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Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes
Insulin resistance is a pathophysiological hallmark of type 2 diabetes and nonalcoholic fatty liver disease. Under the condition of fat accumulation in the liver, suppression of hepatic glucose production by insulin is diminished. In order to gain deeper understanding of dysregulation of glucose pro...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093908/ https://www.ncbi.nlm.nih.gov/pubmed/30131871 http://dx.doi.org/10.1038/s41525-018-0062-7 |
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author | Zou, Haixia Liu, Qian Meng, Li Zhou, Jingye Da, Chenxiao Wu, Xikun Jiang, Lichun Shou, Jianyong Hua, Haiqing |
author_facet | Zou, Haixia Liu, Qian Meng, Li Zhou, Jingye Da, Chenxiao Wu, Xikun Jiang, Lichun Shou, Jianyong Hua, Haiqing |
author_sort | Zou, Haixia |
collection | PubMed |
description | Insulin resistance is a pathophysiological hallmark of type 2 diabetes and nonalcoholic fatty liver disease. Under the condition of fat accumulation in the liver, suppression of hepatic glucose production by insulin is diminished. In order to gain deeper understanding of dysregulation of glucose production in metabolic diseases, in the present study, we performed an unbiased phenotypic screening in primary human hepatocytes to discover novel mechanisms that regulate gluconeogenesis in the presence of insulin. To optimize phenotypic screening process, we used a chemical genetic screening approach by building a small-molecule library with prior knowledge of activity-based protein profiling. The “positive hits” result from the screen will be small molecules with known protein targets. This makes downstream deconvolution process (i.e., determining the relevant biological targets) less time-consuming. To unbiasedly decipher the molecular targets, we developed a novel statistical method and discovered a set of genes, including DDR3 and CACNA1E that suppressed gluconeogenesis in human hepatocytes. Further investigation, including transcriptional profiling and gene network analysis, was performed to understand the molecular functions of DRD3 and CACNA1E in human hepatocytes. |
format | Online Article Text |
id | pubmed-6093908 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60939082018-08-21 Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes Zou, Haixia Liu, Qian Meng, Li Zhou, Jingye Da, Chenxiao Wu, Xikun Jiang, Lichun Shou, Jianyong Hua, Haiqing NPJ Genom Med Article Insulin resistance is a pathophysiological hallmark of type 2 diabetes and nonalcoholic fatty liver disease. Under the condition of fat accumulation in the liver, suppression of hepatic glucose production by insulin is diminished. In order to gain deeper understanding of dysregulation of glucose production in metabolic diseases, in the present study, we performed an unbiased phenotypic screening in primary human hepatocytes to discover novel mechanisms that regulate gluconeogenesis in the presence of insulin. To optimize phenotypic screening process, we used a chemical genetic screening approach by building a small-molecule library with prior knowledge of activity-based protein profiling. The “positive hits” result from the screen will be small molecules with known protein targets. This makes downstream deconvolution process (i.e., determining the relevant biological targets) less time-consuming. To unbiasedly decipher the molecular targets, we developed a novel statistical method and discovered a set of genes, including DDR3 and CACNA1E that suppressed gluconeogenesis in human hepatocytes. Further investigation, including transcriptional profiling and gene network analysis, was performed to understand the molecular functions of DRD3 and CACNA1E in human hepatocytes. Nature Publishing Group UK 2018-08-15 /pmc/articles/PMC6093908/ /pubmed/30131871 http://dx.doi.org/10.1038/s41525-018-0062-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zou, Haixia Liu, Qian Meng, Li Zhou, Jingye Da, Chenxiao Wu, Xikun Jiang, Lichun Shou, Jianyong Hua, Haiqing Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes |
title | Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes |
title_full | Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes |
title_fullStr | Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes |
title_full_unstemmed | Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes |
title_short | Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes |
title_sort | chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093908/ https://www.ncbi.nlm.nih.gov/pubmed/30131871 http://dx.doi.org/10.1038/s41525-018-0062-7 |
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