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The Regulation of Hepatic Metabolic Zonation by the Diabetes Gene TCF7L2

糖尿病基因TCF7L2对肝脏代谢分区的调节

基本信息

批准号：
10542424
负责人：
Luke Norton
金额：
$ 48.94万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542424
关键词：
Address Adult Ammonia Architecture Biological Assay Candidate Disease Gene Catabolism Cell Nucleus Central Vein Chromatin Cirrhosis Clinical Couples Data Defect Development Diabetes Mellitus Disease Drug Metabolic Detoxication Enzymes Equilibrium Fibrosis Genes Genetic Polymorphism Genetic Transcription Genomics Glucose Glutamate-Ammonia Ligase Glutamates Glutamine HMG-Box Domains Hepatic Hepatocyte Homeostasis Human Link Lipids Liver Liver Fibrosis Liver diseases Lobular Lobule Maintenance Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic dysfunction Metabolism Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pathologic Processes Pathway interactions Peripheral Physiological Play Population Portal triad Prevalence Primary carcinoma of the liver cells Proteins Public Health Publishing Regulation Rodent Rodent Model Role Signal Pathway TCF7L2 gene Techniques Testing Tissues Transcriptional Regulation Transposase amino acid metabolism beta catenin design dietary experimental study fibrogenesis glucose metabolism hormone regulation human model in vivo lipid metabolism mouse model multiple omics non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel single nucleus RNA-sequencing spatiotemporal tool transcription factor transcriptome treatment strategy

项目摘要

ABSTRACT The mammalian liver consists of functional units called lobules, which are spatially separated into zones relative to the portal triad and central vein. Each zone contains hepatocytes with distinct functions that differentially impact metabolic processes. This spatial division of labor in liver has been appreciated for decades, but the molecular and physiological determinants of metabolic zonation are poorly understood. Moreover, whether dis- ordered hepatic metabolic architecture plays a pathophysiological role in prevalent liver diseases remains un- clear. As part of our long-term effort to dissect the functional role of leading type 2 diabetes (T2D) candidate genes, we have identified the protein encoded by the transcription factor 7-like 2 (TCF7L2) gene as a key regu- lator of hepatic metabolic zonation. Leveraging a unique mouse model of TCF7L2 inactivation in liver and an integrative combination of cellular, genomic and in vivo physiological approaches, we will examine the regulation of metabolic zonation by TCF7L2, and will determine the significance of the zonated pathways regulated by TCF7L2 to the development of hepatic fibrosis in nonalcoholic steatohepatitis (NASH). In published studies, we unveiled a striking role for TCF7L2 in the transcriptional regulation of a diverse set of metabolic genes in hepato- cytes, including those involved in zonated pathways of glucose, lipid, and amino acid metabolism. In preliminary studies we discovered that the expression of the Tcf7l2 gene is ubiquitous across the liver lobule, but TCF7L2 transcriptional activity is highly restricted to a population of hepatocytes surrounding the central vein in adult mouse liver. These data, and additional preliminary studies, prompted us to develop a unique mouse model that expresses transcriptionally inactive TCF7L2 exclusively in the liver (Hep-TCF7L2ΔDBD). Using this model, in this proposal we will test the central hypothesis that TCF7L2 is an important regulator of hepatic metabolic zonation, and that TCF7L2-mediated disruption of pericentral amino acid metabolism predisposes Hep-TCF7L2ΔDBD mice to dietary induced fibrosis and NASH. In specific aim 1, we will dissect the spatiotemporal transcriptional function of TCF7L2 in liver using cutting-edge single-nuclei Assay for Transposase-Accessible Chromatin sequencing (snATAC-Seq) with snRNA-Seq in distinct hepatocyte populations across the mouse liver lobule. In Specific Aim 2, we will determine the role of TCF7L2 in the maintenance of hepatic metabolic zonation and will test the impact of TCF7L2 inactivation on the lobular distribution of pericentral and periportal hepatocyte populations in Hep- TCF7L2ΔDBD mice. Finally, in Specific Aim 3 we will link hepatic fibrosis disrupted zonal amino acid metabolism in Hep-TCF7L2ΔDBD mice using integrative in vivo physiological approaches. These experiments will dissect the molecular and physiological mechanisms by which TCF7L2 influences hepatic metabolic zonation, and will de- scribe the consequences of disordered hepatic organization on the development of metabolic diseases.

摘要