Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters

Abstract

The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis.

Keywords: HIF; Hepatocytes; ROS; antioxidants; antioxidative enzymes; diet; fibrosis; homeostasis; hypoxia; liver; matrix; metabolic zonation; metabolism; morphogen signaling; optimization; pathology; regulatory network; sinusoid.

Figure 1

Microcirculatory architecture of the liver acinus. Classic hexagonal lobules are centered around a portal tract (PT) and blood flows as mixture of arterial and venous blood into the sinusoids which extend into the direction of the central veins (CV). The oxygen gradient generated ranges from ~60–65 mm Hg (dark blue) to ~30–35 mm HG (light blue); three zones exist: one around the portal triads (i.e., the periportal zone or zone 1), another around the central vein (i.e., the perivenous zone, or zone 3) and a midzonal layer or zone 2. Hepatocytes, fenestrated endothelial cells, hepatic stellate cells residing in the Space of Disse, separating hepatocytes and endothelial cells, Kupffer cells as resident macrophages and Pit cells are the building blocks of the sinusoids.

Figure 2

Interplay of major zonation signaling pathways. The sinusoids facilitate free exchange of nutrients, metabolites, and various substrates, such as oxygen. Although the gradient may vary, the periportal to perivenous oxygen gradient (in blue) exists inevitably under almost all conditions. Hypoxia-inducible factors (HIFs) may be major orchestrators since they adapt the gene expression profile in response to changing oxygen tensions. The HIF system in hepatocytes but also in the other sinusoidal cells can undergo cross-talks with other major zonation regulating pathways such as the WNT/β-catenin pathway and associated components, hormone and growth factor signaling pathways, the Hippo pathway and the hedgehog (HH) pathway. All these pathways and factors exempt the oxygen gradient; depend, to the more or lesser extent, on the presence of specific ligands which are secreted from other cells than the hepatocytes, e.g., liver endothelial cells which contribute to the synthesis of certain WNTs, whereas cholangiocytes and stellate cells can secrete hedgehog ligands. PT, portal tract consisting of branches from the hepatic artery (HA), portal vein (PV) and a bile duct; CV, central vein.

Figure 3

Targeting HIF-signaling for the treatment of liver diseases. Activation of HIF signaling appears to be beneficial during ischemia-reperfusion (I/R) injury and partially in ALD. Activation of HIFs can be achieved by HIF prolyl hydroxylase inhibitors. In NAFLD, NASH fibrosis, cirrhosis, and HCC inhibition of HIFs may be of benefit.