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

Abstract

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. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl 4 (2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl 4 intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl 4 -induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. 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. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar 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.

Influence of Liver Fibrosis on Lobular Zonation

“…Periportalization seems to represent a stereotypical response to different types of inflammatory stress, possibly because the liver lacks the ability to activate distinct adaptive zonation programs for pericentral and periportal damage. This corresponds to previous studies, demonstrating that different types of acute and chronic inflammatory stimuli activate the same gene regulatory networks, whereby upregulation of inflammatory genes occurs simultaneously to the downregulation of metabolic genes [52]; interestingly, both inflammatory and metabolic genes are controlled by the same upstream mechanisms [52]. A strength of the present study is that six individual mice were included for each condition of the time-resolved analysis.…”

The human hepatocyte TXG-MAPr: WGCNA transcriptomic modules to support mechanism-based risk assessment

“…Immune response: Immune response pathways including inflammatory mediators are activated in hepatocytes during liver injury and in disease states (Campos et al, 2020;Woolbright, 2017). Immune response and inflammation terms are enriched in several preserved modules (PHH:12, PHH:247, PHH26, PHH:22 and PHH:136) that respond to inflammatory agents such as interferon-α and TNF-α (Figure 2C, panel iii, Table 1).…”

“…Liver is a primary target organ for drug and chemical toxicants due to its role in metabolism and disposition (J. Zhang & Venkat, 2020).…”

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

“…In parallel, the availability of advanced high-throughput approaches was exploited to increase the applicability domains and throughput levels of the test methods. Screening transcriptomics data were provided from hepatic (Albrecht et al 2019 ; Campos et al 2020 ; Copple et al 2019 ; Ramirez et al 2018 ), renal (Limonciel et al 2018a , b ) and neuronal (Delp et al 2019 ) cell systems. High-content imaging was expanded to complex toxicological endpoints, such as DART (Dreser et al 2020 ; Nyffeler et al 2018 ) and systemic RDT with the establishment of novel fluorescent protein reporter cell lines (Bischoff et al 2019 ; Schimming et al 2019 ; Wink et al 2018 ; Yang et al 2020 ).…”