SREBP1), encoded by SREBF1 gene, is a master regulator of lipogenic gene expression. SREBP1 and its target genes are overexpressed in a variety of cancers; however, the role of SREBP1 in endometrial cancer is largely unknown. We have screened a cohort of endometrial cancer (EC) specimen for their lipogenic gene expression and observed a significant increase of SREBP1 target gene expression in cancer cells compared with normal endometrium. By using immunohistochemical staining, we confirmed SREBP1 protein overexpression and demonstrated increased nuclear distribution of SREBP1 in EC. In addition, we found that knockdown of SREBP1 expression in EC cells suppressed cell growth, reduced colonigenic capacity and slowed tumor growth in vivo. Furthermore, we observed that knockdown of SREBP1 induced significant cell death in cultured EC cells. Taken together, our results show that SREBP1 is essential for EC cell growth both in vitro and in vivo, suggesting that SREBP1 activity may be a novel therapeutic target for endometrial cancers. 相似文献
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Atanas G. Atanasov Jian N. Wang Shi P. Gu Jing Bu Matthias P. Kramer Lisa Baumgartner Nanang Fakhrudin Angela Ladurner Clemens Malainer Anna Vuorinen Stefan M. Noha Stefan Schwaiger Judith M. Rollinger Daniela Schuster Hermann Stuppner Verena M. Dirsch Elke H. Heiss 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.Methods
We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.Results
The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.Conclusion
We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.General significance
This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. 相似文献5.
3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the target of the statins, important drugs that lower blood cholesterol levels and treat cardiovascular disease. Consequently, the regulation of HMGCR has been investigated in detail. However, this enzyme acts very early in the cholesterol synthesis pathway, with ∼20 subsequent enzymes needed to produce cholesterol. How they are regulated is largely unexplored territory, but there is growing evidence that enzymes beyond HMGCR serve as flux-controlling points. Here, we introduce some of the known regulatory mechanisms affecting enzymes beyond HMGCR and highlight the need to further investigate their control. 相似文献
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Chiakang Ho Ya Gao Danning Zheng Yanjun Liu Shengzhou Shan Bin Fang Yixuan Zhao Dingzhong Song Yifan Zhang Qingfeng Li 《Journal of cellular and molecular medicine》2019,23(8):5108-5118
Obesity and its associated metabolic disorders such as diabetes, hepatic steatosis and chronic heart diseases are affecting billions of individuals. However there is no satisfactory drug to treat such diseases. In this study, we found that alisol A, a major active triterpene isolated from the Chinese traditional medicine Rhizoma Alismatis, could significantly attenuate high‐fat‐diet‐induced obesity. Our biochemical detection demonstrated that alisol A remarkably decreased lipid levels, alleviated glucose metabolism disorders and insulin resistance in high‐fat‐diet‐induced obese mice. We also found that alisol A reduced hepatic steatosis and improved liver function in the obese mice model.In addition, protein expression investigation revealed that alisol A had an active effect on AMPK/ACC/SREBP‐1c pathway. As suggested by the molecular docking study, such bioactivity of alisol A may result from its selective binding to the catalytic region of AMPK.Therefore, we believe that Alisol A could serve as a promising agent for treatment of obesity and its related metabolic diseases. 相似文献
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Takemoto T Nishio Y Sekine O Ikeuchi C Nagai Y Maeno Y Maegawa H Kimura H Kashiwagi A 《FEBS letters》2007,581(2):218-222
In rodents a high-fructose diet induces metabolic derangements similar to those in metabolic syndrome. Previously we suggested that in mouse liver an unidentified nuclear protein binding to the sterol regulatory element (SRE)-binding protein-1c (SREBP-1c) promoter region plays a key role for the response to high-fructose diet. Here, using MALDI-TOF MASS technique, we identified an X-chromosome-linked RNA binding motif protein (RBMX) as a new candidate molecule. In electrophoretic mobility shift assay, anti-RBMX antibody displaced the bands induced by fructose-feeding. Overexpression or suppression of RBMX on rat hepatoma cells regulated the SREBP-1c promoter activity. RBMX may control SREBP-1c expression in mouse liver in response to high-fructose diet. 相似文献
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