Defective endoplasmic reticulum stress response via X box-binding protein 1 is a major cause of poor liver regeneration after partial hepatectomy in mice with non-alcoholic steatohepatitis

Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Poor regeneration after hepatectomy in NAFLD is well recognized, but the mechanism is unclear. Endoplasmic reticulum (ER) stress plays an important role in the development of NAFLD. Here, we show that an impaired ER stress response contributes to poor liver regeneration in partially hepatectomized mice.
Methods
Non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) was induced in mice using our patented feed and 70% partial hepatectomy (PH) was performed. Mice were sacrificed 0, 4, 8, 24, or 48 hours, or 7 days after PH, and liver regeneration and the mRNA expression of ER stress markers were assessed.
Results
NAFLD activity score was calculated as 4–6 points for NAFL and 7 points for NASH. NASH was characterized by inflammation and high ER stress marker expression before PH. After PH, NASH mice showed poorer liver regeneration than controls. High expression of proinflammatory cytokine genes was present in NASH mice 4 hours after PH. Xbp1-s mRNA expression was high in control and NAFL mice after PH, but no higher in NASH mice.
Conclusions
Dysfunction of the ER stress response might be a cause of poor liver regeneration in NASH.

内容要旨・審査要旨・論文本文の公開
本論文は，著者Katsuki Miyazakiの学位論文として提出され，学位審査・授与の対象となっている。
This is the peer reviewed version of the following article: Miyazaki, K., Saito, Y.,Ichimura-Shimizu, M., Imura, S., Ikemoto, T., Yamada, S., Tokuda, K., Morine, Y., Tsuneyama, K., Shimada, M., (2022), Defective endoplasmic reticulum stress response via X box-binding protein 1 is a major cause of poor liver regeneration after partial hepatectomy in mice with non-alcoholic steatohepatitis. Journal of Hepato-Biliary-Pancreatic Sciences, 29, 12, 1241-1252., which has been published in final form at https://doi.org/10.1002/jhbp.1142. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.