The Role of Liver Zonation in Physiology, Regeneration, and Disease

Abstract

As blood flows from the portal triad to the central vein, cell-mediated depletion establishes gradients of soluble factors such as oxygen, nutrients, and hormones, which act through molecular pathways (e.g., Wnt/β-catenin, hedgehog) to spatially regulate hepatocyte functions along the sinusoid. Such “zonation” can lead to the compartmentalized initiation of several liver diseases, including alcoholic/non-alcoholic fatty liver diseases, chemical/drug-induced toxicity, and hepatocellular carcinoma, and can also modulate liver regeneration. Transgenic rodent models provide valuable information on the key molecular regulators of zonation, while in vitro models allow for subjecting cells to precisely controlled factor gradients and elucidating species–specific differences in zonation. Here, we discuss the latest advances in both in vivo and in vitro models of liver zonation and pending questions to be addressed moving forward. Ultimately, obtaining a deeper understanding of zonation can lead to the development of more effective therapeutics for liver diseases, microphysiological systems, and scalable cell-based therapies.

The native liver as inspiration to create superior in vitro hepatic models

“…Especially the occurrence of zonation is mimicked more reliably in this way, which has turned-out to have an impact on the metabolism of some drug compounds, and by consequence on their toxicity. 227…”

“…125 The hepatic artery provides oxygenrich blood and the portal vein provides deoxygenated and nutrient-rich blood originating from the intestines. 122 Both blood flows are mixed and the composition of the blood changes continuously in its concentration of, amongst other, oxygen, 131,132 ammonia, glucose and some hormones 133 such as insulin and glucagon throughout its path through the hepatic lobule due to the metabolic activity of the hepatocytes, leading to zonation. Hence, the specific function and phenotype of the hepatocytes depends on the blood composition they are exposed to and by consequence to their specific location 134 (called zone) in the hepatic lobule.…”

Simulation of the crosstalk between glucose and acetaminophen metabolism in a liver zonation model

“…The model contains only 13 zonation-dependent kinetic parameters (Supplementary Material), and metabolic zonation was simulated by manually changing enzyme activities depending on the zone that the cell belongs to, either the periportal or pericentral region. Conversely, the actual zonation is gradual and continuous along the sinusoidal axis without any histological borders and involves crosstalks of various metabolisms (Panday et al, 2022). This model also lacked the dynamic interaction of hepatocytes between the periportal and the pericentral regions through sinusoidal blood flow Kennedy et al, 2019) and omitted the regulatory effects of oxygen and growth factors that are critical for maintaining metabolic zonation (Schmierer et al, 2010;Kietzmann, 2017;Scheidecker et al, 2020).…”

Advancing Key Gaps in the Knowledge of Plasmodium vivax Cryptic Infections Using Humanized Mouse Models and Organs-on-Chips

“…These structures are composed mostly by parenchymal cells hepatocytes (up to 60%) while the remaining includes non-parenchymal cells as hepatic stem cells, connective tissue cells, hepatic stellate cells, monocytic Kupffer cells and endothelial cells ( Miyajima et al., 2014 ). The lobular acinus can be further divided into three main zones of decreasing oxygen tension due to increasing distance towards the radial hepatic arterioles ( Panday et al., 2022 ). Most notably the liver zonation seems to display distinct hepatocyte metabolic profiles and functions.…”