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

BACKGROUND

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).

METHODS

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.

RESULTS

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.

CONCLUSIONS

Our results provide the first evidence supporting BCL6 as an important protective agent of HIR. This suggests a potential therapeutic approach for HIR.