Regulation of autophagy protects against liver injury in liver surgery‐induced ischaemia/reperfusion

Hu, Chenxia; Zhao, Lingfei; Zhang, Fen; Li, Lanjuan

doi:10.1111/jcmm.16943

Cited by 22 publications

(19 citation statements)

References 100 publications

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“…Increasing studies have shown that cold exposure can result in liver damage [ 21 , 22 ]. In addition, the involvement of pyroptosis, inflammasomes and oxidative stress in the pro-inflammatory response is observed in many liver diseases, such as metabolic-associated fatty liver disease, nonalcoholic fatty liver disease and alcohol-associated liver disease [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

et al. 2022

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The body needs to generate heat to ensure basic life activities when exposed to cold temperatures. The liver, as the largest glycogen storage organ in the body and main heat-producing organ at rest, may play a role in chronic cold exposure. Recent studies suggested that pyroptosis plays a crucial role in liver diseases. However, the role of pyroptosis in cold stress-induced liver injury is not clear. Hence, in this study, we attempted to investigate the effects of chronic cold exposure on liver function, apoptosis, oxidative stress and inflammation in mice by establishing a mouse model of chronic cold exposure, and to investigate whether pyroptosis pathways are involved in the process of chronic cold exposure. In vivo, our results show that inflammatory cell infiltration and other pathological changes in liver cells and the activity of liver enzyme evidently increased in the serum and liver of cold-exposed mice, suggesting cold stress may result in liver injury. Remarkably, increased expression of heat shock protein 70 (HSP70) and HSP90 proteins proved the cold stress model is successfully constructed. Then, elevated levels of apoptosis, inflammation, oxidative stress and pyroptosis related proteins and mRNAs, such as cysteinyl aspartate specific proteinase-3 (Caspase-3), inducible nitric oxide synthase (iNOS), nuclear factor erythroid2-related factor 2 (Nrf2) and gasdermins D (GSDMD), confirmed that cold exposure activated apoptosis, oxidative stress and pyroptosis, and released inflammation cytokines. Meanwhile, in vitro, we got similar results as in vivo. Further, adding an NLR family pyrin domain containing 3 (NLRP3) inhibitors found that suppression expression of NLRP3 results in the essential proteins of pyroptosis and antioxidant evidently reduced, and adding GSDMD inhibitor found that suppression expression of GSDMD accompanies with the level of Nrf2 and heme oxygenase-1 (HO-1) obviously reduced. In summary, these findings provide a new understanding of the underlying mechanisms of the cold stress response, which can inform the development of new strategies to combat the effects of hypothermia.

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Section: Discussionmentioning

confidence: 99%

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

et al. 2022

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“…As reported previously, the KLF family is involved in autophagy regulation [17,18]. Autophagy also plays a crucial role in liver I/R injury [15]. Accordingly, we hypothesized that KLF6 may play an important role in liver I/R injury by regulating autophagy.…”

Section: Klf6 De Ciency Aggravates H/r-induced Aml12 Cell Injurymentioning

confidence: 56%

“…Autophagy is a conserved intracellular catabolic process that delivers cellular components to the lysosome for degradation, providing nutrients and necessary material basis for cell survival, thereby playing pivotal roles in maintaining cellular homeostasis [14]. Accumulating evidence suggests critical roles of autophagy in I/R injury of the heart, liver, brain, kidney, and lung [15]. As a compensatory mechanism, autophagy alleviates the impacts of ATP deprivation on cells during ischemia, thereby exerting a protective effect; however, during reperfusion, persistent and excessive activation of autophagy can lead to cell death.…”

Section: Introductionmentioning

confidence: 99%

KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy

Zhang

Yu³

et al. 2022

Preprint

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Hepatic ischemia-reperfusion (I/R) injury, a common clinical complication of liver transplantation, gravely affects patient prognosis. Krüppel-like factors (KLFs) are a family of C2/H2 zinc finger DNA-binding proteins. KLF6, a member of the KLF family proteins, plays crucial roles in proliferation, metabolism, inflammation and injury responses; however, its role in HIR largely remains unclear. Herein, we found that KLF6 expression was significantly up-regulated in mice and hepatocytes after I/R injury. Subsequently, mice were subjected to I/R after tail vein injection of shKLF6- and KLF6-overexpressing adenovirus. KLF6 deficiency markedly aggravated liver damage and cell apoptosis along with the activation of hepatic inflammatory responses, whereas hepatic overexpression of KLF6 in mice showed opposite effects. Furthermore, we knocked out or overexpressed KLF6 in AML12 cells, and then exposed to hypoxia-reoxygenation challenge. KLF6 knockout significantly reduced cell viability, and increased hepatocyte inflammation, apoptosis, and ROS, whereas overexpression of KLF6 showed the opposite effects. Mechanistically, KLF6 inhibited the overactivation of autophagy at the initial stage, and the regulatory effect of KLF6 on I/R injury was autophagy-dependent. CHIP-qPCR and luciferase reporter gene assays confirmed that KLF6 was bound to the promoter region of Beclin1 and inhibited its transcription. Moreover, KLF6 activated the mTOR/ULK1 pathway. Finally, we retrospectively analyzed the clinical data of liver transplantation patients and observed significant associations between KLF6 expression and liver function after liver transplantation. In summary, KLF6 inhibited the overactivation of autophagy by transcriptional regulation of Beclin1 and activation of the mTOR/ULK1 pathway, thereby playing a protective role against hepatic I/R injury. KLF6 is expected to serve as a biomarker to predict the severity of I/R injury after liver transplantation.

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“…Zhu et al 42 reported that rapamycin alleviated hepatic I/R injury by enhancing autophagy, but others have debated whether inactivation of autophagy ameliorates hepatic I/R injury. 43 Although the evidence is inconclusive, recent studies highlight the therapeutic potential of controlled autophagy in the suppression of hepatic I/R injury. In our study, LDP2 significantly inhibited autophagy in hepatocytes, as evidenced by the reduced expression of autophagy marker proteins, indicating that autophagy contributed to hepatocyte injury and that LDP2 had a protective effect against hepatocyte damage via autophagy inhibition.…”

Section: Discussionmentioning

confidence: 99%

Peptidomic Analysis Reveals that Novel Peptide LDP2 Protects Against Hepatic Ischemia/Reperfusion Injury

Bao¹,

Wang²,

Cheng³

et al. 2022

J Clin Transl Hepatol

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Regulation of autophagy protects against liver injury in liver surgery‐induced ischaemia/reperfusion

Cited by 22 publications

References 100 publications

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy

Peptidomic Analysis Reveals that Novel Peptide LDP2 Protects Against Hepatic Ischemia/Reperfusion Injury

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