气候变化领域集成服务门户(CCPortal): An integrative transcriptional logic model of hepatic insulin resistance

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DOI	10.1073/pnas.2102222118
	An integrative transcriptional logic model of hepatic insulin resistance
	Kitamoto T.; Kuo T.; Okabe A.; Kaneda A.; Accili D.
发表日期	2021
ISSN	1091-6490
卷号	118 期号:45
英文摘要	Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional regulatory logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPAR-α, and glucocorticoid receptor. We found that glucose metabolic genes are primarily regulated by promoter and intergenic enhancers in a fasting-dependent manner, while lipid genes are regulated through fasting-dependent intron enhancers and fasting-independent enhancerless introns. Glucose genes also showed a remarkable transcriptional resiliency (i.e., the ability to compensate following constitutive FoxO1 ablation through an enrichment of active marks at shared PPAR-α/FoxO1 regulatory elements). Unexpectedly, insulin resistance and hyperglycemia were associated with a "spreading" of FoxO1 binding to enhancers and the emergence of unique target sites. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.
英文关键词	animal models of human disease; chromatin structure; diabetes; drug failures; insulin sensitizers
语种	英语
scopus关键词	Foxo1 protein, mouse; transcription factor FKHR; animal; biological model; C57BL mouse; diet restriction; gene expression regulation; genetic transcription; insulin resistance; liver; male; metabolism; mouse; Animals; Fasting; Forkhead Box Protein O1; Gene Expression Regulation; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Models, Biological; Transcription, Genetic
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250993
作者单位	Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032; tk2752@cumc.columbia.edu; Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, NY, NY 10032; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, NY, NY 10032; Department of Molecular Oncology, Graduate School of Medicine, Chiba UniversityChiba 260-8677, Japan
推荐引用方式 GB/T 7714	Kitamoto T.,Kuo T.,Okabe A.,et al. An integrative transcriptional logic model of hepatic insulin resistance[J],2021,118(45).
APA	Kitamoto T.,Kuo T.,Okabe A.,Kaneda A.,&Accili D..(2021).An integrative transcriptional logic model of hepatic insulin resistance.Proceedings of the National Academy of Sciences of the United States of America,118(45).
MLA	Kitamoto T.,et al."An integrative transcriptional logic model of hepatic insulin resistance".Proceedings of the National Academy of Sciences of the United States of America 118.45(2021).