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

• Published in: Toxicology and applied pharmacology Vol. 274; no. 1; pp. 42 - 54
• Main Authors: Seth, Ratanesh Kumar, Das, Suvarthi, Kumar, Ashutosh, Chanda, Anindya, Kadiiska, Maria B., Michelotti, Gregory, Manautou, Jose, Diehl, Anna Mae, Chatterjee, Saurabh
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-01-2014; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; APOPTOSIS; Biological and medical sciences; BIOLOGICAL MARKERS; Bromodichloromethane; CD3; CD57 Antigens - biosynthesis; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; Cytochrome P-450 CYP2E1 - deficiency; Cytokines - biosynthesis; DIET; Environmental Exposure - adverse effects; Fatty Liver - chemically induced; Fatty Liver - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation; IL-2; Inflammation Mediators - metabolism; LEPTIN; Leptin - deficiency; Lipid peroxidation; LIVER; Liver. Biliary tract. Portal circulation. Exocrine pancreas; LYMPHOCYTES; LYMPHOKINES; Male; Medical sciences; MICE; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; MITOCHONDRIA; Non-alcoholic Fatty Liver Disease; Obesity - chemically induced; Obesity - metabolism; Other diseases. Semiology; OXIDATION; Oxidative Stress - drug effects; Oxidative Stress - physiology; STRESSES; Toxicology; TOXINS; Trihalomethanes - toxicity; TYROSINE; Lipid peroxidation; Bromodichloromethane; IL-2; CD3; Leptin; Apoptosis; Prognosis; Digestive system; Enzyme; Isozyme; Cytochrome P450; Liver; Cytokine; Hepatic disease; Lipids; Adipokine; Interleukin 2; Cell death; Non alcoholic steatohepatitis; Digestive diseases; Environment; Evolution; CD8 T lymphocyte; Peroxidation
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.10.029

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.
•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.