Liver zonation: Novel aspects of its regulation and its impact on homeostasis

Abstract

Liver zonation, the spatial separation of the immense spectrum of different metabolic pathways along the liver sinusoids, is fundamental for proper functioning of this organ. Recent progress in elucidating localization and interactions of different metabolic pathways by using “omics” techniques and novel approaches to couple them with refined spatial resolution and in characterizing novel master regulators of zonation by using transgenic mice has created the basis for a deeper understanding of core mechanisms of zonation and their impact on liver physiology, pathology and metabolic diseases. This review summarizes the fascinating technical achievements for investigating liver zonation and the elucidation of an emerging network of master regulators of zonation that keep the plethora of interrelated and sometimes opposing functions of the liver in balance with nutritional supply and specific requirements of the entire body. In addition, a brief overview is given on newly described zonated functions and novel details on how diverse the segmentation of metabolic zonation may be. From these facts and developments a few fundamental principles are inferred which seem to rule zonation of liver parenchyma. In addition, we identify important questions that still need to be answered as well as interesting fields of research such as the connection of zonation with circadian rhythm and gender dimorphism which need to be pushed further, in order to improve our understanding of metabolic zonation. Finally, an outlook is given on how disturbance of liver zonation and its regulation may impact on liver pathology and the development of metabolic diseases.

Keywords: Homeostasis, Liver, Metabolic zonation, Metabolism, Morphogen signalling, Optimization, Pathology, Regulatory network, Sinusoid, Systems biology

Core tip: Liver metabolism comprises an immense spectrum of interrelated anabolic and catabolic functions which are performed simultaneously without wasting energy. To cope with this challenge, liver parenchyma shows a considerable heterogeneity and functional plasticity known as metabolic zonation. This review summarizes fascinating technical achievements in this field, covers recent progress in characterizing and visualizing zonation, and outlines an emerging network of master regulators that ensures proper maintenance of homeostasis and energetic optimization of liver function. Finally, an outlook is given on how disturbance of liver zonation and its regulation may impact on liver pathology and the development of metabolic diseases.