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Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver.
Am J Physiol Gastrointest Liver Physiol. 2020 03 01; 318(3):G428-G438.AJ

Abstract

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.

Authors+Show Affiliations

Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska.Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska.Department of Biochemistry, University of Nebraska Lincoln, Lincoln, Nebraska.Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31928222

Citation

Gopal, Thiyagarajan, et al. "Nanoformulated SOD1 Ameliorates the Combined NASH and Alcohol-associated Liver Disease Partly Via Regulating CYP2E1 Expression in Adipose Tissue and Liver." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 318, no. 3, 2020, pp. G428-G438.
Gopal T, Kumar N, Perriotte-Olson C, et al. Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver. Am J Physiol Gastrointest Liver Physiol. 2020;318(3):G428-G438.
Gopal, T., Kumar, N., Perriotte-Olson, C., Casey, C. A., Donohue, T. M., Harris, E. N., Talmon, G., Kabanov, A. V., & Saraswathi, V. (2020). Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver. American Journal of Physiology. Gastrointestinal and Liver Physiology, 318(3), G428-G438. https://doi.org/10.1152/ajpgi.00217.2019
Gopal T, et al. Nanoformulated SOD1 Ameliorates the Combined NASH and Alcohol-associated Liver Disease Partly Via Regulating CYP2E1 Expression in Adipose Tissue and Liver. Am J Physiol Gastrointest Liver Physiol. 2020 03 1;318(3):G428-G438. PubMed PMID: 31928222.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver. AU - Gopal,Thiyagarajan, AU - Kumar,Narendra, AU - Perriotte-Olson,Curtis, AU - Casey,Carol A, AU - Donohue,Terrence M,Jr AU - Harris,Edward N, AU - Talmon,Geoffrey, AU - Kabanov,Alexander V, AU - Saraswathi,Viswanathan, Y1 - 2020/01/13/ PY - 2020/1/14/pubmed PY - 2020/8/4/medline PY - 2020/1/14/entrez KW - AALD KW - catalase KW - cytochrome P450 2E1 KW - ethanol KW - superoxide dismutase SP - G428 EP - G438 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 318 IS - 3 N2 - Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/31928222/Nanoformulated_SOD1_ameliorates_the_combined_NASH_and_alcohol_associated_liver_disease_partly_via_regulating_CYP2E1_expression_in_adipose_tissue_and_liver_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00217.2019?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -