2005 Fiscal Year Final Research Report Summary
The involvement of lipid signaling to the onset and progression of nonalcoholic steatohepatitis and the development of hepatocellular carcinoma
| Project/Area Number |
16590574
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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 | Akita University |
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Principal Investigator |
HORIE Yasuo Akita University, School of Medicine, lecturer, 医学部, 講師 (30282164)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Sumio Akita University, School of Medicine, Professor, 医学部, 教授 (20138225)
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| Project Period (FY) |
2004 – 2005
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| Keywords | nonalcoholic steatohepatitis / PTEN / gene-mutated mice / inflammation / carcinogenesis / lipopolysaccharide / osteopontin / oxidative stress |
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| Research Abstract |
In the livers of 10-week-old hepatocyte-specific Pten deficient (Pten deficient) mice, hepatocytes around the central vein contains lipid droplets. By 40 weeks, Pten deficient livers show ballooning hepatocytes, Mallory bodies, lobular inflammatory cells infiltration, mild sinusoidal fibrogenic changes, and adenoma as well as fatty changes of increased severity throughout the hepatic lobules. Hepatocellular carcinomas develop in Pten deficient mice livers by 78 weeks of age. These histological findings and natural course of hepatic lesions are strikingly similar to those reported for nonalcoholic steatohepatitis (NASH) in humans. Thus, Pten deficient mice are thought to be an animal model of human NASH.
PTEN deficiency induces the activation of PI3 kinase in hepatocytes, resulting in the increased expression of PPARγ and SREBP1c that are famous nuclear transcriptional factors. The activation of these nuclear factors enhance the expression of their downstream molecules such as aP2, adips
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in, adiponectin, SCD1, fatty acid synthetase, and acyl-CoA carboxylase and then promote the synthesis of triglyceride in hepatocytes, resulting in the fatty livers. We consider that the increased expression of β-oxidation-promoting enzymes such as acyl-CoA oxidase, L-PBE, and PTL in hepatocytes possessing excessive lipid droplets produces oxidative stress that injuries themselves, resulting in hepatitis. The hypersensitivity of Pten deficient livers to LPS derived from intestinal bacteria also contributes to the onset and exacerbation of hepatitis. Oxidative DNA damage induced by excessive oxidative stress in the Pten deficient livers and increased proliferation of Pten deficient hepatocytes based on the activation of Akt and MAPK contribute to the tumor development. The increase of oleic acid and the decrease of stearic acid in the Pten deficient livers are also related to the tumor formation. Moreover, we carried out cDNA microarray using RNA derived from Pten deficient and wild type hepatocytes to find the candidate genes related to the progression of inflammation, fibrosis, and carcinogenesis in the Pten deficient livers. As a result, it was suggested that osteopontin, a cytokine that activates Th1 cells, played an important role in the development of the hepatic lesions of Pten deficient mice.
The immunohiostological analysis of hepatocellular carcinoma and non-cancerous lesion derived from human NASH suggested that decreased expression of PTEN and accumulation of oxidative stress were related to the development of NASH containing carcinogenesis in humans. These findings suggest that hepatic lesions in some of human NASH develop based on the same mechanisms as those seen in Pten deficient livers as described above. Less
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Research Products
(12 results)
