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

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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Molecular Medicine

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Dixon, Laura J.

Contributors dc:contributor

• Nagy, Laura
• Feldstein, Ariel

• Biology
• Biomedical Research
• Cellular Biology
• Pathology
• non-alcoholic steatohepatitis
• innate immunity
• inflammasome
• caspase
• inflammation
• fibrosis
• stellate cell
• kupffer cell
• hepatocyte
• steatosis.

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1355861009

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1355861009