I kappa B zeta regulates the development of nonalcoholic fatty liver disease through the attenuation of hepatic steatosis in mice

I kappa B zeta is a transcriptional regulator that augments inflammatory responses from the Toll-like receptor or interleukin signaling. These innate immune responses contribute to the progression of nonalcoholic fatty liver disease (NAFLD); however, the role of I kappa B zeta in the pathogenesis of NAFLD remains elusive. We investigated whether I kappa B zeta was involved in the progression of NAFLD in mice. We generated hepatocyte-specific I kappa B zeta-deficient mice (Alb-Cre; Nfkbiz(fl/fl)) by crossing Nfkbiz(fl/fl) mice with Alb-Cre transgenic mice. NAFLD was induced by feeding the mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). CDAHFD-induced I kappa B zeta expression in the liver was observed in Nfkbiz(fl/fl) mice, but not in Alb-Cre; Nfkbiz(fl/fl) mice. Contrary to our initial expectation, I kappa B zeta deletion in hepatocytes accelerated the progression of NAFLD after CDAHFD treatment. Although the increased expression of inflammatory cytokines and apoptosis-related proteins by CDAHFD remained unchanged between Nfkbiz(fl/fl) and Alb-Cre; Nfkbiz(fl/fl) mice, early-stage steatosis of the liver was significantly augmented in Alb-Cre; Nfkbiz(fl/fl) mice. Overexpression of I kappa B zeta in hepatocytes via the adeno-associated virus vector attenuated liver steatosis caused by the CDAHFD in wild-type C57BL/6 mice. This preventive effect of I kappa B zeta overexpression on steatosis was not observed without transcriptional activity. Microarray analysis revealed a correlation between I kappa B zeta expression and the changes of factors related to triglyceride biosynthesis and lipoprotein uptake. Our data suggest that hepatic I kappa B zeta attenuates the progression of NAFLD possibly through the regulation of the factors related to triglyceride metabolism.