AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis

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 eficient (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. DH+ 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 AMPKa deactivation and reduced expression of CPT1A was attenuated by AMPKa agonist. Therefore, we hypothesize that attenuation of chronic EtOH-induced inhibition of pancreatic CPT1A by AMPKa agonist prevents dysregulated pancreatic lipid phenotype along with formation of FAEEs and associated lipotoxic inflammation, and fibrosis in alcoholic chronic pancreatitis.