The pancreatic clock is a key determinant of pancreatic fibrosis progression and exocrine dysfunction

Author:

Jiang Weiliang12ORCID,Jin Linzi3,Ju Dapeng45ORCID,Lu Zhanjun12ORCID,Wang Chuanyang12,Guo Xingya12,Zhao Haijiao4ORCID,Shen Shien12,Cheng Zhiyuan12,Shen Jie12,Zong Guanzhao12,Chen Jiahui12,Li Kai12,Yang Lijuan12,Zhang Zhijian6,Feng Yun12,Shen Jia Z.7ORCID,Zhang Eric Erquan4ORCID,Wan Rong12ORCID

Affiliation:

1. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.

2. Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.

3. Department of Emergency, Shanghai Fourth People’s Hospital, Tongji University School of Medicine, Shanghai 200434, China.

4. National Institute of Biological Sciences, Beijing 102206, China.

5. Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 401336, China.

6. Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.

7. Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

Abstract

Chronic pancreatitis (CP) is characterized by progressive fibrosis and exocrine dysregulation, which have long been considered irreversible. As a peripheral oscillator, the pancreas harbors autonomous and self-sustained timekeeping systems in both its endocrine and exocrine compartments, although the role of the latter remains poorly understood. By using different models of CP established in mice with dysfunctional pancreatic clocks, we found that the local clock played an important role in CP pathology, and genetic or external disruption of the pancreatic clock exacerbated fibrogenesis and exocrine insufficiency. Mechanistically, an impaired retinoic acid receptor–related orphan receptor A (Rora)/nuclear receptor subfamily 1, group D, member 1 (Nr1d1)/aryl hydrocarbon receptor nuclear translocator-like (Arntl or Bmal1) loop, called the circadian stabilizing loop, resulted in the deficiency of pancreatic Bmal1, which was responsible for controlling the fibrogenic properties of pancreatic stellate cells (PSCs) and for rewiring the function of acinar cells in a clock–TGF signaling–IL-11/IL-11RA axis–dependent manner. During PSC activation, the antagonistic interaction between Nr1d1 and Rora was unbalanced in response to the loss of cytoplasmic retinoid-containing lipid droplets. Patients with CP also exhibited reduced production of endogenous melatonin. Enhancing the clock through pharmacological restoration of the circadian stabilizing loop using a combination of melatonin and the Rora agonist SR1078 attenuated intrapancreatic pathological changes in mouse models of CP. Collectively, this study identified a protective role of the pancreatic clock against pancreatic fibrosis and exocrine dysfunction. Pancreatic clock–targeted therapy may represent a potential strategy to treat CP.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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