Insulin Regulation of Hepatic Function via Zone-Specific Transcriptional Programs

胰岛素通过区域特异性转录程序调节肝功能

• 批准号: 10396110
• 负责人: Sudha B Biddinger
• 金额: $ 56.05万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396110
• 关键词: Adult; Affect; Bile Acid Biosynthesis Pathway; Bile Acids; CYP8B1 gene; Cell Nucleus; Cells; Cholesterol; Clinical; Clinical Research; Data; Development; Disease; Disease Progression; Enzymes; Epidemic; Fluorescent in Situ Hybridization; Gene Expression; Genes; Genetic Transcription; Goals; Hepatic; Hepatocyte; Homeostasis; Human; Hydroxylation; Individual; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Knock-out; Lead; Lipids; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Measures; Mediating; Metabolic; Mus; Pathogenesis; Pathway interactions; Patients; Physiological; Population; Predisposition; Prevention; Process; Reaction; Reporting; Repression; Resistance development; Role; Site; Societies; Study models; Techniques; Testing; Transcriptional Regulation; Triglyceride Metabolism; Triglycerides; base; beta catenin; bile acid metabolism; cell injury; effective therapy; insulin mediators; insulin regulation; insulin signaling; liver inflammation; liver injury; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; prevent; programs; response; single molecule; targeted treatment

Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions in our society, and yet our understanding of the pathogenesis of this disorder remains rudimentary 7. Clinical studies show a close correlation between insulin resistance and the development and progression of NAFLD 8,9. To understand mechanistically the changes in triglyceride, cholesterol, and bile acid metabolism that occur with the development of NAFLD, a clear understanding of how insulin regulates these processes is necessary. Until now, studies of insulin action in the liver have been done with the assumption that all hepatocytes are equivalent. This assumption was made out of practicality, as our ability to isolate and analyze different populations of hepatocytes individually was limited. Yet, hepatocytes clearly vary in terms of the metabolic functions they perform, and their susceptibility to different insults 10. For example, the perivenous hepatocytes are the predominant site of bile acid synthesis and the most common site of triglyceride accumulation in NAFLD 11,12. Here, we will determine how insulin modulates gene expression in the perivenous hepatocytes to maintain homeostasis. Our novel, unpublished preliminary data reveal a striking example of zone-specific transcriptional regulation by insulin. We find that insulin suppresses Cyp8b1 only in the perivenous hepatocytes. Cyp8b1 encodes the sole enzyme capable of catalyzing the 12a-hydroxylation of bile acids 13; 12a-hydroxylated bile acids increase hepatic cholesterol and promote the progression to non-alcoholic steatohepatitis (NASH) 14-16. In the absence of insulin, the de-repression of Cyp8b1 in the perivenous hepatocytes is associated with increased 12a- hydroxylated bile acids, increased hepatic cholesterol, and severe inflammation. The fact that NAFLD progression in humans is also associated with an increase in 12a-hydroxylated bile acids and hepatic cholesterol, and the fact that inflammation marks the development of non-alcoholic steatohepatitis, a more severe and progressive form of disease, highlight the importance of studying this pathway 17-19. Based on these and other preliminary data, we hypothesize that insulin modulates the activity of b-catenin, a master transcriptional regulator that is activated only in the perivenous hepatocytes 20, to maintain normal lipid homeostasis and prevent inflammation. To test this hypothesis, we aim to (1) define the insulin-regulated cellular transcriptional programs in the liver using single-nuclei sequencing; and (2) dissect the role of b-catenin in producing the transcriptional and physiological response to insulin. We expect that insulin can reprogram the perivenous hepatocytes by modulating b-catenin driven transcription, and that this is required for normal homeostasis. Such results may ultimately lead to the development of precise interventions that reverse the effects of insulin resistance in the perivenous hepatocytes, preventing NASH.

非酒精性脂肪性肝病（NAFLD）在我们的社会中已经达到流行病的程度，但我们的 对这种疾病的发病机理的理解仍然是初步的。临床研究显示， 胰岛素抵抗与NAFLD发展和进展之间的相关性8，9.了解 机制上，甘油三酯，胆固醇和胆汁酸代谢的变化，发生的发展， 对于NAFLD，清楚地了解胰岛素如何调节这些过程是必要的。到目前为止， 胰岛素在肝脏中的作用是在假设所有肝细胞都是等效的情况下进行的。这 假设是出于实用性，因为我们能够分离和分析不同的肝细胞群体， 个人是有限的。然而，肝细胞在它们执行的代谢功能方面明显不同，并且它们的 对不同的侮辱的敏感性10.例如，静脉周围肝细胞是胆汁的主要部位， 酸合成和NAFLD中甘油三酯积累的最常见部位11，12。在这里，我们将确定 胰岛素如何调节静脉周围肝细胞的基因表达以维持体内平衡。 我们新的，未发表的初步数据揭示了一个引人注目的区域特异性转录的例子， 胰岛素的调节。我们发现，胰岛素抑制Cyp 8b 1只在静脉周围肝细胞。Cyp8b1 编码唯一能够催化胆汁酸13的12 α-羟基化的酶; 12 α-羟基化的胆汁酸 增加肝脏胆固醇并促进非酒精性脂肪性肝炎（NASH）的进展14-16。在 在缺乏胰岛素的情况下，静脉周围肝细胞中Cyp 8b 1的去抑制与12 a- 羟基化胆汁酸、肝胆固醇增加和严重炎症。事实上，NAFLD 在人类中的进展也与12 α-羟基化胆汁酸和肝细胞的增加有关。 事实上，炎症标志着非酒精性脂肪性肝炎的发展， 严重和进行性的疾病，强调研究这一途径的重要性17-19。基于这些 和其他初步数据，我们假设胰岛素调节β-连环蛋白的活性， 仅在静脉周围肝细胞20中被激活的转录调节因子，以维持正常的脂质 体内平衡和预防炎症。为了验证这一假设，我们的目标是（1）定义胰岛素调节的细胞 使用单核测序在肝脏中的转录程序;和（2）剖析β-连环蛋白在肝脏中的作用。 产生对胰岛素的转录和生理反应。我们希望胰岛素可以重新编程 静脉周围肝细胞通过调节β-连环蛋白驱动的转录，这是正常的 体内平衡。这样的结果可能最终导致精确干预的发展， 静脉周围肝细胞中胰岛素抵抗的影响，预防NASH。