Abstract
The liver serves as a central hub for a diverse set of functions including metabolic homeostasis, detoxification, and protein synthesis. While appearing homogeneous, hepatocytes, the major workhorse in the liver, demonstrate spatial identity within the lobule, which in turn dictates gene and protein expression and, eventually, function. Presenting as an axis from the portal triad to the central vein, this organization has been conventionally referred to as metabolic zonation. In recent years, the heterogeneity in expression and function is now understood to extend well beyond hepatocytes and metabolism to include nonparenchymal cells and diverse functions. Although the lobule is conventionally divided into three zones, spatial multi-omics technologies reveal a more nuanced picture, where zonation provides a coordinate system for an eclectic but highly functional hepatic milieu. We summarize the current understanding of liver zonation as it contributes to division of labor, injury compartmentalization, and stepwise arrangement of metabolic pathways and discuss the implications of this framework for liver homeostasis, regeneration, and disease.