TLR4 Knockout Attenuates BDL-induced Liver Cholestatic Injury through Amino Acid and Choline Metabolic Pathways

Zhang, Shou-Hua; Yu, Ming; Yan, Jing; Xiao, Jianghong; Yu, Xiao; Yang, Jiale; Lei, Jun; Yu, Xin; Chen, Wei-Long; Chai, Yong

doi:10.1007/s11596-021-2364-8

Cited by 4 publications

(2 citation statements)

References 28 publications

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“…Amino acids are essential small molecular metabolites that mirror the body's metabolic function. Amino acid disorder is closely related to the occurrence and development of liver injury (26). Numerous altered amino acid metabolism genes were observed in the liver tissue of septic rats in our research.…”

Section: Discussionsupporting

confidence: 54%

Transcriptomics combined with metabolomics analysis of the mechanism of agmatine in the treatment of septic liver injury

Huang¹,

Gan²,

Pan³

et al. 2022

Ann Transl Med

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Background: Acute liver injury can occur at any stage of sepsis and is an important sign of multiple organ dysfunction syndrome (MODS). Studies have shown that agmatine (AGM) can effectively improve liver injury caused by sepsis. However, due to the numerous metabolites and metabolic pathways of AGM in the human body, its mechanism in treating septic liver injury is unclear.Methods: In this study, a liver injury model of septic Sprague-Dawley rats was established by cecal ligation and perforation (CLP). After AGM treatment, transcriptomics combined with metabolomics was employed to analyze the gene expression levels and metabolite changes. Results:The results showed that AGM decreased the expression levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), procalcitonin (PCT), and inflammatory factors [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)] in the serum of septic rats. It also reduced liver inflammatory cell infiltration and abnormal lipid metabolism, and promoted the survival rate of septic rats. In addition, 17 differentially-expressed genes were identified by transcriptomics, mainly in arginine and proline metabolism, the arachidonic acid metabolism pathway, as well as the nuclear factor kappa B (NF-κB) and AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor α (PPARα) signal transduction pathways. Metabolomics analysis was carried out to study the potential liver metabolism spectrum changes induced by AGM treatment. The results showed significant changes in 26 metabolites in the rat liver samples, mainly involved in arginine and proline metabolism, arachidonic acid metabolism, linoleic acid metabolism, and fatty acid metabolism. Conclusions:The integrated transcriptomics and metabolomics analysis demonstrated that AGM improved septic liver injury by regulating lipid metabolism, and reduced the inflammatory reaction by affecting fatty acid metabolism, amino acid metabolism, and the arachidonic acid metabolism pathway. The integration of transcriptomics and metabolomics provides an effective means to elucidate AGM's therapeutic pathways and biomarkers.

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Section: Discussionsupporting

confidence: 54%

Transcriptomics combined with metabolomics analysis of the mechanism of agmatine in the treatment of septic liver injury

Huang¹,

Gan²,

Pan³

et al. 2022

Ann Transl Med

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“…Several studies have demonstrated that TLR4 targeting improved renal function, ameliorated tubulointerstitial damage, and reduced proinflammatory signaling in experimental models of AKI, including ischemia–reperfusion [ 13 ], sepsis [ 14 ], cyclosporine nephrotoxicity [ 15 ], and rhabdomyolysis [ 16 ]. Genetic or pharmacological disruption of TLR4 signaling also reduced liver injury in experimental models of ischemia–reperfusion [ 17 ], cholestasis [ 18 ], and hepatic sinusoidal obstruction syndrome [ 19 ]. However, no previous study had analyzed the role of TLR4 in intravascular hemolysis and whether heme‐mediated damage may be prevented by targeting TLR4.…”

Section: Introductionmentioning

confidence: 99%

Role of Toll‐like receptor 4 in intravascular hemolysis‐mediated injury

Vázquez‐Carballo

Herencia

Guerrero‐Hue

et al. 2022

The Journal of Pathology

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Massive intravascular hemolysis is a common characteristic of several pathologies. It is associated with the release of large quantities of heme into the circulation, promoting injury in vulnerable organs, mainly kidney, liver, and spleen. Heme activates Toll-like receptor 4 (TLR4), a key regulator of the inflammatory response; however, the role of TLR4 in hemolysis and whether inhibition of this receptor may protect from heme-mediated injury are unknown. We induced intravascular hemolysis by injection of phenylhydrazine in wildtype and Tlr4-knockout mice. In this model, we analyzed physiological parameters, histological damage, inflammation and cell death in kidney, liver, and spleen. We also evaluated whether heme-mediated-inflammatory effects were prevented by TLR4 inhibition with the compound TAK-242, both in vivo and in vitro. Induction of massive hemolysis elicited acute kidney injury characterized by loss of renal function, morphological alterations of the tubular epithelium, cell death, and inflammation. These pathological effects were significantly ameliorated in the TLR4-deficient mice and in wildtype mice treated with TAK-242.In vitro studies showed that TAK-242 pretreatment reduced heme-mediated inflammation by inhibiting the TLR4/ NF-κB (nuclear factor kappa B) axis. However, analysis in liver and spleen indicated that TLR4 deficiency did not protect against the toxic accumulation of heme in these organs. In conclusion, TLR4 is a key molecule involved in the renal inflammatory response triggered by massive intravascular hemolysis. TLR4 inhibition may be a potential therapeutic approach to prevent renal damage in patients suffering from hemolysis.

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Unveiling the hub genes associated with aflatoxin B1-induced hepatotoxicity in chicken

Yang,

2023

Environmental Research

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TLR4 Knockout Attenuates BDL-induced Liver Cholestatic Injury through Amino Acid and Choline Metabolic Pathways

Cited by 4 publications

References 28 publications

Transcriptomics combined with metabolomics analysis of the mechanism of agmatine in the treatment of septic liver injury

Transcriptomics combined with metabolomics analysis of the mechanism of agmatine in the treatment of septic liver injury

Role of Toll‐like receptor 4 in intravascular hemolysis‐mediated injury

Unveiling the hub genes associated with aflatoxin B1-induced hepatotoxicity in chicken

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