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Review
. 2017 Apr:11:622-630.
doi: 10.1016/j.redox.2017.01.012. Epub 2017 Jan 17.

Metabolic zonation of the liver: The oxygen gradient revisited

Thomas Kietzmann  1
Affiliations
Review

Metabolic zonation of the liver: The oxygen gradient revisited

Thomas Kietzmann. Redox Biol. 2017 Apr.

Abstract

The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.

Keywords: Hepatocytes; Hypoxia, HIF, Liver; Metabolic zonation; Metabolism; Morphogen signaling; Optimization; Pathology; ROS, Antioxidants, Antioxidative enzymes, Matrix, Diet, Fibrosis, Homeostasis; Regulatory network; Sinusoid.

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Figures

Fig. 1.
Fig. 1
Liver micro architecture, the oxygen gradient and zonation of metabolism. (A) Classic hexagonal shaped liver lobule with a central vein (CV) in the middle and portal triad (PT) corners with branch from the portal vein also called terminal portal vein (TPV, blue dot), and a branch from the hepatic artery also called terminal hepatic arteriole (THA, red dot) as well as a bile duct (BD, green dot). The acinus extends from a PT into the direction of two adjacent central veins. Three zones can be distinguished. 1, the periportal zone; 2, the intermediary zone; 3, the perivenous, pericentral, or centrilobular zone. (B) Liver sinusoid and oxygen gradient. Hepatocytes (HC), are connected with each other, bile canaliculi (BC) transport the bile formed in HC into the bile duct (BD). Sinusoids are wrapped with fenestrated endothelial cells (EC). HC and EC are separated by the Space of Disse which is the residence niche for hepatic stellate cells (HC). Resident macrophages, the Kupffer cells (KC) are also to be found in the sinusoid. (C) Distribution of major metabolic pathways. pp, periportal; pv, perivenous; AA, amino acids; Cho, cholesterol synthesis; CYP, cytochrome P450 enzymes; Ggn, glycogen; Lac, lactate; GPX, glutathione peroxidase; GS, glutamin synthesis; GST, glutathione transferase. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2.
Fig. 2
Impact of the oxygen gradient on β-catenin and hedgehog signaling and metabolic zonation. Non-parenchymal cells such as bile duct cells and hepatic stellate cells are more abundant in the oxygen rich periportal area and secrete Hh signals (nPC Hh) and inhibit β-catenin signaling. The low oxygen content in the perivenous zone activates the HIF system, induces LGR5 expression and activates β-catenin as well as suppresses expression of the negative β-catenin regulator APC. Rspondins secreted from the central vein endothelial cells, activate β-catenin via LGR5 in perivenous hepatocytes. To maintain homeostasis, hypoxia activates expression of Hh components in hepatocytes (HC Hh) to feedback inhibit β-catenin.
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