國家衛生研究院 NHRI:Item 3990099045/9718
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    題名: Cisd2 haploinsufficiency leads to non-alcoholic fatty liver disease (NAFLD) and accelerates hepatocarcinogenesis in mice
    作者: Kao, CH;Shen, ZQ;Chen, YF;Tsai, TF
    貢獻者: Institute of Molecular and Genomic Medicine
    摘要: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic steatosis (fatty liver) is a vulnerable factor that could lead to liver damage, inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). However, despite the high prevalence of NAFLD, the genetic factor determining the disease progression remains poorly understood. CISD2 is a previously uncharacterized novel gene located within the overlapping region of HCC critical region and human longevity region on chromosome 4q. We have recently demonstrated for the first time that Cisd2 is a mitochondrial outer membrane protein which mediates mitochondrial integrity and lifespan in mammals. Surprisingly, we have observed phenotype similar to NAFLD in the liver of Cisd2 heterozygous (+/−) knockout mice. Cisd2 haplo-insufficiency led to abnormal lipid metabolism accompanying with fatty liver, cell death, severe inflammation and fibrosis in the liver. Moreover, there was a low incidence (1/18; 5.6%) of HCC developed at 16-18 months of age in the Cisd2+/− mice. Interestingly, our results revealed a significant increase of the Srebp1c which is the master regulator of lipogenesis; the increase in Srebp1-c seems to further up-regulate the expression of its target gene, fatty acid synthase (Fas), in the Cisd2+/− livers. In addition, we found that liver fibrosis was associated with activation of hepatic stellate cells, as revealed by increased expression of α-ΣMA, in the Cisd2+/− livers. Furthermore, we provide evidence that Cisd2 haplo-insufficiency promoted hepatocarcinogenesis and accelerated HCC development by 4-6 months in the transgenic mice expressing HBV X protein. In summary, our results suggested that Cisd2 is likely to be a haplo-insufficient tumor suppressor gene for HCC. Heterozygous deficiency of Cisd2 led to NAFLD, and accelerated the progression of HBV-associated HCC. Our data suggest that Cisd2 is a molecular target for the development of chemoprevention and therapeutic strategy for NAFLD.
    日期: 2012-04
    關聯: Cancer Research. 2012 Apr;72:Abstract number 1332.
    Link to: http://dx.doi.org/10.1158/1538-7445.am2012-1332
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000209701504377
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