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Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease

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  • Gisela Campos, Wolfgang Schmidt-Heck, Jonathan De Smedt, Agata Widera, Ahmed Ghallab, Larissa Pütter, Daniela González, Karolina Edlund, Cristina Cadenas, Rosemarie Marchan, Reinhard Guthke, Catherine Verfaillie, Claudio Hetz, Agapios Sachinidis, Albert Braeuning, Michael Schwarz, Thomas S. Weiß, Benjamin K Banhart, Jan Hoek, Rajanikanth Vadigepalli, Jeffry Willy, James L. Stevens, David C. Hay, Jan G. Hengstler, Patricio Godoy

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Original languageEnglish
JournalArchives of toxicology
Publication statusPublished - 9 Jan 2020

Abstract

Background & aims: Inflammation has been recognized as essential for restorative regeneration. Here we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function and regeneration. Methods: Genome-wide expression and TRN analysis were performed time-dependently in mouse liver after acute injury by CCl4 (2h, 8h, 1, 2, 4, 6, 8, 16 days) as well as lipopolysaccharide (LPS, 24h) and compared to publicly available data after tunicamycin exposure (mouse, 6h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatio-temporal investigation differentiated lobular zones for signaling and transcription factor expression. Results: Acute CCl4 intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl4 induced necrosis but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Conclusions: Downregulation of metabolic genes occurs concomitantly to induction of inflammation-associated genes as an early response and appears to be initiated bysimilar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.

ID: 132066103