thapsigargin and Chemical-and-Drug-Induced-Liver-Injury

Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver-identity (LIVER-ID) transcription factor (TF) network, initiated by rapid LIVER-ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER-ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co-recruitment of LIVER-ID TFs and decommissioning of BRD4 super-enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER-ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.

Topics: Animals; Basic-Leucine Zipper Transcription Factors; Cell Cycle Proteins; Cell Line; Cells, Cultured; Chemical and Drug Induced Liver Injury; Chromatin Immunoprecipitation Sequencing; Down-Regulation; Endoplasmic Reticulum Stress; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Hepatocytes; Humans; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Thapsigargin; Transcription Factors; Transcriptome; Up-Regulation

To investigate the impact of alpha subunit of eukaryotic initiation factor 2 (eIF2α) phosphorylation on liver regeneration.. Male BALB/c mice were intraperitoneally injected with carbon tetrachloride (CCl4) to induce liver injury. Human hepatocyte LO2 cells were incubated with thapsigargin to induce endoplasmic reticulum (ER) stress. Salubrinal, integrated stress response inhibitor (ISRIB), and DnaJC3 overexpression were used to alter eIF2α phosphorylation levels.. CCl4 administration induced significant ER stress and eIF2α phosphorylation, and increased hepatocyte proliferation proportionally to the extent of injury. Inhibiting eIF2α dephosphorylation with salubrinal pretreatment significantly mitigated liver injury and hepatocyte proliferation. In LO2 cells, thapsigargin induced significant eIF2α phosphorylation and inhibited proliferation. Inhibiting eIF2α dephosphorylation partly restored cell proliferation during ER stress.. In acute liver injury, inhibiting eIF2α dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation.

Topics: Animals; Apoptosis; Carbon Tetrachloride; Cell Proliferation; Chemical and Drug Induced Liver Injury; Cinnamates; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Eukaryotic Initiation Factor-2; Hepatocytes; HSP40 Heat-Shock Proteins; Humans; Liver Regeneration; Male; Mice; Mice, Inbred BALB C; Phosphorylation; Thapsigargin; Thiourea