Abstract
Background and Objectives: IL-21R has been implicated in immune functions such as lymphocyte maturation and autoimmune diseases. In this study, we analyzed the involvement of IL-21R in the development of nonalcoholic steatohepatitis (NASH) in order to investigate the life-style-related pathophysiological significance of IL-21R in the liver.
Methods: Six-week-old male C57BL/6J mice, wild-type or IL-21R deficient, were fed with a control diet or a choline-deficient, L-amino acid-defined, high-fat, trans-fat free diet (CDAA HF-T(-)) (45% fat by a shortening without trans fat, methionine 0.1%), for 4 or 13 weeks. A human hepatic stellate cell line, LX-2 was stimulated with TGF-βor IL-21 alone or combined.
Results: In the CDAA-HF-T(-) group, blood alanine aminotransferase (ALT) activity was increased, and in the liver lipid accumulation, inflammation, and fibrosis were developed with overexpression of IL-21 and IL-21R. In the IL-21R-deficient mice, ALT elevation, liver steatosis, and inflammation were induced but inhibited the development of hepatic fibrosis. In association with fibrosis, collagen type 1, 4, SOX9, and CK19 gene expressions and protein levels were elevated in the wild-type mice, and these were suppressed in the IL-21R-deficient mice. In LX-2, TGF-β stimulation increasedαSMA protein, IL-21R gene, and fibrosis-related gene expressions. IL-21 stimulation resulted in a slight increase in αSMA protein expression and a transient increase of collagen type 4 gene expression. Furthermore, combined administration of TGF-β and IL-21 revealed an enhanced effect on LX-2 activation.
Conclusions: In the murine NASH induced by the CDAA-HF-T(-), it is suggested that IL-21R is specifically involved in the progression of hepatic fibrosis, but not hepatic steatosis and inflammation.
