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Thesis
Dissertation.pdf
(2012)
  • Zhipeng Meng, University of California - San Diego
Abstract
Bile acids promote the processing of dietary fat and regulate glucose homeostasis in liver mainly via its receptor, FXR. In our study, we show that bile acid/FXR signaling also plays an important role in hepatic tissue homeostasis and hepatocarcinogenesis. Either decreased bile acid level or deletion of the FXR gene leads to impaired liver regeneration after carbon tetrachloride-induced liver injury or 70% partial hepatectomy in mice, which indicates that FXR is an essential liver protector by regulating liver cell proliferation and death and promoting tissue repair. We hypothesize that the loss of FXR contributes to hepatocarcinogenesis because of insufficient repair to damaged liver, which induces chronic inflammation and compensatory hepatocyte proliferation. Indeed FXR-/- mice spontaneously develop liver cancer when they are aged due to their chronic liver injury and deregulated repair. In addition, FXR expression is down-regulated in human liver cancer and the hepatocarcinogenesis in FXR-/- mice recapitulates the process of liver cancer initiation and progression in human. Therefore, FXR-/- mice provide a unique animal model to identify or predict more differentially expressed genes in human liver cancer. One liver-rich microRNA, miR-194, which is down-regulated in the liver tumors of FXR-/- mice, is demonstrated to be an important liver epithelial cell marker and prevents cancer metastasis. In conclusion, ablation of FXR increases susceptibility to liver injury and tumorigenesis and the study of FXR will provide novel insights into human liver repair and liver diseases.
Disciplines
Publication Date
2012
Citation Information
Zhipeng Meng. "Dissertation.pdf" (2012)
Available at: http://works.bepress.com/zhipeng-meng/2/