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

摘要/摘要 急性胰腺炎(AP)是一种发病率和死亡率都很高的疾病，缺乏治疗。这个 溶酶体/自噬途径--细胞清除受损胞浆的关键分解代谢机制 细胞器-在实验性胰腺炎和人类胰腺炎中都受到损害。此外，特别是基因改变 靶向自噬或溶酶体会导致小鼠自发性胰腺炎。这些发现牵涉到 溶酶体/自噬途径在胰腺炎的启动和驱动中的作用。无序通过的机制 然而，导致这种疾病的这些途径中，仍不清楚。其他器官和疾病模型的研究 显示溶酶体/自噬途径在调节细胞必需的胆固醇动态平衡中起关键作用 生存能力和功能。此外，最近的研究表明，使用降胆固醇药物他汀类药物 与较低的AP发生率和较低的死亡率相关。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 降胆固醇药物对腺泡细胞胆固醇稳态和AP反应的影响还没有研究。我们 这里对胰腺炎的发病机制提出了一个新的假说：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。 我们的初步结果表明，临床前模型和人类胰腺炎都与 腺泡细胞胆固醇稳态的严重失调，以及溶酶体/自噬功能障碍 AP在这些效应中起着关键的中介作用。它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。 这一假设将在三个具体目标上进行检验： 1)。研究实验性胰腺炎和人胰腺炎腺泡细胞胆固醇稳态失调。 它在胰腺炎反应中的作用。 2)。确定胆固醇失调在溶酶体/自噬破坏所致胰腺炎中的作用 小路。 3)。研究胆固醇失调在线粒体氧化应激导致炎症反应中的作用 胰腺炎。 这项拟议的研究意义重大，因为它将确立胆固醇代谢在临床上的相关性。 胰腺炎严重程度的调节因子和识别潜在的分子靶点，服从于药物 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，我们将 阐明他汀类药物和其他胆固醇调节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.