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 »
- Authors:
-
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States)
- Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States)
- Division of Gastroenterology, Duke University, Durham, NC 27707 (United States)
- 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}
}