Dysregulated cholesterol homeostasis, caused by lysosomal/autophagy dysfunction, mediates pancreatitis

总结/摘要 急性胰腺炎（AP）是一种发病率和死亡率高且缺乏治疗的疾病。的 溶酶体/自噬途径-细胞消除受损细胞质的关键分解代谢机制 细胞器-在实验性和人类胰腺炎中都受损。此外，遗传变异特别是 靶向自噬或溶酶体导致小鼠自发性胰腺炎。这些发现表明 溶酶体/自噬途径在启动和驱动胰腺炎中的作用。无序化的机制 然而，这些途径导致疾病的原因仍然未知。其他器官和疾病模型的研究 显示了溶酶体/自噬途径在调节胆固醇稳态中的关键作用， 可行性和功能。此外，最近的研究表明，使用降胆固醇药物，他汀类药物， 与AP发病率降低和死亡率降低相关。然而，人们对胆固醇知之甚少 胰腺外分泌代谢及其在胰腺炎中的失调。他汀类药物和其他药物的作用 尚未研究降胆固醇药物对腺泡细胞胆固醇稳态和AP反应的影响。我们 本文提出了胰腺炎发病机制新假说：溶酶体/自噬 功能障碍导致腺泡细胞胆固醇稳态失调，导致线粒体氧化应激 和胰腺炎的病理反应。 我们的初步研究结果表明，临床前模型和人类胰腺炎都与 腺泡细胞中胆固醇稳态的严重失调，以及溶酶体/自噬功能障碍， 与AP相关的一个关键的中介作用，在这些影响。他们进一步显示了胆固醇的作用 疾病严重程度的失调，特别是线粒体氧化应激和炎症。 将在三个具体目标中检验假设： 1）。研究实验性胰腺炎和人类胰腺炎中腺泡细胞胆固醇稳态的失调， 其在胰腺炎反应中的作用。 2）。确定胆固醇失调在溶酶体/自噬破坏引起的胰腺炎中的作用 途径。 3）。研究胆固醇失调在线粒体氧化应激导致炎症中的作用， 胰腺炎 这项拟议中的研究是重要的，因为它将建立胆固醇代谢作为临床相关的 胰腺炎严重程度的调节剂，并确定潜在的分子靶点，适用于药理学 干预，使胆固醇代谢正常化，从而降低胰腺炎的严重程度。特别是要 阐明他汀类药物和其他调胆固醇药物对胰腺炎的作用机制。

Summary/Abstract Acute pancreatitis (AP) is a disorder with significant morbidity and mortality that lacks treatments. The lysosomal/autophagy pathway – a key catabolic mechanism by which cells eliminate damaged cytoplasmic organelles – is impaired in both experimental and human pancreatitis. Further, genetic alterations specifically targeting autophagy or lysosomes cause spontaneous pancreatitis in mice. These findings implicate impaired lysosomal/autophagy pathways in initiating and driving pancreatitis. The mechanisms through which disordering of these pathways causes the disease remain, however, unknown. Studies in other organs and disease models showed a critical role for lysosomal/autophagy pathways in regulating cholesterol homeostasis, essential for cell viability and function. Moreover, recent studies indicate that use of cholesterol-lowering drugs, statins, is associated with lower incidence of AP and decreased mortality. However, there is little known about cholesterol metabolism in the exocrine pancreas and its’ dysregulation in pancreatitis. The effects of statins and other cholesterol-lowering drugs on acinar cell cholesterol homeostasis and AP responses have not been studied. We here propose a novel hypothesis for the pathogenic mechanism of pancreatitis: that lysosomal/autophagy dysfunction causes dysregulation of acinar cell cholesterol homeostasis, leading to mitochondrial oxidative stress and pathologic responses of pancreatitis. Our preliminary results indicate that both preclinical models and human pancreatitis are associated with profound dysregulation of cholesterol homeostasis in acinar cells, and that lysosomal/autophagy dysfunction associated with AP plays a key mediatory role in these effects. They further show the role of cholesterol dysregulation in disease severity, in particular mitochondrial oxidative stress and inflammation. The hypothesis will be tested in three Specific Aims: 1). Investigate dysregulation of acinar cell cholesterol homeostasis in experimental and human pancreatitis and its role in pancreatitis responses. 2). Determine the role of cholesterol dysregulation in pancreatitis caused by disrupted lysosomal/autophagy pathways. 3). Examine the role of cholesterol dysregulation in mitochondrial oxidative stress leading to inflammation in pancreatitis. The proposed research is significant because it will establish cholesterol metabolism as a clinically relevant modulator of pancreatitis severity and identify potential molecular targets, amenable for pharmacologic intervention, to normalize cholesterol metabolism and thus reduce pancreatitis severity. In particular, we will elucidate the mechanisms of the effects of statins and other cholesterol-modulating drugs on pancreatitis.