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.

Figure 1

Immunohistochemical staining of Indian hedgehog in normal liver and after up-regulation of β-catenin signalling. Ihh protein was detected in liver sections of wild type (WT) mice (A) and mice with down-regulated expression of APC protein after three month of age (B). Ihh protein in WT mice shows a clear gradient which is highest in hepatocytes surrounding the central veins. After up-regulation of β-catenin signalling the zone of Ihh-positive hepatocytes is considerably extended as are other known pericentral markers (e.g., glutamine synthetase; c.f.[8,42]). Sections were stained with Rabbit anti-mouse Ihh polyclonal antibody (Abcam) followed by the EnVision^® + Dual Link System-horse radish peroxidase (DAKO) and counterstained with hemalum (Mayer solution).

Figure 2

Scheme illustrating aspects of zonation of central metabolism in normal mice. Selected functions of central metabolism are depicted as conical boxes showing the direction of their porto-central gradients with specific emphasis of the strength of this gradient in the glutamine synthetase-positive zone (right of the vertical line). Dashed boxes indicate gradients that have been determined using a single method only (proteome analysis), instead of at least two independent methods (other boxes). Since the data is valid for normal mice, the presumably corresponding gradient of Wnt/β-catenin signalling is depicted at the top of the scheme, above the row of the hepatocytes. PP: Periportal; PC: Pericentral.