Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states
Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states
ABSTRACT The liver acts as a master regulator of metabolic homeostasis in part by performing gluconeogenesis. This process is dysregulated in type 2 diabetes, leading to elevated hepatic glucose output. The parenchymal cells of the liver (hepatocytes) are heterogeneous, existing on an axis between the portal triad and the central vein, and perform distinct functions depending on location in the lobule. Here, using single cell analysis of hepatocytes across the liver lobule, we demonstrate that gluconeogenic gene expression (Pck1 and G6pc) is relatively low in the fed state and gradually increases first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases, and following entry into the starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression to the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting state but only 1.5-fold higher in the starvation state. In parallel, starvation suppresses canonical beta-catenin signaling and modulates expression of pericentral and periportal glutamine synthetase and glutaminase, resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These findings demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule, underscoring the critical importance of using well-defined feeding and fasting conditions to define the basis of hepatic insulin resistance and glucose production.
Liu Li、Kurland Irwin J.、Eliscovich Carolina、Shinoda Kosaku、Landgraf Austin、Horton Maxwell、Yang Fajun、Pessin Jeffrey E.、Qiu Yunping、Okada Junichi、Sidoli Simone、Xiaoli Alus M.、Schuster Victor L.
Departments of Medicine, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of Medicine||Developmental and Molecular Biology, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of Medicine||Molecular Pharmacology, Albert Einstein College of MedicineMolecular Pharmacology, Albert Einstein College of MedicineMolecular Pharmacology, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of Medicine||Developmental and Molecular Biology, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of Medicine||Molecular Pharmacology, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of MedicineBiochemistry. Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of Medicine||Developmental and Molecular Biology, Albert Einstein College of MedicineDepartments of Medicine, Albert Einstein College of Medicine
基础医学生物化学生理学
Liu Li,Kurland Irwin J.,Eliscovich Carolina,Shinoda Kosaku,Landgraf Austin,Horton Maxwell,Yang Fajun,Pessin Jeffrey E.,Qiu Yunping,Okada Junichi,Sidoli Simone,Xiaoli Alus M.,Schuster Victor L..Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/2024.04.29.591168.点此复制
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