Exp Mol Med.  2017 Nov;49(11):e392. 10.1038/emm.2017.156.

Piperidylmethyloxychalcone improves immune-mediated acute liver failure via inhibiting TAK1 activity

• Park SH
• Kwak JA
• Jung SH
• Ahn B
• Cho WJ
• Yun CY
• Na CS
• Hwang BY
• Hong JT
• Han SB
• Kim Y

• KMID: 2396797
• DOI: http://doi.org/10.1038/emm.2017.156

Abstract

Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF. Post treatment with PMOC sequentially ameliorated hepatic inflammation, apoptosis of hepatocytes, severe liver injury and shock-mediated death in ALF-induced mice. As a mechanism, PMOC inhibited the catalytic activity of TGF-β-activated kinase 1 (TAK1) in a competitive manner with respect to ATP, displaced fluorescent ATP probe from the complex with TAK1, and docked at the ATP-binding active site on the crystal structure of TAK1. Moreover, PMOC inhibited TAK1 auto-phosphorylation, which is an axis in the activating pathways of nuclear factor-κB (NF-κB) or activating protein 1 (AP1), in the liver with ALF in vivo or in primary liver cells stimulated with TLR agonists in vitro. PMOC consequently suppressed TAK1-inducible NF-κB or AP1 activity in the inflammatory injury, an early pathogenesis leading to ALF. The results suggested that PMOC could contribute to the treatment of TLR/MyD88-associated ALF with the ATP-binding site of TAK1 as a potential therapeutic target.

MeSH Terms

Adenosine Triphosphate
Animals
Apoptosis
Catalytic Domain
Chalcone
Death, Sudden
Escherichia coli
Hepatocytes
In Vitro Techniques
Inflammation
Liver
Liver Failure, Acute*
Mice
Myeloid Differentiation Factor 88
Phosphotransferases
Plants, Medicinal
Toll-Like Receptors
Adenosine Triphosphate
Chalcone
Myeloid Differentiation Factor 88
Phosphotransferases
Toll-Like Receptors