AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis

Abstract public domain (NIH RePORTER)

Abstract Chronic alcohol intake/abuse costing ~250 billion dollars to the US economy and ~100,000 deaths annually is the major cause of chronic pancreatitis (CP). Alcoholic chronic pancreatitis (ACP) is a serious fibro-inflammatory disorder resulting in exocrine insufficiency and such severe co-morbidities as diabetes and pancreatic cancer. Several patients with a history of chronic alcohol use die even before the disease becomes clinically manifested. The exocrine pancreas, which constitutes ~85% of the gland, is a prime target of alcohol toxicity. Although the amount and duration of alcohol consumed are key factors driving pathogenesis of ACP, the mechanism and metabolic basis of ACP are complex and still not well understood. Besides, no effective therapeutics for ACP is available for the clinics. Chronic alcohol (ethanol, EtOH) consumption in humans impairs hepatic alcohol dehydrogenase (ADH) and increases fatty infiltration and formation of fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) in the pancreas. Recently we found that the six-months-old hepatic ADH1 deficient (ADH-) vs. hepatic ADH normal (ADH+) deer mice fed chronic EtOH for 3 months results in exceedingly high body burden of EtOH, dysregulated pancreatic lipid phenotype including elevated levels of FAEEs, lipotoxic inflammation and mimic several fibro-immunological characteristics of ACP. Besides, we found a decreased expression of carnitine palmitoyl transferase (CPT)1A in the pancreatic tissue of chronic EtOH fed ADH- vs. ADH+ deer mice and in EtOH treated human pancreatic acinar cells (hPACs). Similar findings were observed in pancreatic tissue of donors with a premortem diagnosis of ACP. Furthermore, EtOH-induced AMPKα deactivation and reduced expression of CPT1A was attenuated by AMPKα agonist. Therefore, we hypothesize that attenuation of chronic EtOH-induced inhibition of pancreatic CPT1A by AMPKα agonist prevents dysregulated pancreatic lipid phenotype along with formation of FAEEs and associated lipotoxic inflammation, and fibrosis in alcoholic chronic pancreatitis. In aim 1 we will determine if chronic EtOH reduces the expression of pancreatic CPT1A, causes pancreatic injury, dysregulates lipid phenotype, increases the formation of FAEEs and mitochondrial stress in our ADH- deer mouse model. In aim 2 we will determine if EtOH exposure inhibits CPT1A and causes dysregulated lipid phenotype and formation of FAEEs, cytotoxicity and mitochondrial stress in hPACs, in vitro, to establish that exocrine pancreatic acinar cells are the target of EtOH induced toxicity. In both aims, we will measure above mentioned parameters by attenuating the EtOH induced inhibition of CPT1A and AMPKα inactivation by AMPKα agonist. Our project is innovative because we will identify key lipid metabolic pathways/networks involved in dysregulated pancreatic lipid phenotype in ADH- deer mouse model of alcoholic pancreatitis using cutting edge lipidomic approach. Besides, findings of this project are expected to establish a link between pancreatic CPT1A and AMPKα signaling and dysregulated lipid phenotype in pathogenesis of ACP and develop its therapeutics.

Public health relevance public domain (NIH RePORTER)

Project Narrative Although the mechanism of alcoholic chronic pancreatitis (ACP) is not well understood, a dysregulated lipid phenotype along with fatty and inflammatory infiltration are initial events in the development of ACP, a painful fibroinflammatory disorder of the exocrine pancreas. Chronic ethanol fed hepatic alcohol dehydrogenase deficient (ADH-) deer mice mimic such key features of ACP as dysregulated pancreatic lipid phenotype, fatty and inflammatory infiltration, and fibrosis. Therefore, characterizing the ethanol induced dysregulated lipid phenotype in the pancreas of chronic ethanol feeding model of ADH- deer mice and in primary human pancreatic acinar cells treated with ethanol should identify various lipid metabolic pathways and targets involved in pathogenesis of ACP.