Gopalakrishnan Natarajan1, Curtis Perriotte-Olson1, Carol A Casey2, Terrence M Donohue2, Geoffrey A Talmon3, Edward N Harris4, Alexander V Kabanov5, Viswanathan Saraswathi6. 1. Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, United States. 2. Department of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE, United States; VA Nebraska-Western Iowa Health Care System, Omaha, NE, United States. 3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States. 4. Department of Biochemistry, University of Nebraska at Lincoln, Lincoln, NE, United States. 5. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. 6. Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, United States; VA Nebraska-Western Iowa Health Care System, Omaha, NE, United States. Electronic address: s.viswanathan@unmc.edu.
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.
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: Erin G Rosenbaugh; James W Roat; Lie Gao; Rui-Fang Yang; Devika S Manickam; Jing-Xiang Yin; Harold D Schultz; Tatiana K Bronich; Elena V Batrakova; Alexander V Kabanov; Irving H Zucker; Matthew C Zimmerman Journal: Biomaterials Date: 2010-04-07 Impact factor: 12.479
Authors: Gopalakrishnan Natarajan; Curtis Perriotte-Olson; Fatema Bhinderwala; Robert Powers; Cyrus V Desouza; Geoffrey A Talmon; Jiang Yuhang; Matthew C Zimmerman; Alexander V Kabanov; Viswanathan Saraswathi Journal: Transl Res Date: 2017-08-15 Impact factor: 7.012
Authors: Thiyagarajan Gopal; Narendra Kumar; Curtis Perriotte-Olson; Carol A Casey; Terrence M Donohue; Edward N Harris; Geoffrey Talmon; Alexander V Kabanov; Viswanathan Saraswathi Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-01-13 Impact factor: 4.052