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具有潜在的致命性，并且发病率正在增加，导致重大的医疗负担和费用。肥胖与严重的AP相关。AP在第一周后的死亡率是由于严重的胰腺坏死及其相关并发症，这给了治疗窗口期。然而，目前的护理包括保守管理和治疗其并发症。人类严重的胰腺坏死与脂肪坏死一起发生，这是由游离脂肪酸皂化和脂肪因子升高引起的。这些是疾病的附带现象还是病因尚不清楚。初步数据：为了研究肥胖相关的AP加重，我们检查了对照和胰腺炎患者尸检的胰腺组织学。我们注意到两组胰腺内脂肪（IPF）随BMI的增加而增加。AP患者脂肪坏死明显多于对照组，并伴有周围腺泡坏死，随着离脂肪坏死距离的增加，腺泡坏死减少。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，并伴有纤维化，其隔离了脂肪坏死，限制了脂肪周围的腺泡损伤。为了从机制上理解这一点，我们建立了一个新的腺泡-脂肪细胞共培养系统。当脂肪酶抑制剂奥利司他存在时，腺泡细胞和脂肪细胞在这种培养基中单独或共同发挥正常功能，奥利司他不存在导致腺泡几乎完全坏死，如碘化丙啶摄取、ATP水平下降和LC3-II缺失增加所证明的那样。与此同时，培养基中脂肪酸和甘油的含量大幅增加，其水平相当于人类严重胰腺坏死的吸入物。奥利司他在培养基中防止腺泡死亡和脂解，并恢复再纯化腺泡对刺激的反应性，类似于对照腺泡。个别情况下，严重胰腺坏死患者吸出的不饱和脂肪酸（不饱和脂肪酸）水平增加了腺泡胞质钙，并引起细胞色素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加重胰腺损伤。我们建议研究脂肪酸和脂肪因子在腺泡损伤和炎症中的相对作用。我们还建议确定导致腺泡损伤的脂肪酶。我们还将比较肥胖与有纤维化和无纤维化的分离性IPF对AP严重程度的影响的相关性。这些研究可以通过靶向特定脂肪酶和根据成像研究中IPF的发现根据严重AP的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。