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

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  • Additional Information
    • Source:
      Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 7707242 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-0277 (Electronic) Linking ISSN: 01456008 NLM ISO Abbreviation: Alcohol Clin Exp Res Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford, UK : Wiley-Blackwell
      Original Publication: New York, N.Y. : Grune & Stratton, c1977-
    • Subject Terms:
      Acinar Cells/*drug effects ; Central Nervous System Depressants/*pharmacology ; Endoplasmic Reticulum Stress/*drug effects ; Ethanol/*pharmacology ; Mitochondria/*drug effects ; Oxidative Stress/*drug effects ; Pancreas/*cytology; AMP-Activated Protein Kinase Kinases/drug effects ; AMP-Activated Protein Kinase Kinases/metabolism ; AMP-Activated Protein Kinases/drug effects ; AMP-Activated Protein Kinases/metabolism ; Acetaldehyde/pharmacology ; Acetyl-CoA Carboxylase/drug effects ; Acetyl-CoA Carboxylase/metabolism ; Acinar Cells/metabolism ; Carnitine O-Palmitoyltransferase/drug effects ; Carnitine O-Palmitoyltransferase/metabolism ; Cell Survival/drug effects ; Esters/pharmacology ; Humans ; Mitochondria/metabolism ; Mitogen-Activated Protein Kinase 1/drug effects ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/drug effects ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinase 8/drug effects ; Mitogen-Activated Protein Kinase 8/metabolism ; Mitogen-Activated Protein Kinase 9/drug effects ; Mitogen-Activated Protein Kinase 9/metabolism
    • Abstract:
      Background: Alcoholic chronic pancreatitis (ACP) is a serious inflammatory disorder of the exocrine pancreatic gland. A previous study from this laboratory showed that ethanol (EtOH) causes cytotoxicity, dysregulates AMPKα and ER/oxidative stress signaling, and induces inflammatory responses in primary human pancreatic acinar cells (hPACs). Here we examined the differential cytotoxicity of EtOH and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters; FAEEs) metabolites in hPACs was examined to understand the metabolic basis and mechanism of ACP.
      Methods: We evaluated concentration-dependent cytotoxicity, AMPKα inactivation, ER/oxidative stress, and inflammatory responses in hPACs by incubating them for 6 h with EtOH, acetaldehyde, or FAEEs at clinically relevant concentrations reported in alcoholic subjects using conventional methods. Cellular bioenergetics (mitochondrial stress and a real-time ATP production rate) were determined using Seahorse XFp Extracellular Flux Analyzer in AR42J cells treated with acetaldehyde or FAEEs.
      Results: We observed concentration-dependent increases in LDH release, inactivation of AMPKα along with upregulation of ACC1 and FAS (key lipogenic proteins), downregulation of p-LKB1 (an oxidative stress-sensitive upstream kinase regulating AMPKα) and CPT1A (involved in β-oxidation of fatty acids) in hPACs treated with EtOH, acetaldehyde, or FAEEs. Concentration-dependent increases in oxidative stress and ER stress as measured by GRP78, unspliced XBP1, p-eIF2α, and CHOP along with activation of p-JNK1/2, p-ERK1/2, and p-P38MAPK were present in cells treated with EtOH, acetaldehyde, or FAEEs, respectively. Furthermore, a significant decrease was observed in the total ATP production rate with subsequent mitochondrial stress in AR42J cells treated with acetaldehyde and FAEEs.
      Conclusions: EtOH and its metabolites, acetaldehyde and FAEEs, caused cytotoxicity, ER/oxidative and mitochondrial stress, and dysregulated AMPKα signaling, suggesting a key role of EtOH metabolism in the etiopathogenesis of ACP. Because oxidative EtOH metabolism is negligible in the exocrine pancreas, the pathogenesis of ACP could be attributable to the formation of FAEEs and related pancreatic acinar cell injury.
      (© 2021 by the Research Society on Alcoholism.)
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    • Grant Information:
      R01 AA025850 United States AA NIAAA NIH HHS; R21 AA024699 United States AA NIAAA NIH HHS; AA25850 United States AA NIAAA NIH HHS; AA24699 United States AA NIAAA NIH HHS
    • Contributed Indexing:
      Keywords: AMPKα; ER stress; acetaldehyde; alcoholic pancreatitis; fatty acid ethyl esters; human pancreatic acinar cells
    • Accession Number:
      0 (Central Nervous System Depressants)
      0 (Esters)
      3K9958V90M (Ethanol)
      EC 2.3.1.21 (CPT1A protein, human)
      EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
      EC 2.7.1.24 (Mitogen-Activated Protein Kinase 9)
      EC 2.7.11.1 (STK11 protein, human)
      EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
      EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
      EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
      EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
      EC 2.7.11.31 (AMP-Activated Protein Kinases)
      EC 6.4.1.2 (ACACA protein, human)
      EC 6.4.1.2 (Acetyl-CoA Carboxylase)
      GO1N1ZPR3B (Acetaldehyde)
    • Publication Date:
      Date Created: 20210310 Date Completed: 20211220 Latest Revision: 20220503
    • Publication Date:
      20231215
    • Accession Number:
      PMC8544284
    • Accession Number:
      10.1111/acer.14595
    • Accession Number:
      33690904