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The role of caspase-1 in liver and adipose tissue during metabolic dysregulation in mouse models on NASH

Dixon, Laura J.

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Consumption of high-energy diets and weight gain are associated with development of several metabolic complications such as insulin resistance and hepatic steatosis, a stage within the spectrum of Non-Alcoholic Fatty Liver Disease (NALFD). NAFLD is a common form of chronic liver disease that affects both adults and children. 10-20% of adults have hepatic steatosis, which is characterized by triglyceride (TG) accumulation and typically follows a benign non-progressive clinical course. Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation and cellular damage, inflammation and early to modest fibrosis. The progression of NAFLD to NASH remains incompletely understood. Therefore, dissection of mechanisms responsible for progressing this disease is an important area of investigation. In this thesis, the role of caspase-1, a pro-inflammatory protease, is explored in murine models of diet-induced NASH. Caspase-1 expression and activation is increased after both MCD and high fat diets, and was detected in hepatocyte and non-parenchymal cells. However, after feeding mice the MCD diet, fractionation of the liver further demonstrated an increase of caspase-1 and interleukin-1¿¿ only in the non-parenchymal fraction. Casp1-/- mice on the MCD diet were protected from diet-induced increases in inflammatory markers, such as TNF¿¿ and F4/80, and increases in HSC activation marker, ¿¿SMA and the deposition of collagen-1. These effects were independent of ALT levels, apoptosis and caspase-3 expression. Deletion of macrophages in the liver by clodronate liposomes suppressed caspase-1 activation and demonstrated a protection from MCD-induced inflammation and fibrogenesis, suggesting that caspase-1 in Kupffer cells plays an important role in NASH pathogenesis. Casp1-/- mice on the high fat diet gained less weight than wild type mice, but had greater adiposity. Casp1-/- mice on the high fat diet were protected from hepatic steatosis and TG accumulation, increases in TNF¿¿ and MCP-1, but were not changed for F4/80. Casp1-/- mice on the high fat diet did not have high fat diet-induced ¿¿SMA and collagen-1 deposition, suggesting a protection from early fibrogenesis. Mice deficient in caspase-1 are protected from both MCD and high fat diet-induced NASH, specifically through steatosis, inflammation, and fibrogenesis. These data point to caspase-1 as a potential target for NASH therapy.
Laura Nagy, PhD (Advisor)
Ariel Feldstein, MD (Advisor)
Nizar Zein, MD (Committee Member)
Alex Almasan, PhD (Committee Member)
Amy Hise, MD (Committee Member)
139 p.

Recommended Citations

Citations

  • Dixon, L. J. (2013). The role of caspase-1 in liver and adipose tissue during metabolic dysregulation in mouse models on NASH [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1355861009

    APA Style (7th edition)

  • Dixon, Laura. The role of caspase-1 in liver and adipose tissue during metabolic dysregulation in mouse models on NASH. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1355861009.

    MLA Style (8th edition)

  • Dixon, Laura. "The role of caspase-1 in liver and adipose tissue during metabolic dysregulation in mouse models on NASH." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1355861009

    Chicago Manual of Style (17th edition)