Recent Advances in Understanding the Complexity of Alcohol-Induced Pancreatic Dysfunction and Pancreatitis Development

Abstract

Chronic excessive alcohol use is a well-recognized risk factor for pancreatic dysfunction and pancreatitis development. Evidence from in vivo and in vitro studies indicates that the detrimental effects of alcohol on the pancreas are from the direct toxic effects of metabolites and byproducts of ethanol metabolism such as reactive oxygen species. Pancreatic dysfunction and pancreatitis development are now increasingly thought to be multifactorial conditions, where alcohol, genetics, lifestyle, and infectious agents may determine the initiation and course of the disease. In this review, we first highlight the role of nonoxidative ethanol metabolism in the generation and accumulation of fatty acid ethyl esters (FAEEs) that cause multi-organellar dysfunction in the pancreas which ultimately leads to pancreatitis development. Further, we discuss how alcohol-mediated altered autophagy leads to the development of pancreatitis. We also provide insights into how alcohol interactions with other co-morbidities such as smoking or viral infections may negatively affect exocrine and endocrine pancreatic function. Finally, we present potential strategies to ameliorate organellar dysfunction which could attenuate pancreatic dysfunction and pancreatitis severity.

Differential cytotoxicity, ER/oxidative stress, dysregulated AMPKα signaling, and mitochondrial stress by ethanol and its metabolites in human pancreatic acinar cells

“…Several putative mechanisms of ethanol (EtOH)‐induced pancreatic damage have been reviewed (Apte et al, 2010; Kaphalia & Ansari, 2001; Pandol et al, 2011; Takahashi et al, 2020). Both oxidative metabolism and nonoxidative metabolism of EtOH to acetaldehyde and fatty acid ethyl esters (FAEEs), respectively, and their toxicity to the pancreas have been reported (Apte et al, 2010; Kaphalia & Ansari, 2001; Rasineni et al, 2020; Vonlaufen et al, 2007). While acetaldehyde has been shown to activate pancreatic stellate cells (Apte et al, 2010; McCarroll et al, 2003), FAEEs cause uncoupling of oxidative phosphorylation and induce inflammatory pathways in the pancreatic acinar cells (Criddle et al, 2006; Gukovskaya et al, 2002; Haber et al, 2004).…”

“…Chronic alcohol consumption is the major cause of chronic pancreatitis (CP), a serious fibro‐inflammatory disorder of the exocrine pancreas, and may result in multiple dysfunctions / insufficiencies of the exocrine and endocrine pancreatic gland including diabetes and pancreatic cancer (Rasineni et al, 2020). The risk of developing alcoholic chronic pancreatitis (ACP) is shown to be directly associated with the amount and duration of alcohol intake.…”

Recent insights about autophagy in pancreatitis

“…These cells metabolise alcohol through oxidative and non-oxidative pathways. 76 107 108 Alcohol dehydrogenase catalyses the oxidative pathway of alcohol metabolism, leading to the production of acetaldehyde and increased reactive oxygen species (ROS), which are highly toxic. The isoform 2 of aldehyde dehydrogenase, found in mitochondria, further metabolises acetaldehyde to acetate.…”

Pathophysiological Consequences of At-Risk Alcohol Use; Implications for Comorbidity Risk in Persons Living With Human Immunodeficiency Virus

“…The principal mechanisms underlying alcohol addiction, alcohol-induced organ injury, and alcohol-related liver injury have been extensively reviewed ( Molina et al, 2014b ; Massey et al, 2015 ; Aberg et al, 2020 ; Arab et al, 2020 ; Maddur and Shah, 2020 ; Rasineni et al, 2020 ; Koob, 2021 ; Osna et al, 2021 ). Here we focus on salient mechanisms of alcohol-induced risk and exacerbation of CMS and neuropathological comorbidities and discuss their implications in the context of HIV infection and their role in exacerbating or accelerating development of associated comorbidities in PLWH.…”