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Altered glycogen metabolism causes hepatomegaly following an Atg7 deletion

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Abstract

Autophagy is a lysosomal degradation process involved in the turnover of organelles or other cell constituents, in providing sources for energy production under starving conditions and in cell metabolism. A key protein in the macroautophagic machinery is the autophagy-related protein (Atg) 7. Constitutive deletion of Atg7 is lethal at birth. A conditional deletion of Atg7 in hepatocytes leads to hepatomegaly and in aged animals to liver tumors. With this study, we aim at analyzing the hepatomegaly development in more detail. The 3- to 4-fold enlargement of the liver takes place between days 25 and 35 after birth (P25–P35) and persists at least until P90. This is accompanied by a change in the expression of enzymes involved in the glycogen/glucose metabolism. While glycogen synthesis is inhibited, glucose is preferentially kept as glucose-6-phosphate inside the cells, inducing a swelling of the cells caused by hyperosmolarity. An increase of lipogenic enzymes suggests that glucose-6-phosphate is delivered to lipogenic pathways, which is supported by the occurrence of a steatosis around P30. The development of hepatomegaly is accompanied by a polyploidisation of hepatocytes, an enhanced expression of genes related to inflammatory processes and an infiltration of macrophages and granulocytes. Our data provide evidence that the attenuation of macroautophagy in hepatocytes leads to a glucose retention that causes cell swelling. The resulting hepatomegaly, which develops in a time interval of about 10 days, perturbs liver perfusion and induces an inflammatory reaction together with polyploidisation.

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Acknowledgments

We thank Waltraud Ackermann and Uschi Lehr for their excellent technical assistance and David Fuhrmann for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Cytobiology and Cytopathobiology, Philipps University, 35033, Marburg, Germany

    Lara Kern, Johanne Spreckels & Hans-Peter Elsässer

  2. Genomics Unit, Philipps University, 35043, Marburg, Germany

    Andrea Nist & Thorsten Stiewe

  3. Institute of Molecular Oncology, Philipps University, 35043, Marburg, Germany

    Thorsten Stiewe & Marco Mernberger

  4. Institute of Laboratory Medicine, Pathobiochemistry and Molecular Diagnostics, Philipps University, 35043, Marburg, Germany

    Chrysanthi Skevaki

  5. Institute of Medical Biometry and Epidemiology, Philipps University, 35037, Marburg, Germany

    Brandon Greene

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  1. Lara Kern
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Correspondence to Hans-Peter Elsässer.

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Kern, L., Spreckels, J., Nist, A. et al. Altered glycogen metabolism causes hepatomegaly following an Atg7 deletion. Cell Tissue Res 366, 651–665 (2016). https://doi.org/10.1007/s00441-016-2477-8

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  • DOI: https://doi.org/10.1007/s00441-016-2477-8

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