We are proposing to investigate how chronic alcohol consumption induces pancreatitis and diabetes and the role that retinoids (vitamin A and its natural metabolites) may have in this process. Mice will be fed either the alcohol- containing or the isocaloric control Lieber-DeCarli diet. Pancreatitis will be induced in these mice by the use of high doses of caerulein as described in the literature. Pancreatic health and functions, both endocrine and exocrine, along with possible disruptions of pancreatic retinoid levels and actions, will be assessed. Our studies will employ wild type mice and an induced mutant mouse model that lacks pancreatic retinoid stores, lecithin: retinol acyltransferase-deficient (Lrat-/-) mice. The overall hypothesis that will be tested is that chronic alcohol consumption impairs pancreatic retinoid metabolism and actions, both in the exocrine pancreas and in pancreatic islets, and that these impairments contribute to alcohol's effect on pancreatic disease and dysfunction. We propose 2 Specific Aims.
In Specific Aim 1, we will investigate the effects of chronic alcohol consumption on the pancreas, focusing on the relationship between alcohol-dependent experimentally induced chronic pancreatitis and how this influences and is influenced by pancreatic retinoid stores. Here we will identify how chronic alcohol-feeding affects the development of pancreatitis in mice that possess normal pancreatic retinoid stores and in mice that possess no retinoid stores in their pancreatic stellate cells (PSCs). Since the loss of PSC retinoid stores is associated with the development of pancreatic fibrosis and pancreatitis, we expect to establish directly a role for pancreatic retinoid stores in slowing or blocking the development of alcohol-induced pancreatic disease.
In Specific Aim 2, we will explore the effects of chronic alcohol consumption on the endocrine pancreas, focusing specifically on the effect of alcohol-induced changes in pancreatic islet functions and how this is associated with all-trans-retinoic acid (ATRA) signaling. ATRA is required for maintaining normal glucose stimulated insulin secretion from the beta-cells of pancreatic islets. Our preliminary data suggest a role for ATRA signaling in glucagon secretion from the alpha-cells of pancreatic islets. Here, we are proposing to investigate how alcohol-induces the loss of normal pancreatic endocrine functions and whether this involves disruption of normal ATRA signaling. Collectively, the research we are proposing will extend understanding of the toxic effects of alcohol on the pancreas.
Alcohol abuse is a significant public health problem. We propose to test the hypothesis that chronic alcohol consumption impairs both the exocrine and the endocrine functions of the pancreas and that this impairment arises in part from alcohol's disruptive effects on vitamin A homeostasis and actions in the pancreas. Our research, upon completion, will provide new understanding of the role of vitamin A in preventing the development of alcohol-induced chronic pancreatitis and diabetes.
