Comparison of hepatic transcriptome profiling between acute liver injury and acute liver failure induced by acetaminophen in mice

Li, Chunmin; Ming, Yanan; Hong, Wenting; Tang, Yingyue; Lei, Xiaoguang; Li, Xiaobo; Mao, Yimin

doi:10.1016/j.toxlet.2017.11.020

Cited by 24 publications

(10 citation statements)

References 40 publications

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“…The concept that progenitor accumulation is excessive in ALF is further supported by a recent functional analysis of RNA sequencing data from mouse models of lethal and sublethal acetaminophen-induced ALF. Livers with lethal injury were dramatically enriched with transcripts encoding factors that promote fetal liver-like functions (eg, cell proliferation, development, differentiation) compared with livers with sublethal injury or healthy livers 12. Together, these findings suggested that ALF may result from dysregulation of fetal reprogramming mechanisms that are necessary for effective liver regeneration.…”

Section: Introductionmentioning

confidence: 95%

Dysregulated activation of fetal liver programme in acute liver failure

Hyun

Premont

et al. 2019

Gut

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ObjectiveUncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3).DesignWe compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury.ResultsLivers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate.ConclusionAfter acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.

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Section: Introductionmentioning

confidence: 95%

Dysregulated activation of fetal liver programme in acute liver failure

Hyun

Premont

et al. 2019

Gut

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“…Clustering of the genes based on their connectivity to each other revealed that the human orthologues of co-expressed zebrafish genes also show high interconnectivity such that genes of the same module (in same colour) cluster 11 together in connectivity groups. This attests to the relevance of zebrafish liver regeneration studies to human liver regeneration.…”

Section: Differential Gene Expression In the Liver During Regenerationmentioning

confidence: 99%

“…Recent transcriptomic and metabolomic studies on a mouse PHx model revealed that cell division post-injury causes metabolic remodelling of the liver cells and that hepatocytes adapt their metabolism to changing conditions during regeneration (10). A comparative transcriptomic study of lethal and sub-lethal doses of acetaminophen driven drug induced liver injury (DILI) in mice identified factors that may give adaptive advantage in cases where the liver is able to regenerate and survive the damage (11). In spite of the ability of the liver to recover from loss of hepatocytes by regeneration, in liver diseases the recovery is usually suboptimal and not sufficient.…”

Section: Introductionmentioning

confidence: 99%

A temporal map of gene expression pattern during zebrafish liver regeneration

Jagtap

Sivadas

Basu

et al. 2019

Preprint

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Highlights: Zebrafish is a valuable model for developing therapeutic strategies to augment liver regeneration  Liver regeneration in zebrafish is not well studied and pathways poorly understood  We develop a hepatocyte ablation model of liver injury and regeneration in adult zebrafish  We generate a comprehensive transcriptomic map of various stages of liver injury and regeneration  We discover a novel regulation of cholesterol biosynthesis pathways during liver regeneration Abstract:Background & Aims: Zebrafish is increasingly being used to study liver injury and regeneration. However, very little is known about molecular players that respond to injury and participate in liver regeneration. Here we aim to generate a temporal map of gene expression changes at injury and during regeneration of the adult zebrafish liver. Methods:We use a metronidazole-nitroreductase (MTZ-nfsb) based system to selectively ablate hepatocytes in adult zebrafish to create a model for liver injury and regeneration. Through RNA sequencing of liver samples at multiple time points we 2 generate a comprehensive temporal map of gene expression changes during injury and regeneration.Results: Gene expression reveals that soon after injury the immediate early transcription factor MYC induces a battery of genes that respond to the metronidazole-induced ROS by activating oxido-reductase pathways and apoptosis machinery. Upon injury, liver cells down regulate genes encoding complement proteins, bile acid and lipid biosynthesis pathway in a concerted manner. Midway through regeneration, we discover a spike of cholesterol biosynthesis and protein folding machinery genes suggesting an important role for these pathways in liver regeneration. Conclusions:The temporal transcriptomic map of liver regeneration would serve as a framework for further studies in understanding, and for screening for compounds that augment liver regeneration. General significance:Using a hepatocyte specific ablation of zebrafish liver, we create a model of adult liver regeneration. This model was used to generate a comprehensive transcriptomic map of gene expression trends during liver regeneration. This temporal map lays the groundwork to study important events in liver regeneration.

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“…There are many factors involved in AHI, such as fulminant hepatitis, drug toxicity, secondary infection, alcohol intake too much, immune‐mediated attack, radiation damage, chemical poisoning, pancreatitis, congestive heart failure, diabetes mellitue, tumor, overfatigue, and trauma (Koneru et al., ; Rivera et al., ; Wang et al., ). AHI may develop into more serious acute hepatic failure (AHF), which leads to liver dysfunction, liver inflammatory disease, liver fibrosis, cirrhosis, and even liver cancer (Gehrke et al., ; Ghafoory et al., ; Li et al., ; Thawley, ). Therefore, to study the mechanism of AHI, a variety of animal hepatic injury models have been used.…”

Section: Introductionmentioning

confidence: 99%

Disodium Guanylate Alleviates Acute Hepatic Injury Induced by Carbon Tetrachloride Via Antioxidative Stress and Antiapoptosis In Vivo and In Vitro

Jin

Liu

Wang

et al. 2019

Journal of Food Science

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Hepatic injury is one of the most common digestive system diseases worldwide in clinic. Guanylic acid or guanosine monophosphate (GMP) was an important component of nucleotides, which is mainly in the form of sodium salt (disodium guanylate, GMP‐Na2). However, its effect on hepatic injury has not yet been investigated. This study is to investigate the protective effects of GMP‐Na2 on acute hepatic injury induced by carbon tetrachloride (CCl4), and to explore its mechanism. The hepatic injury models of mice and HL‐7702 cells were induced by CCl4. The alanine transaminase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), glutathione peroxidase (GSH‐Px), malondialdehyde (MDA), total antioxidant capacity (T‐AOC) were determined by biochemical method. Hematoxylin–eosin staining were used to determine the morphological changes on liver tissue in mice. The mRNA and protein expressions of caspase‐3, Bax, and Bcl‐2 were detected by RT‐PCR and Western blot analysis. Our results show that GMP‐Na2 treatment significantly decreased the activities of ALT and AST, and the levels of MDA as well as increased the levels of SOD, GSH‐Px, and T‐AOC. Importantly, GMP‐Na2 effectively enhanced the antiapoptosis function by upregulating Bcl‐2 expression and downregulating caspase‐3 and Bax expressions in vivo and in vitro. Moreover, the histopathological changes of liver tissue were obviously improved after GMP‐Na2 treatment. These findings suggest that GMP‐Na2 has protective effects on hepatic injury, and its mechanisms may be associated with antioxidative stress and antiapoptosis.

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Comparison of hepatic transcriptome profiling between acute liver injury and acute liver failure induced by acetaminophen in mice

Cited by 24 publications

References 40 publications

Dysregulated activation of fetal liver programme in acute liver failure

Dysregulated activation of fetal liver programme in acute liver failure

A temporal map of gene expression pattern during zebrafish liver regeneration

Disodium Guanylate Alleviates Acute Hepatic Injury Induced by Carbon Tetrachloride Via Antioxidative Stress and Antiapoptosis In Vivo and In Vitro

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