Linking dysregulated ampk signaling and er stress in ethanol-induced liver injury in hepatic alcohol dehydrogenase deficient deer mice

Bhupendra S. Kaphalia, Mukund P. Srinivasan, Kamlesh K. Bhopale, Samir M. Amer, Jie Wan, Lata Kaphalia, Ghulam S. Ansari

Research output: Contribution to journalArticle

Abstract

Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH-) and ADH normal (ADH+) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH- deer mice fed 3.5% EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH- deer mice fed 3.5% EtOH. Both strains fed 3.5% EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH- deer mice fed 3.5% EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.

Original languageEnglish (US)
Article number560
JournalBiomolecules
Volume9
Issue number10
DOIs
StatePublished - Oct 2019

Fingerprint

Peromyscus
Alcohol Dehydrogenase
Liver
Ethanol
Wounds and Injuries
AMP-Activated Protein Kinases
Endoplasmic Reticulum Stress
Cytochrome P-450 CYP2E1
Transferases
Alanine
Blood
Alcohols
Carnitine O-Palmitoyltransferase
Lipids
Peptide Initiation Factors
Alcoholic Liver Diseases
Lipogenesis
Histology
Cell death
Fatty Liver

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Linking dysregulated ampk signaling and er stress in ethanol-induced liver injury in hepatic alcohol dehydrogenase deficient deer mice. / Kaphalia, Bhupendra S.; Srinivasan, Mukund P.; Bhopale, Kamlesh K.; Amer, Samir M.; Wan, Jie; Kaphalia, Lata; Ansari, Ghulam S.

In: Biomolecules, Vol. 9, No. 10, 560, 10.2019.

Research output: Contribution to journalArticle

@article{135fd38439f447c9bf5f68b8541cf01b,
title = "Linking dysregulated ampk signaling and er stress in ethanol-induced liver injury in hepatic alcohol dehydrogenase deficient deer mice",
abstract = "Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH-) and ADH normal (ADH+) deer mice fed 1{\%}, 2{\%} or 3.5{\%} EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH- deer mice fed 3.5{\%} EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH- deer mice fed 3.5{\%} EtOH. Both strains fed 3.5{\%} EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH- deer mice fed 3.5{\%} EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.",
author = "Kaphalia, {Bhupendra S.} and Srinivasan, {Mukund P.} and Bhopale, {Kamlesh K.} and Amer, {Samir M.} and Jie Wan and Lata Kaphalia and Ansari, {Ghulam S.}",
year = "2019",
month = "10",
doi = "10.3390/biom9100560",
language = "English (US)",
volume = "9",
journal = "Biomolecules",
issn = "2218-273X",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",

}

TY - JOUR

T1 - Linking dysregulated ampk signaling and er stress in ethanol-induced liver injury in hepatic alcohol dehydrogenase deficient deer mice

AU - Kaphalia, Bhupendra S.

AU - Srinivasan, Mukund P.

AU - Bhopale, Kamlesh K.

AU - Amer, Samir M.

AU - Wan, Jie

AU - Kaphalia, Lata

AU - Ansari, Ghulam S.

PY - 2019/10

Y1 - 2019/10

N2 - Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH-) and ADH normal (ADH+) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH- deer mice fed 3.5% EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH- deer mice fed 3.5% EtOH. Both strains fed 3.5% EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH- deer mice fed 3.5% EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.

AB - Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH-) and ADH normal (ADH+) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH- deer mice fed 3.5% EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH- deer mice fed 3.5% EtOH. Both strains fed 3.5% EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH- deer mice fed 3.5% EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.

UR - http://www.scopus.com/inward/record.url?scp=85072924393&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072924393&partnerID=8YFLogxK

U2 - 10.3390/biom9100560

DO - 10.3390/biom9100560

M3 - Article

C2 - 31581705

AN - SCOPUS:85072924393

VL - 9

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 10

M1 - 560

ER -