The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Issue 4 (1st September 2006)

• Record Type: Journal Article
• Authors: Yamazaki, Yuichi; Kakizaki, Satoru; Horiguchi, Norio; Sohara, Naondo; Sato, Ken; Takagi, Hitoshi; Mori, Masatomo; Negishi, Masahiko
• Is Part Of: Gut. Volume 56:Issue 4(2007)
• Page Start: 565
• Page End: 574
• Publication Date: 2006-09-01
• Subjects: ALT, alanine aminotransferase -- CAR, constitutive androstane receptor -- CYP, cytochrome P450 -- F2-isoprostane, 8-iso-prostaglandin F2α -- iNOS, inducible nitric oxide synthase -- MCD, methionine and choline-deficient -- NASH, non-alcoholic steatohepatitis -- NF-κB, nuclear factor-κB -- 8-OHdG, 8-hydroxy-2′-deoxyguanosine -- RXR, retinoid X receptor -- PXR, pregnane X receptor -- αSMA, α smooth muscle actin -- TCPOBOP, 1, 4 bis[2-(3, 5-dichloropyridyloxy)]benzene -- TNFα, tumour necrosis factor α; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2006.093260
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: 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. Methods and results: 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 F2α (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, α 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 α1(1) and the tissue inhibitor of metalloproteinase-1 were found to be elevated in CAR +/+ mice. Conclusion: 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.