Article Text

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


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.

  • ALT, alanine aminotransferase
  • CAR, constitutive androstane receptor
  • CYP, cytochrome P450
  • F2-isoprostane, 8-iso-prostaglandin F
  • 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

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.