Effect of nanoformulated copper/zinc superoxide dismutase on chronic ethanol-induced alterations in liver and adipose tissue.

Abstract

BACKGROUND:

We previously reported that nanoformulated copper/zinc superoxide dismutase (Nano) attenuates non-alcoholic fatty liver disease and adipose tissue (AT) inflammation in obese animals. Here, we sought to determine whether Nano treatment attenuates alcohol-associated liver disease (AALD) and AT inflammation in alcohol-fed mice.

METHODS:

We pre-treated E-47 cells (HepG2 cells that over-express CYP2E1) with native- or nano-superoxide dismutase (SOD) for 6 h, followed by treatment with ethanol and/or linoleic acid (LA), a free fatty acid. For in vivo studies, male C57BL/6 mice were fed the Lieber-DeCarli control or ethanol liquid diet for 4 weeks. The mice received Nano once every 2 days during the last 2 weeks of ethanol feeding.

RESULTS:

Our in vitro studies revealed that Nano pretreatment reduced LA + ethanol-induced oxidative stress in E-47 cells. Our in vivo experiments showed that ethanol-fed Nano-treated mice had 22% lower hepatic triglyceride levels than mice fed ethanol alone. Nano-treated ethanol-fed mice also had 2-fold lower levels of Cd68 and similarly reduced levels of Ccl2 and Mmp12 mRNAs, than in untreated ethanol-fed mice. We also noted that ethanol feeding caused a remarkable increase in hepatic and/or plasma MCP-1 and CCR2 protein, which was blunted in ethanol + Nano-treated animals. The hepatic content of SREBP-1c, a transcription factor that promotes lipogenesis, was higher in ethanol-fed mice than controls but was attenuated in ethanol + Nano-treated animals. Further, livers of ethanol + Nano-treated mice had significantly higher levels of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) than both control and ethanol-fed mice. In AT, the levels of Il6 mRNA, a hepatoprotective cytokine, and that of Arg1, a marker of anti-inflammatory macrophages, were significantly increased in ethanol + Nano-treated mice compared with control mice.

CONCLUSION:

Our data indicate that Nano treatment attenuates ethanol-induced steatohepatitis and that this effect is associated with an apparent activation of AMPK signaling. Our data also suggest that Nano induces Arg1 and Il6 expression in AT, suggesting anti-inflammatory effects in this tissue.

• Authors: Gopalakrishnan Natarajan, Curtis Perriotte-Olson, Carol A Casey, Terrence M Donohue Jr, Geoffrey A Talmon, Edward N Harris, Alexander V Kabanov, Viswanathan Saraswathi
• Journal: Alcohol (Fayetteville, N.Y.) (Alcohol) Vol. 79 Pg. 71-79 (09 2019) ISSN: 1873-6823 [Electronic] United States
• PMID: 30611703 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD68 protein, mouse
• Ccl2 protein, mouse
• Ccr2 protein, mouse
• Chemokine CCL2
• Free Radical Scavengers
• Receptors, CCR2
• Sterol Regulatory Element Binding Protein 1
• Ethanol
• Cytochrome P-450 CYP2E1
• Superoxide Dismutase
• Protein Kinases
• AMP-Activated Protein Kinase Kinases
• Matrix Metalloproteinase 12
• matrix metallopeptidase 12, mouse

Topics

• AMP-Activated Protein Kinase Kinases
• Adipose Tissue (drug effects)
• Animals
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Chemokine CCL2 (metabolism)
• Cytochrome P-450 CYP2E1 (genetics)
• Drug Compounding
• Ethanol (adverse effects)
• Free Radical Scavengers (pharmacology)
• Gene Expression
• Hep G2 Cells
• Humans
• Inflammation (enzymology)
• Lipid Metabolism
• Liver (drug effects)
• Liver Diseases, Alcoholic (enzymology)
• Male
• Matrix Metalloproteinase 12 (metabolism)
• Mice
• Mice, Inbred C57BL
• Nanostructures
• Oxidative Stress
• Protein Kinases (metabolism)
• Receptors, CCR2 (metabolism)
• Sterol Regulatory Element Binding Protein 1 (metabolism)
• Superoxide Dismutase (pharmacology)