Acute Lipotoxicity Regulates Severity of Biliary Acute Pancreatitis without Affecting Its Initiation

Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O–positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate–induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction.The mystique of acute pancreatitis (AP) lies in its diverse origins, unpredictable course, and outcomes, ranging from resolution with minimal care to being a debilitating, protracted, and potentially lethal condition despite intensive care and complex interventions to manage its complications. The course AP takes seems unrelated to the origin in most cases, with differences in the predominant origin of AP reported in studies from different countries.^1–5 However, studies have repeatedly reported a higher body mass index (BMI) or obesity to be associated with severe AP (SAP).^1–8 SAP may result from severe pancreatic necrosis, in which >30% of the pancreas is necrosed,^9,10 or from persistent or multisystem organ failure, such as respiratory and renal failure. Obese patients have been reported to be more prone to both these types of complications of AP.¹⁻⁸In contrast to the clinical scenario, conventional animal models of AP differ in the initiating factor used, and the severity associated with these has been attributed to the inciting stimulus^11–13 or species in which the model has been executed.^12–15 For example, rat intraductal bile salt–induced pancreatitis has been classified as severe in contrast to the caerulein model, which is mild.^12,13 Interestingly, caerulein-induced AP is milder in rats than in mice, which have more pancreatic necrosis, and thus mouse caerulein pancreatitis is classified as severe.^14,15 However, in both these cases, the pancreas returns to normal a few days after cessation of the insult, with no residual necrotic areas or organ failure. On the basis of such models, a potential target is regarded as therapeutically relevant if it plays a role in mechanistically dissimilar models of AP. An example of this is phosphatidylinositol 3-kinases and associated trypsin generation,^11,16,17 which we and others have previously found to be relevant to AP of different causes.^11,16,17This discord (ie, the lack of association of outcomes to cause as noted clinically) and how animal models are interpreted have resulted in serious discrepancies between what is predicted to be beneficial in animal models of AP and the success of such interventions in clinical trials. The failure of serine protease and trypsin inhibition to improve outcomes of AP in >70 clinical trials performed during the last 5 decades is a classic example.^18–27Recently, the mechanistic proof of obesity being a modifier of AP outcomes has emerged, with the same model being mild in lean mice and severe in obese mice, associated with an exaggerated inflammatory response and mortality.²⁸ Our recent studies have found that lipolysis of visceral fat in obese mice may contribute to this severity.²⁹ However, obesity is also associated with a baseline proinflammatory state,^30–32 and because fatty acids (FAs) are proinflammatory,^29,33,34 it has yet to be decided whether short-term generation of FAs by the lipolysis of visceral fat or the preexistent inflammatory state associated with obesity determines the severity of AP in these models.We therefore analyzed human postpancreatitis necrotic collections (PPNCs) for the nature of FAs in them. We also noted the most common cause of AP in our patients. Because biliary AP was the most common type of AP and unsaturated FAs (UFAs) were abundant in PPNCs, we studied whether their acute lipolytic generation in rats, which are otherwise normal, results in the severe outcomes noted in SAP and whether inhibition of such lipolysis, using 2 distinct lipase inhibitors separately, alters the initiation of AP or the parameters of its severity. Interestingly, we realize that the beneficial effect of lipase inhibition, which decreases the generation of UFAs, is independent of the initiation of biliary AP. These findings have relevance to how we design and interpret animal models of AP in the context of human disease.