Over the 4 year funding of this grant (RO1 DK92460) we have made major strides in understanding why acute pancreatitis (AP) presents more often as severe AP (SAP) in obese patients. We discovered that the several pounds of excess triglyceride stored in adipocytes within and around the pancreas can get hydrolyzed by pancreatic lipases during AP in a vicious unregulated phenomenon termed fat necrosis, and release large amounts of unsaturated fatty acids (UFAs). Fat necrosis of SAP has prognostic value unlike the pancreatic lipase independent fat stranding noted in diverticulitis, appendiciti etc. UFAs released from fat necrosis in the pancreas worsen pancreatic necrosis and those from fat surrounding the pancreas cause distant organ (e.g. lung and kidney) injury. UFAs damage via increasing cytosolic calcium and inhibiting mitochondrial complexes I and V. These findings have huge implications regarding how FDA recommendations on fat consumption affect the course of AP, and also offer an avenue to therapeutically target the pathophysiology converting AP->SAP. PRELIMINARY DATA: Human: 1) 22 papers from different countries over the last 25 years show studies from countries consuming less milk (richest source of saturated fat) and more fish (high in UFAs) reported SAP at lower body mass index than vice versa. 2) Necrotic collections from the pancreas of SAP patients have very high concentrations of UFAs, as do the sera of SAP patients. 3) Dietary UFAs enrich in the fat stored during obesity. Basic: 1) Changing the fatty acids supplemented to fat cells or mice correspondingly changes the composition of stored triglyceride, with saturated fatty acids (SFAs) causing a milder AP vs. UFAs 2) Pancreatic lipases (i.e. pancreatic triglyceride lipase; PTL and pancreatic lipase related protein 2; PLRP2) and colipase are enriched in fat necrosis 3) PLRP2 alone can damage adipocyte membranes by its phospholipase activity, potentially giving PTL, colipase access to the triglyceride droplet stored in adipocytes. 4) PTL which forms 80-90% of pancreatic lipase may play a major role in hydrolyzing the triglyceride stored in fat. 5) Colipase is essential for ft necrosis mediated by both PTL and PLRP2. 6) This fat necrosis releases large amounts of cytokines (IL-6 and MCP-1) and free fatty acids. PROPOSAL:
Aim 1 : Study the impact of changing the fatty acids supplemented to adipocytes and mice on the severity of fat necrosis, inflammatory mediator generation, distant cell and organ injury during AP. If SFAs protect, this is a case to present to the FDA.
Aim 2 : A) Study how adipocyte membrane phospholipid affects their susceptibility to the phospholipase activity of PLRP2 causing their death. B) Study if the PLRP2 remaining in PTL-/- mice can cause SAP and fat necrosis, or if this requires PTL. Identifying and Inhibiting the culprit lipase has therapeutic relevance for SAP Aim 3: Establish the role of colipase in fat necrosis and SAP by omitting colipase, using colipase mutants in vitro and obese conditional colipase knockout mice, and immuno-neutralizing colipase during SAP. If effective, colipase neutralization could be a therapy for SAP.

Public Health Relevance

Acute pancreatitis (AP) affects 274,000 persons in the US annually and obesity is a risk for severe AP (SAP) including pancreatic necrosis, kidney, respiratory failure and death. We propose dietary unsaturated fatty acids accumulate in abdominal fat, and their excessive release by pancreatic lipases converts AP?SAP. We aim to understand and inhibit this in SAP and also make a case that the FDA factors this in its diet recommendations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK092460-07
Application #
9106401
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
2011-07-06
Project End
2020-03-31
Budget Start
2016-04-03
Budget End
2017-03-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
de Oliveira, Cristiane; Patel, Krutika; Mishra, Vivek et al. (2016) Characterization and Predictive Value of Near Infrared 2-Deoxyglucose Optical Imaging in Severe Acute Pancreatitis. PLoS One 11:e0149073
Noel, Pawan; Patel, Krutika; Durgampudi, Chandra et al. (2016) Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. Gut 65:100-11
Patel, Krutika; Durgampudi, Chandra; Noel, Pawan et al. (2016) Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis. Am J Pathol 186:874-84
Loverdos, Ines; Swan, Marc C; Shekherdimian, Shant et al. (2015) A case of pancreatitis, panniculitis and polyarthritis syndrome: Elucidating the pathophysiologic mechanisms of a rare condition. J Pediatr Surg Case Rep 3:223-226
Patel, Krutika; Trivedi, Ram N; Durgampudi, Chandra et al. (2015) Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation. Am J Pathol 185:808-19
Acharya, Chathur; Navina, Sarah; Singh, Vijay P (2014) Role of pancreatic fat in the outcomes of pancreatitis. Pancreatology 14:403-8
Patel, Krutika S; Noel, Pawan; Singh, Vijay P (2014) Potential influence of intravenous lipids on the outcomes of acute pancreatitis. Nutr Clin Pract 29:291-4
Scherer, John; Singh, Vijay P; Pitchumoni, C S et al. (2014) Issues in hypertriglyceridemic pancreatitis: an update. J Clin Gastroenterol 48:195-203
Durgampudi, Chandra; Noel, Pawan; Patel, Krutika et al. (2014) Acute lipotoxicity regulates severity of biliary acute pancreatitis without affecting its initiation. Am J Pathol 184:1773-84
Mishra, Vivek; Cline, Rachel; Noel, Pawan et al. (2013) Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium. PLoS One 8:e66471

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