Abstract
BACKGROUND: Liver zonation, the fact that metabolic pathways are spatially separated along the liver sinusoids, is fundamental for proper functioning of this organ. For example, glutamine synthesis from glutamate and ammonia is localized pericentrally in only 7% of the hepatocytes concentrically arranged around the central veins. Recently, we found that FOXO transcription factors lead to upregulation of glutamine synthetase expression inducing autophagy via increasing glutamine production. Since in liver this mechanism can only be functioning in the pericentral zone it remains unclear how autophagy might be regulated in the rest of liver parenchyma. PRESENTATION OF THE HYPOTHESIS: We hypothesize that the regulation of autophagy by glutamine in liver is zonated. In the periportal zone, autophagy is inhibited by low intracellular glutamine but high essential amino acids, while in the pericentral zone it is stimulated by high intracellular glutamine. This zonation may be controlled by the Wnt and Hedgehog signalling pathways through reciprocal influence on the expression of amino acid transporters and metabolic enzymes in the different zones of the parenchyma. TESTING THE HYPOTHESIS: The hypothesis can be tested in transgenic mice with conditional hepatocyte-specific modulation of Wnt and Hedgehog signalling. Isolated periportal and pericentral hepatocyte populations allow for determining the different activities of autophagy and its regulating mechanisms in different zones of the parenchyma. IMPLICATIONS OF THE HYPOTHESIS: Zonation of the regulation of autophagy may allow adapting the extent of the proteolytic breakdown of proteins and organelles to different physiological needs in different zones of liver parenchyma. In this manner metabolic functions can be supported in one zone, for example maintenance of blood glucose levels during starvation which is a periportal issue, while simultaneously preventing cytotoxic events in the opposite zone. Likewise, lipid metabolism can be differentially influenced by uncoupling periportal lipophagy from pericentral breakdown of peroxisomes. Further implications concern the shaping of morphogen gradients along the sinusoidal axis by autophagy, and the different contribution of autophagy to the development of various different liver pathologies. The proposed dependence of the dual glutamine-dependent regulatory mechanisms of autophagy on inverse gradients of Wnt and hedgehog signalling may be relevant for other tissues in which GS is heterogeneously expressed.