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

Toxicol Appl Pharmacol. 2014 Jan 1;274(1):42-54. doi: 10.1016/j.taap.2013.10.029. Epub 2013 Nov 7.


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.

Keywords: Apoptosis; Bromodichloromethane; CD3; IL-2; Leptin; Lipid peroxidation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD57 Antigens / biosynthesis*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cytochrome P-450 CYP2E1 / deficiency*
  • Cytokines / biosynthesis
  • Environmental Exposure / adverse effects*
  • Fatty Liver / chemically induced
  • Fatty Liver / metabolism*
  • Gene Expression Regulation
  • Inflammation Mediators / metabolism
  • Leptin / deficiency*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease
  • Obesity / chemically induced
  • Obesity / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Trihalomethanes / toxicity


  • CD57 Antigens
  • Cytokines
  • Inflammation Mediators
  • Leptin
  • Trihalomethanes
  • bromodichloromethane
  • Cytochrome P-450 CYP2E1