Deoxyarbutin attenuates severe acute pancreatitis via the HtrA2/PGC-1α pathway

Abstract

Severe acute pancreatitis (SAP) is an inflammatory disorder of the exocrine pancreas associated with high morbidity and mortality. SAP has been proven to trigger mitochondria dysfunction in the pancreas. We found that Deoxyarbutin (dA) recovered impaired mitochondrial function. High-temperature requirement protein A2 (HtrA2), a mitochondrial serine protease upstream of PGC-1α, is charge of quality control in mitochondrial homeostasis. The molecular docking study indicated that there was a potential interaction between dA and HtrA2. However, whether the protective effect of dA against SAP is regulated by HtrA2/PGC-1α remains unknown. Our study in vitro showed that dA significantly reduced the necrosis of primary acinar cells and reactive oxygen species (ROS) accumulation, recovered mitochondrial membrane potential (ΔΨm) and ATP exhaustion, while UCF-101 (HtrA2 inhibitor), and SR-18292 (PGC-1α inhibitor) eliminated the protective effect of dA. Moreover, HtrA2 siRNA transfection efficiently blocked the protective of dA on HtrA2/PGC-1α pathway in 266-6 acinar cells. Meanwhile, dA also decreased LC3II/I ration, as well as p62, and increased Parkin expression, while UCF-101 and Bafilomycin A1 (autophagy inhibitor) reversed the protective effect of dA. Our study in vivo confirmed that dA effectively alleviated severity of SAP by reducing pancreatic edema, plasma amylase, and lipase levels and improved the HtrA2/PGC-1α pathway. Therefore, this is the first study to identify that dA inhibits pancreatic injury caused by oxidative stress, mitochondrial dysfunction, and impaired autophagy in a HtrA2/PGC-1α dependent manner.

Keywords:

• Deoxyarbutin
• severe acute pancreatitis
• high-temperature requirement protein A2
• PGC-1α
• mitochondria

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant [number 81973580 and 81803866]; the COVID-19 Science and Technology Emergency Project of Sichuan Province of China under Grant [number 2021YFS0408]; the Key Technology Research and Development Program of Sichuan Province of China under Grant [number 2022YFS0425 and 2022YFS0426]; Innovative Chinese Medicine and Health Products Research Academician Workstation of Academician Boli Zhang and Academician Beiwei Zhu, West China Hospital, Sichuan University under Grant [number HXYS19001 and HXYS19002]; 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan Universtiy under Grant [number ZYXY21002]; and Innovative Chinese Medicine Preclinical Research Fund of ‘Liqing No. 2′,West China Hospital, Sichuan University under Grant [number 161200012].