2007 Fiscal Year Final Research Report Summary
The role of nuclear receptor CAR in the pathogenesis of non-alcoholic Steatohepatitis
| Project/Area Number |
18590716
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Gunma University |
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Principal Investigator |
KAKIZAKI Satoru Gunma University, School of Medicine, Associate professor (80344935)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHINARI Kouichi Tohoku University, Graduate School of Pharmaceutical Sciences, Lecturer (60343399)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Non alcoholic steatohepatitis / Nuclear receptor / CAR / cytochrome P450 |
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| Research 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 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. 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.
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[Journal Article] Primary liver cancers with nonalcoholic steatohepatitis2007
Author(s)
Hashizume H, Sato K, Takagi H, Hirokawa T, Kojima A, Sohara N, Kakizaki S, Mochida Y, Shimura T, Sunose Y, Ohwada S, Mori M.
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Journal Title
Eur J Gastroenterol Hepatol 19
Pages: 827-34
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Adult onset type II citrullinemia as a cause of non-alcoholic steatohepatitis2006
Author(s)
Takagi H, Hagiwara S, Hashizume H, Kanda D, Sato K, Sohara N, Kakizaki S, Takahashi H, Mori M, Kaneko H, Ohwada S, Ushikai M, Kobayashi K, Saheki T.
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Journal Title
J Hepatol 44
Pages: 236-9
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Clinicopathological analyses of nine cases of primary liver cancers with nonalcoholic steatohepatitis2006
Author(s)
Hashizume H, Toyoda M, Katakai K, Arai T, Sato K, Kojima A, Hirokawa T, Sohara N, Kakizaki S, Takagi H, Mori M, Mochida Y, Shimura T, Sunose Y, Kawate S, Ohwada S.
Organizer
The 42nd annual meeting of Japanese Society of Hepatology
Place of Presentation
Kyoto
Year and Date
20060525-26
Description
「研究成果報告書概要(欧文)」より
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