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.


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 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.


CONCLUSIONS
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.
Yamazaki
Yuichi
Y
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Kakizaki
Satoru
S
Horiguchi
Norio
N
Sohara
Naondo
N
Sato
Ken
K
Takagi
Hitoshi
H
Mori
Masatomo
M
Negishi
Masahiko
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight; D002796:Choline Deficiency / Q000150:complications; D000090702:Constitutive Androstane Receptor; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014178:Translocation, Genetic
D000090702:Constitutive Androstane Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D008715:Methionine; D000410:Alanine Transaminase