Abstract
The hepatic lobule is divided into three zones along the portal-central vein axis. Hepatocytes within each zone exhibit a distinctive gene expression profile that coordinates their metabolic compartmentalization. The zone-dependent heterogeneity of hepatocytes has been hypothesized to result from the differential degree of exposure to oxygen, nutrition and gut-derived toxins. In addition, the gradient of Wnt signaling that increases towards the central vein seen in rodent models is believed to play a critical role in shaping zonation. Furthermore, hepatic zonation is coupled to the site of the homeostatic renewal of hepatocytes. Despite its critical role, the regulatory mechanisms that determine the distinctive features of zonation and its relevance to humans are not well understood. The present study first conducted a comprehensive zone-dependent transcriptome analysis of normal human liver using laser capture microdissection. Upstream pathway analysis revealed the signatures of host responses to gut-derived toxins in the periportal zone, while both the canonical Wnt pathway and the xenobiotic response pathway govern the perivenular zone. Furthermore, we found that the hypoxic environment of the perivenular zone promotes Wnt11 expression in hepatocytes, which then regulates unique gene expression via activation of the non-canonical Wnt pathway. In summary, our study reports the comprehensive zonation-dependent transcriptome of the normal human liver. Our analysis revealed that the LPS response pathway shapes the characteristics of periportal hepatocytes. By contrast, the perivenular zone is regulated by a combination of three distinct pathways: the xenobiotic response pathway, canonical Wnt signaling, and hypoxia-induced noncanonical Wnt signaling.
Highlights
Hepatic zonality divides the hepatic lobule into three zones along the line connecting the portal triads and the central vein.[1]The periportal (PP) zone is located adjacent to the portal triad where hepatocytes are most exposed to oxygenated blood, nutrients and gut-derived toxins.[2]
Zone-1 specializes in gluconeogenesis and β-oxidation, while zone-3 is dedicated to glycolysis and lipogenesis.[5]
Experimental & Molecular Medicine reverse transcription quantitative PCR (RT-qPCR) analysis demonstrated that tissue in OCT, but not FFPE, well preserved the abundance of three selected mRNAs comparable to freshly isolated primary hepatocytes (Supplementary Figure 1B)
Summary
The periportal (PP) zone (zone-1) is located adjacent to the portal triad where hepatocytes are most exposed to oxygenated blood, nutrients and gut-derived toxins.[2] By contrast, the perivenous (PV) zone (zone-3) is surrounded by the most deoxygenized, detoxified, and the least nutrient-rich blood.[3] The middle zone (zone-2) is presumed to be an intermediate environment. The environmental differences among each zone are hypothesized to modulate the gene expression profile, resulting in zone-dependent functional heterogeneity, namely, hepatic zonation.[4] For example, zone-1 specializes in gluconeogenesis and β-oxidation, while zone-3 is dedicated to glycolysis and lipogenesis.[5] zone-3 hepatocytes abundantly express cytochrome P450s, which facilitate xenobiotic metabolism. Recent studies in mice revealed that zone-3 might be designated for homeostatic renewal of hepatocytes through upregulation of canonical Wnt signaling.[6,7,8]
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