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Title: CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis

Abstract

Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8 + CD57 + cytotoxic T cells but not CD4 + CD57 + cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lowermore » in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8 + CD57 + T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH. - Highlights: • Metabolic oxidative stress caused increased levels of hepatic CD57 expression. • CD8+ CD57+ cytotoxic T cells were decreased in mice lacking CYP2E1 and leptin. • There was a significant increase in T cell cytokines in toxin-treated mice. • Apoptosis was significantly lower in leptin and Pfp/Rag2 KO mice. • Leptin mediated CD8+CD57+ T cells play an important role in NASH.« less

Authors:
;  [1];  [2];  [1];  [2];  [3];  [4];  [3];  [1]
  1. Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States)
  2. Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States)
  3. Division of Gastroenterology, Duke University, Durham, NC 27707 (United States)
  4. Dept. of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States)
Publication Date:
OSTI Identifier:
22285555
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 274; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; BIOLOGICAL MARKERS; DIET; LEPTIN; LIVER; LYMPHOCYTES; LYMPHOKINES; MICE; MITOCHONDRIA; OXIDATION; STRESSES; TOXINS; TYROSINE

Citation Formats

Seth, Ratanesh Kumar, Das, Suvarthi, Kumar, Ashutosh, Chanda, Anindya, Kadiiska, Maria B., Michelotti, Gregory, Manautou, Jose, Diehl, Anna Mae, and Chatterjee, Saurabh. CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2013.10.029.
Seth, Ratanesh Kumar, Das, Suvarthi, Kumar, Ashutosh, Chanda, Anindya, Kadiiska, Maria B., Michelotti, Gregory, Manautou, Jose, Diehl, Anna Mae, & Chatterjee, Saurabh. CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis. United States. https://doi.org/10.1016/J.TAAP.2013.10.029
Seth, Ratanesh Kumar, Das, Suvarthi, Kumar, Ashutosh, Chanda, Anindya, Kadiiska, Maria B., Michelotti, Gregory, Manautou, Jose, Diehl, Anna Mae, and Chatterjee, Saurabh. 2014. "CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis". United States. https://doi.org/10.1016/J.TAAP.2013.10.029.
@article{osti_22285555,
title = {CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis},
author = {Seth, Ratanesh Kumar and Das, Suvarthi and Kumar, Ashutosh and Chanda, Anindya and Kadiiska, Maria B. and Michelotti, Gregory and Manautou, Jose and Diehl, Anna Mae and Chatterjee, Saurabh},
abstractNote = {Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8 + CD57 + cytotoxic T cells but not CD4 + CD57 + cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8 + CD57 + T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH. - Highlights: • Metabolic oxidative stress caused increased levels of hepatic CD57 expression. • CD8+ CD57+ cytotoxic T cells were decreased in mice lacking CYP2E1 and leptin. • There was a significant increase in T cell cytokines in toxin-treated mice. • Apoptosis was significantly lower in leptin and Pfp/Rag2 KO mice. • Leptin mediated CD8+CD57+ T cells play an important role in NASH.},
doi = {10.1016/J.TAAP.2013.10.029},
url = {https://www.osti.gov/biblio/22285555}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 274,
place = {United States},
year = {Wed Jan 01 00:00:00 EST 2014},
month = {Wed Jan 01 00:00:00 EST 2014}
}