Obesity related pancreatic fat worsens local injury via unsaturated fatty acids

肥胖相关的胰腺脂肪通过不饱和脂肪酸加剧局部损伤

• 批准号: 8158687
• 负责人: Vijay Prem Singh
• 金额: $ 34.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8158687
• 关键词: Acinar Cell; Acinus organ component; Acute Necrotizing Pancreatitis; Adipocytes; Affect; Aspirate substance; Autopsy; Body fat; Calcium; Calcium Signaling; Caring; Cell Culture Techniques; Cell Death; Cessation of life; Coculture Techniques; Cytochromes; Data; Disease; Drops; Exhibits; Exposure to; Extravasation; Fat necrosis; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Figs - dietary; Generations; Glycerol; Healthcare; Histologic; Histology; Human; Image; In Vitro; Incidence; Inflammation; Inflammation Mediators; Injury; Learning; Lipase; Lipolysis; Mediating; Mediator of activation protein; Modeling; Mus; Necrosis; Nonesterified Fatty Acids; Obese Mice; Obesity; Organ failure; Pancreas; Pancreatic Injury; Pancreatitis; Patients; Pattern; Physiological; Play; Propidium Diiodide; Publishing; Relative (related person); Risk; Risk Factors; Role; Sampling; Saturated Fatty Acids; Severities; Stimulus; Stratification; Supportive care; System; Therapeutic; United States; Unsaturated Fatty Acids; Visceral; Work; X-Ray Computed Tomography; acute pancreatitis; adipokines; base; care burden; cell injury; cell type; chronic pancreatitis; cost; drug development; frontier; in vivo; inhibitor/antagonist; mortality; mouse model; novel; novel therapeutics; orlistat; overexpression; prevent; research study; uptake

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).

描述（由申请人提供）：急性胰腺炎在严重时可能致命，发病率增加，导致巨大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坏死及其相关并发症引起的，因此可以治疗窗户期。但是，护理目前包括保守的管理及其并发症的治疗。人类严重的胰腺坏死发生在脂肪坏死中，这是由于游离脂肪酸的皂化以及脂肪因子升高而导致的。这些是该疾病中的epiphenomenon还是因果关系。初步数据：为了研究这种与肥胖相关的AP加重，我们检查了对照和胰腺炎患者尸检的胰腺组织学。我们注意到两组中BMI的癌间脂肪（IPF）量增加。在AP患者中，与对照组相比，脂肪坏死明显更多，伴随着周围的腺泡坏死，随着与脂肪坏死的距离的增加，脂肪坏死。这种肥胖腺泡坏死造成了总腺泡坏死的一半。相比之下，患有慢性胰腺炎患者的IPF似乎与BMI无关，伴有纤维化，纤维化使脂肪坏死堵塞，限制了毛毛脂肪毒素的损害。为了理解这一机械，我们生成了一种新型的腺泡脂肪细胞共培养系统。 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增加。这伴随着培养基中脂肪酸和甘油的大量增加，水平与人类严重胰腺坏死的吸入物中的水平相当。培养基中的Orlistat防止了腺泡死亡和脂解，并恢复了与对照ACINI相似的刺激的重新抗性刺激的反应性。单独的，不饱和但不是饱和的脂肪酸在患有严重胰腺坏死患者的抽吸物中存在的水平上增加了腺泡胞质钙，并导致细胞色素c泄漏和细胞死亡。因此，我们假设与肥胖相关的癌间脂肪通过局部脂解产生的不饱和脂肪酸通过胰腺损伤恶化。 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。我们还建议鉴定脂肪酶导致腺泡损伤。我们还将比较肥胖与具有和没有纤维化的孤立IPF的相关性，其对AP的严重程度的影响。这些研究可以通过针对特定的脂肪酶来为这种毁灭性疾病打开新的治疗领域，并根据IPF成像研究的发现，根据严重AP的风险对患者进行分层。 公共卫生相关性：急性胰腺炎可能致命，不可预测的严重，发病率增加，导致巨大的医疗保健负担和费用（每年30万患者和30亿美元），但没有具体的治疗。肥胖与严重的AP有关。我们的初步数据表明，与肥胖相关的癌间脂肪通过局部脂肪分解（脂解）恶化了AP。我们提出的研究可以通过防止脂肪分解来帮助治疗这种毁灭性疾病，并有助于预测基于成像研究中癌间脂肪的严重AP的患者（例如CT扫描）。