The pancreatic clock is a key determinant of pancreatic fibrosis progression and exocrine dysfunction
The pancreatic clock is a key determinant of pancreatic fibrosis progression and exocrine dysfunction
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胰腺时钟是胰腺纤维化进展和外分泌功能障碍的关键决定因素
DOI：
10.1126/scitranslmed.abn3586
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发表时间：
2022-09-28
影响因子：
17.1
通讯作者：
Wan，Rong
中科院分区：
文献类型：
--
作者：
Jiang，Weiliang;Jin，Linzi;Wan，Rong
慢性胰腺炎(CP)以进行性纤维化和外分泌失调为特征，长期以来被认为是不可逆转的。作为一种外周振荡器，胰腺在内分泌和外分泌两个部分都有自主和自我维持的计时系统，尽管后者的作用仍然知之甚少。通过建立不同的胰钟功能障碍小鼠CP模型，我们发现局部时钟在CP的病理过程中起着重要的作用，而胰腺时钟的遗传或外部破坏加剧了纤维化和外分泌不足。从机制上讲，维甲酸受体相关的孤儿受体A(RORA)/核受体亚家族1，D组成员1(Nr1d1)/芳香烃受体核转位器样(ARNTL或BMAL1)环被称为昼夜稳定环，导致胰腺BMal1的缺失，它负责控制胰腺星状细胞(PSCs)的纤维化特性，并以时钟-转化生长因子信号-IL-11/IL-11RA轴依赖的方式重新连接腺泡细胞的功能。在PSC激活过程中，Nr1d1和RORA之间的拮抗作用是不平衡的，以响应细胞质中含有维甲酸的脂滴的丢失。CP患者还表现出内源性褪黑素的减少。使用褪黑激素和RORA激动剂SR1078的组合，通过药物恢复昼夜节律稳定环来增强时钟，减轻慢性胰腺炎小鼠模型的胰腺内病变。总而言之，这项研究确定了胰腺时钟对胰腺纤维化和外分泌功能障碍的保护作用。胰腺时钟靶向治疗可能是治疗CP的一种潜在策略。
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.