GBP5 promotes liver injury and inflammation by inducing hepatocyte apoptosis

Ding, Kaixin; Li, Xinzhi; Ren, Xiaomeng; Ding, Na; Li, Tao; Dong, Xue; Chen, Zheng

doi:10.1096/fj.202101448r

Cited by 20 publications

(10 citation statements)

References 42 publications

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“…TNF protein superfamily members, including TNF-a, Fas cell surface death receptor ligand (FASL), and TNF-associated apoptosis-inducing ligand (TRAIL), are the main inducers of hepatocyte death. The TNF-a/tumor necrosis factor receptor (TNFR1), FAS/FASL, and TRAIL/TRAILR pathways can activate CASP8 and then initiate a proteolytic cascade that involves CASP3, CASP6, and CASP7, which ultimately leads to hepatocyte apoptosis [ 24 , 25 , 26 ]. We showed that TRAILR, FAS, CASP8, and CASP3 were upregulated in the LPS-stimulated piglet livers, and that the predicted lncRNA target genes were also enriched in the apoptosis pathway.…”

Section: Discussionmentioning

confidence: 99%

RNA-Sequencing Characterization of lncRNA and mRNA Functions in Septic Pig Liver Injury

Zhang

Xue

Zhao

et al. 2023

Genes

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We assessed differentially expressed (DE) mRNAs and lncRNAs in the liver of septic pigs to explore the key factors regulating lipopolysaccharide (LPS)-induced liver injury. We identified 543 DE lncRNAs and 3642 DE mRNAs responsive to LPS. Functional enrichment analysis revealed the DE mRNAs were involved in liver metabolism and other pathways related to inflammation and apoptosis. We also found significantly upregulated endoplasmic reticulum stress (ERS)-associated genes, including the receptor protein kinase receptor-like endoplasmic reticulum kinase (PERK), the eukaryotic translation initiation factor 2α (EIF2S1), the transcription factor C/EBP homologous protein (CHOP), and activating transcription factor 4 (ATF4). In addition, we predicted 247 differentially expressed target genes (DETG) of DE lncRNAs. The analysis of protein-protein interactions (PPI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway detected key DETGs that are involved in metabolic pathways, such as N-Acetylgalactosaminyltransferase 2 (GALNT2), argininosuccinate synthetase 1 (ASS1), and fructose 1,6-bisphosphatase 1 (FBP1). LNC_003307 was the most abundant DE lncRNA in the pig liver, with a marked upregulation of >10-fold after LPS stimulation. We identified three transcripts for this gene using the rapid amplification of the cDNA ends (RACE) technique and obtained the shortest transcript sequence. This gene likely derives from the nicotinamide N-methyltransferase (NNMT) gene in pigs. According to the identified DETGs of LNC_003307, we hypothesize that this gene regulates inflammation and endoplasmic reticulum stress in LPS-induced liver damage in pigs. This study provides a transcriptomic reference for further understanding of the regulatory mechanisms underlying septic hepatic injury.

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Section: Discussionmentioning

confidence: 99%

RNA-Sequencing Characterization of lncRNA and mRNA Functions in Septic Pig Liver Injury

Zhang

Xue

Zhao

et al. 2023

Genes

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“…The activation of the NLRP3 inflammasome requires two stages: Hepatic inflammatory responses co-occur with all of the liver diseases and were assumed to be involved in the onset and progression of hepatic lesions [27]. Innate immune cell activation and multiple pro-inflammatory cytokines, including TNF-α and IL-6, trigger and amplify the inflammatory hepatic damage [28]. In the current study, the LPS upregulated the pro-inflammatory mediators TNF-α, IL-6, and IL-22, which were reversed by thymol.…”

Section: Discussionmentioning

confidence: 99%

Thymol Alleviates LPS-Induced Liver Inflammation and Apoptosis by Inhibiting NLRP3 Inflammasome Activation and the AMPK-mTOR-Autophagy Pathway

et al. 2022

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Thymol is a natural antibacterial agent found in the essential oil extracted from thyme, which has been proven to be beneficial in food and medicine. Meanwhile, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and autophagy have been reported to play key roles in the progression of liver injury. However, the effects of thymol on the NLRP3 inflammasome and autophagy in protecting the liver remain unclear. The present study used a mouse model with liver injury induced by lipopolysaccharides (LPS) to investigate the regulatory mechanisms of thymol. We found that thymol alleviated LPS-induced liver structural damage, as judged by reduced inflammatory cell infiltration and improved structure. In addition, elevated levels of the liver damage indicators (alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (TBIL)) dropped after thymol administration. The mRNA and protein expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-22), apoptosis-related genes (caspase3 and caspase9), and the activity of apoptosis-related genes (caspase3 and caspase9) were increased in LPS-treated livers, whereas the changes were alleviated after thymol administration. Thymol inhibited LPS-induced increment in lactate dehydrogenase (LDH) activity in primary hepatocytes of the mouse. In addition, thymol protected mice from liver injury by inhibiting NLRP3 inflammasome activation induced by LPS. Mechanistically, the present study indicates that thymol has liver protective activity resulting from the modulation of the AMP-activated protein kinase—mammalian target of rapamycin (AMPK–mTOR) to regulate the autophagy pathway, hence curbing inflammation.

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“…23 , 35 , 36 Previous research has shown that inflammatory responses, oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis mainly contributed to LPS/D-GalN-induced ALF. 30 , 37 , 38 , 39 , 40 However, Liu et al 41 and Yang et al 42 found that pyroptosis occurred in LPS/D-GalN-induced ALF through activating caspase 1 and inflammasome NLR family pyrin domain containing 3 (NLRP3). Studies also showed that ferroptosis took place in LPS/D-GalN-induced ALF by increasing lipid peroxidation with cyclooxygenase (COX) and lysyl oxidase (LOX) pathway up-regulation and inhibiting GSH synthesis.…”

Section: Discussionmentioning

confidence: 99%

Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

Huang

Wang

Xie

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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GBP5 promotes liver injury and inflammation by inducing hepatocyte apoptosis

Cited by 20 publications

References 42 publications

RNA-Sequencing Characterization of lncRNA and mRNA Functions in Septic Pig Liver Injury

RNA-Sequencing Characterization of lncRNA and mRNA Functions in Septic Pig Liver Injury

Thymol Alleviates LPS-Induced Liver Inflammation and Apoptosis by Inhibiting NLRP3 Inflammasome Activation and the AMPK-mTOR-Autophagy Pathway

Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

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