Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by beta-catenin signaling

Although hyperglycemia has been documented as an unfavorable element that can further induce liver ischemia-reperfusion injury (IRI), the related molecular mechanisms remain to be clearly elaborated. This study investigated the effective manner of endoplasmic reticulum (ER) stress signaling in hyperglycemia-exacerbated liver IRI. Here we demonstrated that in the liver tissues and Kupffer cells (KCs) of DM patients and STZ-induced hyperglycemic mice, the ER stress-ATF6-CHOP signaling pathway is activated. TLR4-mediated pro-inflammatory activation was greatly attenuated by the addition of 4-phenylbutyrate (PBA), one common ER stress inhibitor. The liver IRI in hyperglycemic mice was also significantly reduced after PBA treatment. In addition, deficiency of CHOP (CHOP-/-) obviously alleviates the hepatic IRI, and pro-inflammatory effects deteriorated by hyperglycemia. In hyperglycemic mice, beta-catenin expression was suppressed while the ATF6-CHOP signal was activated. In the liver tissues of PBA-treated or CHOP-/- hyperglycemic mice, the expression of beta-catenin was restored. Furthermore, CHOP deficiency can induce protection against hyperglycemia-related liver IRI, which was disrupted by the knockdown of beta-catenin will cause this protection to disappear. High glucose (HG) treatment stimulated ATF6-CHOP signaling, reduced cellular beta-catenin accumulation, and promoted the TLR4-related inflammation of BMDMs. But the above effects were partially rescued in BMDMs with CHOP deficiency or by PBA treatment. In BMDMs cultured in HG conditions, the anti-inflammatory functions of CHOP-/- were destroyed by the knockdown of beta-catenin. Finally, chimeric mice carrying WT or CHOP-/- BMDMs by bone marrow transplantation were adopted to verify the above conclusion. The current study suggested that hyperglycemia could trigger ER stress-ATF6-CHOP axis, inhibit beta-catenin activation, accelerate inflammation, and deteriorate liver IRI, thus providing the treatment potential for management of sterile liver inflammation in DM patients.