Obesity related pancreatic fat worsens local injury via unsaturated fatty acids

描述（由申请人提供）：急性胰腺炎在严重时可能致命，并且发病率正在增加，导致显著的医疗保健负担和成本。肥胖与严重的AP有关。第一周后AP的死亡率是由于严重的胰腺坏死及其相关并发症造成的，这使得有一个治疗窗口期。然而，目前的护理包括保守管理和治疗其并发症。人的严重胰腺坏死伴随着脂肪坏死，这是由于游离脂肪酸沿着脂肪因子升高而发生的。这些是疾病的附带现象还是因果关系尚不清楚。初步数据：为了研究肥胖相关的AP恶化，我们检查了对照组和胰腺炎患者尸检的胰腺组织学。我们注意到两组中胰腺内脂肪（IPF）的量随着BMI的增加而增加。在AP患者中，与对照组相比，有更多的脂肪坏死，这是伴随着周围的腺泡坏死，随着距离脂肪坏死的增加而减少。脂肪周围腺泡坏死约占总腺泡坏死的一半。相比之下，慢性胰腺炎患者的IPF似乎与BMI无关，伴有纤维化，从而阻止脂肪坏死，限制脂肪周围腺泡损伤。为了从机理上理解这一点，我们产生了一种新的腺泡-脂肪细胞共培养系统。虽然腺泡和脂肪细胞在脂肪酶抑制剂奥利司他存在下单独和一起在该培养基中正常发挥作用，但奥利司他的缺失导致几乎全部腺泡坏死，如碘化丙啶摄取、ATP水平下降和LC 3-II增加的缺乏所证明的。这伴随着培养基中脂肪酸和甘油的大量增加，其水平相当于人类严重胰腺坏死的吸出物中的水平。培养基中的奥利司他防止了腺泡死亡和脂解，并恢复了再纯化腺泡对类似于对照腺泡的刺激的反应。个别而言，严重胰腺坏死患者抽吸物中存在的不饱和但不饱和脂肪酸水平增加了腺泡胞质钙，并导致细胞色素C渗漏和细胞死亡。因此，我们假设肥胖相关的胰腺内脂肪通过局部脂肪分解产生的不饱和脂肪酸而导致胰腺损伤。 我们建议研究脂肪酸和脂肪因子对腺泡损伤和炎症的相对贡献。我们还建议确定脂肪酶（S）负责腺泡损伤。我们还将比较肥胖与伴有和不伴有纤维化的孤立性IPF的相关性，以了解其对AP严重程度的影响。这些研究可以通过靶向特定的脂肪酶并根据基于IPF影像学研究结果的重度AP风险对患者进行分层，为这种毁灭性疾病开辟新的治疗前沿。 公共卫生相关性：急性胰腺炎具有潜在的致命性，不可预测的严重性，发病率增加，导致显著的医疗保健负担和成本（每年30万患者和30亿美元），但没有特异性治疗。肥胖与严重的AP有关。我们的初步数据表明，肥胖相关的胰腺内脂肪通过局部脂肪分解（脂解）使AP发生。我们提出的研究可以通过预防脂肪分解来帮助治疗这种毁灭性的疾病，并根据成像研究（例如CT扫描）的胰腺内脂肪来帮助预测有严重AP风险的患者。

DESCRIPTION (provided by applicant): Acute Pancreatitis is potentially lethal when severe and is increasing in incidence, resulting in significant health care burden and costs. Obesity is associated with severe AP. Mortality from AP after the first week results from severe pancreatic necrosis and its associated complications, allowing a therapeutic window period. However, care currently consists of conservative management and treatment of its complications. Severe pancreatic necrosis in humans occurs with fat necrosis, which results from the saponification of free fatty acids along with elevated adipokines. Whether these are an epiphenomenon or causal in the disease is unknown. PRELIMINARY DATA: To study this obesity-associated exacerbation of AP, we examined pancreas histology from autopsies of controls and patients with pancreatitis. We noted an increase in the amount of intrapancreatic fat (IPF) with BMI in both groups. In AP patients, there was significantly more fat necrosis compared with controls, which was accompanied by surrounding acinar necrosis, which decreased with increasing distance from the fat necrosis. This peri-fat acinar necrosis contributed to about half of the total acinar necrosis. In contrast, IPF in patients with chronic pancreatitis seemed unrelated to BMI, was accompanied by fibrosis, which walled off fat necrosis, limiting peri-fat acinar damage. To understand this mechanistically, we generated a novel acinar-adipocyte co-culture system. While acini and adipocytes functioned normally in this medium both individually and together in the presence of the lipase inhibitor orlistat, omission of orlistat resulted in near total acinar necrosis, as evidenced by propidium iodide uptake, drop in ATP levels, and absence of LC3-II increase. This was accompanied by a large increase in fatty acids and glycerol in the medium, with levels equivalent to those in aspirates from severe pancreatic necrosis in humans. Orlistat in the medium prevented acinar death and lipolysis and restored responsiveness of repurified acini to stimuli similar to control acini. Individually, unsaturated but not saturated fatty acids at levels present in aspirates from patients with severe pancreatic necrosis increased acinar cytosolic calcium and caused cytochrome C leakage and cell death. We therefore hypothesize that obesity-associated intrapancreatic fat worsens pancreatic injury via unsaturated fatty acids generated from local lipolysis. We propose to study the relative contribution of fatty acids and adipokines to acinar injury and inflammation. We additionally propose to identify the lipase(s) responsible for acinar injury. We will also compare the relevance of obesity to isolated IPF with and without fibrosis with regard to its impact on the severity of AP. These studies could open a new therapeutic frontier for this devastating disease by targeting specific lipases(s) and by stratifying patients according to risk of severe AP based on findings of IPF on imaging studies. PUBLIC HEALTH RELEVANCE: Acute Pancreatitis is potentially lethal, unpredictably severe, increasing in incidence, resulting in significant health care burden and costs (300,000 patients and $3 billion annually), but has no specific treatment. Obesity is associated with severe AP. Our preliminary data show that obesity-associated intrapancreatic fat worsens AP via local fat breakdown (lipolysis). Our proposed studies could help treat this devastating disease by preventing lipolysis and help predict patients at risk of severe AP based on intrapancreatic fat on imaging studies (e.g. CT scan).