Alcohol, Retinoids and Pancreas Biology

摘要 我们建议研究长期饮酒如何导致胰腺炎和糖尿病及其作用。 维甲酸(维生素A及其天然代谢物)在这一过程中可能产生的物质。小白鼠将被喂以酒精- 含或等卡路里对照的利伯-德卡利饮食。将在这些小鼠中通过使用 文献中所描述的大剂量的雨蛙素。胰腺的健康和功能，包括内分泌和 外分泌，以及可能的胰腺维甲酸水平和作用的中断，将被评估。我们的研究 将使用野生型小鼠和缺乏胰腺维甲酸储存的诱导突变小鼠模型，卵磷脂： 视黄醇酰基转移酶缺陷(LRAT-/-)小鼠。将被检验的总体假设是慢性酒精 消耗损害胰腺的维甲酸代谢和作用，无论是在胰腺外分泌还是在 胰岛，这些损伤有助于酒精对胰腺疾病和 功能障碍。我们提出了两个具体目标。 在具体目标1中，我们将研究长期饮酒对胰腺的影响，重点是 酒精依赖实验性慢性胰腺炎的关系及其影响 并受到胰腺维甲酸储存的影响。在这里，我们将确定长期饮酒是如何影响 拥有正常胰腺维甲酸储备的小鼠和不具有正常胰腺维甲酸储备的小鼠发生胰腺炎 维甲酸储存在它们的胰腺星状细胞(PSCs)中。因为PSC维甲酸商店的损失与 在胰腺纤维化和胰腺炎的发展过程中，我们期望能直接确立对胰腺的作用 维甲酸储存在延缓或阻止酒精诱导的胰腺疾病的发展中。 在具体目标2中，我们将探讨长期饮酒对胰腺内分泌的影响， 重点关注酒精引起的胰岛功能改变的影响及其机制 与全反式维甲酸(ATRA)信号相关。维甲酸是维持正常血糖所必需的 刺激胰岛β细胞分泌胰岛素。我们的初步数据表明全反式维甲酸的作用 胰岛α细胞分泌胰高血糖素的信号。在这里，我们提议调查 酒精如何导致正常胰腺内分泌功能丧失，以及这是否涉及 正常的ATRA信号。 总而言之，我们提议的研究将扩大对酒精对人的毒性影响的理解 胰腺。

ABSTRACT We are proposing to investigate how chronic alcohol consumption induces pancreatitis and diabetes and the role that retinoids (vitamin A and its natural metabolites) may have in this process. Mice will be fed either the alcohol- containing or the isocaloric control Lieber-DeCarli diet. Pancreatitis will be induced in these mice by the use of high doses of caerulein as described in the literature. Pancreatic health and functions, both endocrine and exocrine, along with possible disruptions of pancreatic retinoid levels and actions, will be assessed. Our studies will employ wild type mice and an induced mutant mouse model that lacks pancreatic retinoid stores, lecithin: retinol acyltransferase-deficient (Lrat-/-) mice. The overall hypothesis that will be tested is that chronic alcohol consumption impairs pancreatic retinoid metabolism and actions, both in the exocrine pancreas and in pancreatic islets, and that these impairments contribute to alcohol's effect on pancreatic disease and dysfunction. We propose 2 Specific Aims. In Specific Aim 1, we will investigate the effects of chronic alcohol consumption on the pancreas, focusing on the relationship between alcohol-dependent experimentally induced chronic pancreatitis and how this influences and is influenced by pancreatic retinoid stores. Here we will identify how chronic alcohol-feeding affects the development of pancreatitis in mice that possess normal pancreatic retinoid stores and in mice that possess no retinoid stores in their pancreatic stellate cells (PSCs). Since the loss of PSC retinoid stores is associated with the development of pancreatic fibrosis and pancreatitis, we expect to establish directly a role for pancreatic retinoid stores in slowing or blocking the development of alcohol-induced pancreatic disease. In Specific Aim 2, we will explore the effects of chronic alcohol consumption on the endocrine pancreas, focusing specifically on the effect of alcohol-induced changes in pancreatic islet functions and how this is associated with all-trans-retinoic acid (ATRA) signaling. ATRA is required for maintaining normal glucose stimulated insulin secretion from the beta-cells of pancreatic islets. Our preliminary data suggest a role for ATRA signaling in glucagon secretion from the alpha-cells of pancreatic islets. Here, we are proposing to investigate how alcohol-induces the loss of normal pancreatic endocrine functions and whether this involves disruption of normal ATRA signaling. Collectively, the research we are proposing will extend understanding of the toxic effects of alcohol on the pancreas.