Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Non-alcoholic fatty liver disease (NAFLD) pathogenesis is linked to excessive reactive oxygen species (ROS).
• Brahma related gene 1 (BRG1) deletion has been shown to mitigate NAFLD by reducing ROS production in hepatocytes.

Purpose of the Study:

• To investigate the mechanism by which BRG1 deletion affects ROS production in hepatocytes.
• To elucidate the role of tank binding kinase 1 (TBK1) and its regulation by BRG1 in ROS homeostasis.

Main Methods:

• Investigated the effect of BRG1 deletion on TBK1 expression and phosphorylation in vivo and in vitro.
• Analyzed the interaction of BRG1 with transcription factors AP-1 and Sp1 to regulate TBK1 and c-SRC.
• Utilized overexpression and depletion strategies for TBK1 and c-SRC to assess their impact on ROS production.

Main Results:

• BRG1 deletion led to decreased expression and phosphorylation of TBK1.
• BRG1 directly activated TBK1 transcription via AP-1 and promoted TBK1 phosphorylation through Sp1-mediated c-SRC activation.
• Restoring c-SRC and TBK1 expression reversed ROS deficiency in BRG1-null hepatocytes, while their depletion reduced ROS.

Conclusions:

• BRG1 plays a dual role in regulating TBK1 activity at both transcriptional and post-transcriptional levels.
• This dual regulation by BRG1 is a key mechanism contributing to excessive ROS production in hepatocytes.
• Targeting BRG1-TBK1 pathway may offer a therapeutic strategy for NAFLD.