The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis.

Abstract

Non-alcoholic fatty liver disease is a common liver injury, but the pathophysiological mechanisms leading to the development of non-alcoholic steatohepatitis (NASH) remain unclear. The pathological roles of the nuclear receptor constitutive androstane receptor (CAR), a key regulator of drug-metabolising enzymes, in the development of NASH were investigated. CAR(+/+) and CAR(-/-) mice were given a methionine and choline-deficient (MCD) diet to establish a dietary model of NASH. Increases in serum alanine aminotransferase (ALT) and in infiltration of inflammatory cells were dominant in CAR(+/+) mice at 8 weeks. There was no significant difference in the lipid concentration of the liver - namely, the first hit between CAR(+/+) and CAR(-/-) mice. The index of lipid peroxidation increased in liver of the CAR(+/+) mice, as demonstrated by 8-iso-prostaglandin F2alpha (F2-isoprostanes). Western blotting analysis showed that nuclear translocation of CAR occurred in CAR(+/+) mice fed the MCD diet. As a result, the CAR activation caused the lipid peroxidation - namely, the second hit. The expressions of cytochrome P450 (CYP)2B10, 2C29, 3A11 all increased considerably in the CAR(+/+) mice. Furthermore, alpha smooth muscle actin immunohistochemistry and Sirius red staining showed an increase in the degree of fibrosis in CAR(+/+) mice fed the MCD diet at 16 weeks. The mRNA expressions of collagen alpha1(1) and the tissue inhibitor of metalloproteinase-1 were found to be elevated in CAR(+/+) mice. CAR caused the worsening of the hepatic injury and fibrosis in the dietary model of NASH. Our results suggest that the CAR nuclear receptor may thus play a critical role in the pathogenesis of NASH.