Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease

Apr 15, 2020Free radical biology & medicine

Oroxylin A may reduce liver cell damage in alcoholic liver disease by boosting energy regulation and blocking harmful mitochondrial molecules

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Abstract

Oroxylin A may alleviate alcoholic liver disease by suppressing hepatocyte pyroptosis through a specific cellular pathway.

Oroxylin A suppressed hepatocyte pyroptosis via the NLRP3 inflammasome-dependent pathway.
The treatment reduced reactive oxygen species (ROS) accumulation, inhibiting NLRP3 inflammasome activation.
Oroxylin A upregulated mitofusin 2 (Mfn2), which helped resist lipid deposition and overproduction of mitochondria-derived ROS.
Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) was identified as an upstream factor that promotes Mfn2 transcription when treated with oroxylin A.

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BACKGROUND: It is well acknowledged that alcoholic liver disease (ALD) is widely prevalent all over the world, characterized by aberrant lipid deposition and excessive oxidative stress in hepatocytes. Recently, pyroptosis, a new type of programmed cell death, has been found in ALD, which provides new ideas for the treatment of ALD.

METHODS: Male ICR mice were treated with the Lieber-De-Carli diet (Dyets) or isocaloric liquid diet for 8 weeks, and binge alcohol model was also used for ALD. Blood and livers were taken to evaluate the efficacy of oroxylin A. The levels of factors related to hepatocyte pyroptosis were measured via western blot analyses, immunofluorescence analyses and quantitative reverse transcriptase in vitro.

RESULT: Our study found that oroxylin A suppressed hepatocyte pyroptosis through a NLRP3 inflammasome dependent-canonical caspase-1 pathway. Results illuminated that oroxylin A inhibited NLRP3 inflammasome activation by reducing ROS accumulation. Furthermore, oroxylin A upregulated mitofusin 2 (Mfn2) to resist lipid deposition and mitochondria-derived ROS overproduction. As an upstream mediator of Mfn2, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a major regulator of mitochondria, was found to promote transcription of Mfn2 under oroxylin A treatment.

CONCLUSION: Our research revealed that oroxylin A could alleviate ALD via PGC-1α/Mfn2 signaling mediated canonical pyroptosis pathway resistance.

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Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease

Abstract

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