TY - JOUR
T1 - Activation of AMP-activated protein kinase attenuates ethanol-induced ER/oxidative stress and lipid phenotype in human pancreatic acinar cells
AU - Srinivasan, Mukund P.
AU - Bhopale, Kamlesh K.
AU - Caracheo, Anna A.
AU - Amer, Samir M.
AU - Khan, Shamis
AU - Kaphalia, Lata
AU - Loganathan, Gopalakrishnan
AU - Balamurugan, Appakalai N.
AU - Kaphalia, Bhupendra S.
N1 - Funding Information:
This work is supported by grants AA24699 and AA25850 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAAA/NIH. The authors sincerely thank Kentucky Organ Donor Affiliates (KODA) for the supply of human pancreas. We also thank the islet isolation team members of Dr. A.N. Balamurugan.
Funding Information:
This work is supported by grants AA24699 and AA25850 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAAA /NIH. The authors sincerely thank Kentucky Organ Donor Affiliates (KODA) for the supply of human pancreas. We also thank the islet isolation team members of Dr. A.N. Balamurugan.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/10
Y1 - 2020/10
N2 - Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved β-oxidation of fatty acids). These cells also showed significant ER stress as evidenced by the increased expression for GRP78, IRE1α, and PERK/CHOP arm of unfolded protein response promoting apoptosis and activating p-JNK1/2 and p-ERK1/2 with increased secretion of cytokines. AR42J cells treated with EtOH showed increased oxidative stress, impaired mitochondrial biogenesis, and decreased ATP production rate. However, AMPKα activation by AICAR attenuated EtOH-induced ER/oxidative stress, lipogenesis, and inflammatory responses as well as the formation of FAEEs and restored mitochondrial function in hPACs as well as AR42J cells. Therefore, it is likely that EtOH-induced inactivation of AMPKα plays a crucial role in acinar cell injury leading to pancreatitis. Findings from this study also suggest that EtOH-induced inactivation of AMPKα is closely related to ER/oxidative stress and synthesis of FAEEs, as activation of AMPKα by AICAR attenuates formation of FAEEs, ER/oxidative stress and lipogenesis, and improves inflammatory responses and mitochondrial bioenergetics.
AB - Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved β-oxidation of fatty acids). These cells also showed significant ER stress as evidenced by the increased expression for GRP78, IRE1α, and PERK/CHOP arm of unfolded protein response promoting apoptosis and activating p-JNK1/2 and p-ERK1/2 with increased secretion of cytokines. AR42J cells treated with EtOH showed increased oxidative stress, impaired mitochondrial biogenesis, and decreased ATP production rate. However, AMPKα activation by AICAR attenuated EtOH-induced ER/oxidative stress, lipogenesis, and inflammatory responses as well as the formation of FAEEs and restored mitochondrial function in hPACs as well as AR42J cells. Therefore, it is likely that EtOH-induced inactivation of AMPKα plays a crucial role in acinar cell injury leading to pancreatitis. Findings from this study also suggest that EtOH-induced inactivation of AMPKα is closely related to ER/oxidative stress and synthesis of FAEEs, as activation of AMPKα by AICAR attenuates formation of FAEEs, ER/oxidative stress and lipogenesis, and improves inflammatory responses and mitochondrial bioenergetics.
KW - AMPKα
KW - Alcoholic pancreatitis
KW - ER stress
KW - Fatty acid ethyl esters
KW - Human pancreatic acinar cells
KW - Mitochondrial stress
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UR - http://www.scopus.com/inward/citedby.url?scp=85091219182&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2020.114174
DO - 10.1016/j.bcp.2020.114174
M3 - Article
C2 - 32717227
AN - SCOPUS:85091219182
SN - 0006-2952
VL - 180
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
M1 - 114174
ER -