BCL6 Alleviates Hepatic Ischemia/Reperfusion Injury Via Recruiting SIRT1 to Repress the NF-κB/NLRP3 Pathway.

in Transplantation by Yulei Gu, Yue Li, Chao Zhang, Yi Liu, Huiting Shi, Xiaoxu Tian, Jiaqi Du, Hao Zhang, Shengli Cao, Lu Gao, Yanzhou Zhang, Guojun Zhao

TLDR

  • The study found that BCL6 overexpression attenuates inflammation and apoptosis after I/R injury, suggesting a potential therapeutic approach for HIRI.
  • The study identified SIRT1 as a critical downstream target of BCL6 in protecting against HIR injury.

Abstract

Hepatic ischemia/reperfusion (I/R) injury (HIRI) is an intrinsic phenomenon observed in the process of various liver surgeries. Unfortunately, there are currently few options available to prevent HIRI. Accordingly, we aim to explore the role and key downstream effects of B-cell lymphoma 6 (BCL6) in hepatic I/R (HIR). BCL6 expression levels were measured in I/R liver tissue and primary hepatocytes stimulated by hypoxia/reoxygenation (H/R). Moreover, we ascertained the BCL6 effect on HIR in vivo using liver-specific BCL6 knockout mice and adenovirus-BCL6-infected mice. RNA-sequencing, luciferase, chromatin immunoprecipitation, and interactome analysis were combined to identify the direct target and corresponding molecular events contributing to BCL6 function. DNA pull-down was applied to identify upstream of BCL6 in the H/R challenge. HIR represses BCL6 expression in vivo and in vitro. Hepatic BCL6 overexpression attenuates inflammation and apoptosis after I/R injury, whereas BCL6 deficiency aggravates I/R-induced liver injury. RNA-sequencing showed that BCL6 modulated nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 inflammasome signaling in HIRI. Mechanistically, BCL6 deacetylated nuclear factor kappa-B p65 lysine 310 by recruiting sirtuin 1 (SIRT1), thereby inhibiting the nuclear factor kappa-B/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 pathway. Moreover, overexpression of SIRT1 blocked the detrimental effects of BCL6 depletion. Moreover, EX 527, a SIRT1 inhibitor, vanished protection from BCL6 overexpression. Furthermore, transcription factor 7 was found to mediate the transcription regulation of BCL6 on H/R challenge. Our results provide the first evidence supporting BCL6 as an important protective agent of HIR. This suggests a potential therapeutic approach for HIR.

Overview

  • The study aims to explore the role and key downstream effects of B-cell lymphoma 6 (BCL6) in hepatic ischemia/reperfusion (HIR) injury.
  • BCL6 expression levels were measured in I/R liver tissue and primary hepatocytes stimulated by hypoxia/reoxygenation (H/R).
  • The study used a combination of in vitro and in vivo experiments to investigate the effect of BCL6 on HIR injury and to identify the downstream molecular events contributing to BCL6 function.

Comparative Analysis & Findings

  • BCL6 overexpression attenuates inflammation and apoptosis after I/R injury, whereas BCL6 deficiency aggravates I/R-induced liver injury.
  • RNA-sequencing showed that BCL6 modulated nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 inflammasome signaling in HIRI.
  • SIRT1, a downstream target of BCL6, was found to play a crucial role in BCL6-mediated protection against HIR injury.

Implications and Future Directions

  • The study provides evidence supporting BCL6 as an important protective agent of HIRI, suggesting a potential therapeutic approach for HIRI.
  • Future studies should investigate the optimal timing and dosage of BCL6 therapy for HIRI.
  • The study highlights the importance of understanding the molecular mechanisms underlying HIRI, and future research should focus on identifying additional therapeutic targets.
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