Dysregulated cholesterol homeostasis, caused by lysosomal/autophagy dysfunction, mediates pancreatitis

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Summary/Abstract Acute pancreatitis (AP) is a disorder with significant morbidity and mortality that lacks treatments. The lysosomal/autophagy pathway – a key catabolic mechanism by which cells eliminate damaged cytoplasmic organelles – is impaired in both experimental and human pancreatitis. Further, genetic alterations specifically targeting autophagy or lysosomes cause spontaneous pancreatitis in mice. These findings implicate impaired lysosomal/autophagy pathways in initiating and driving pancreatitis. The mechanisms through which disordering of these pathways causes the disease remain, however, unknown. Studies in other organs and disease models showed a critical role for lysosomal/autophagy pathways in regulating cholesterol homeostasis, essential for cell viability and function. Moreover, recent studies indicate that use of cholesterol-lowering drugs, statins, is associated with lower incidence of AP and decreased mortality. However, there is little known about cholesterol metabolism in the exocrine pancreas and its’ dysregulation in pancreatitis. The effects of statins and other cholesterol-lowering drugs on acinar cell cholesterol homeostasis and AP responses have not been studied. We here propose a novel hypothesis for the pathogenic mechanism of pancreatitis: that lysosomal/autophagy dysfunction causes dysregulation of acinar cell cholesterol homeostasis, leading to mitochondrial oxidative stress and pathologic responses of pancreatitis. Our preliminary results indicate that both preclinical models and human pancreatitis are associated with profound dysregulation of cholesterol homeostasis in acinar cells, and that lysosomal/autophagy dysfunction associated with AP plays a key mediatory role in these effects. They further show the role of cholesterol dysregulation in disease severity, in particular mitochondrial oxidative stress and inflammation. The hypothesis will be tested in three Specific Aims: 1). Investigate dysregulation of acinar cell cholesterol homeostasis in experimental and human pancreatitis and its role in pancreatitis responses. 2). Determine the role of cholesterol dysregulation in pancreatitis caused by disrupted lysosomal/autophagy pathways. 3). Examine the role of cholesterol dysregulation in mitochondrial oxidative stress leading to inflammation in pancreatitis. The proposed research is significant because it will establish cholesterol metabolism as a clinically relevant modulator of pancreatitis severity and identify potential molecular targets, amenable for pharmacologic intervention, to normalize cholesterol metabolism and thus reduce pancreatitis severity. In particular, we will elucidate the mechanisms of the effects of statins and other cholesterol-modulating drugs on pancreatitis.