{"id":{"repo_id":"ohiolink","oai_identifier":"oai:etd.ohiolink.edu:case1355861009"},"canonical_url":"https://search.dev.ndltd.org/etd/ohiolink/oai:etd.ohiolink.edu:case1355861009","repository":{"repo_id":"ohiolink","name":"OhioLINK","base_url":"https://etd.ohiolink.edu/acprod/odb_etd/ws/oai/oai"},"display":{"title":"The role of caspase-1 in liver and adipose tissue during metabolic dysregulation in mouse models on NASH","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Dixon, Laura J."],"institution":"Case Western Reserve University School of Graduate Studies","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Molecular Medicine","degree_department":null,"school":null,"contributors":["Nagy, Laura","Feldstein, Ariel"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-03-07","date_published":"2013-03-07","updated_at":"2026-07-24T03:35:52Z","subjects":["Biology","Biomedical Research","Cellular Biology","Pathology","non-alcoholic steatohepatitis","innate immunity","inflammasome","caspase","inflammation","fibrosis","stellate cell","kupffer cell","hepatocyte","steatosis."],"languages":["English"],"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."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://rave.ohiolink.edu/etdc/view?acc_num=case1355861009","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Nagy, Laura","Feldstein, Ariel"]},{"key":"dc:creator","label":"Author","values":["Dixon, Laura J."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013-03-07"]},{"key":"dc:publisher","label":"Institution","values":["Case Western Reserve University School of Graduate Studies / OhioLINK"]},{"key":"dc:type","label":"Dc Type","values":["Electronic Thesis or Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Molecular Medicine"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Case Western Reserve University School of Graduate Studies"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biology","Biomedical Research","Cellular Biology","Pathology","non-alcoholic steatohepatitis","innate immunity","inflammasome","caspase","inflammation","fibrosis","stellate cell","kupffer cell","hepatocyte","steatosis."]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]},{"key":"dc:rights","label":"Dc Rights","values":["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."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://rave.ohiolink.edu/etdc/view?acc_num=case1355861009"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","p.139","9.22 MB"]},{"key":"dc:title","label":"Title","values":["The role of caspase-1 in liver and adipose tissue during metabolic dysregulation in mouse models on NASH"]}]}],"canonical_facts":{"dc:contributor":["Nagy, Laura","Feldstein, Ariel"],"dc:creator":["Dixon, Laura J."],"dc:date":["2013-03-07"],"dc:description":["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."],"dc:format":["application/pdf","p.139","9.22 MB"],"dc:identifier":["http://rave.ohiolink.edu/etdc/view?acc_num=case1355861009"],"dc:language":["English"],"dc:publisher":["Case Western Reserve University School of Graduate Studies / OhioLINK"],"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."],"dc:subject":["Biology","Biomedical Research","Cellular Biology","Pathology","non-alcoholic steatohepatitis","innate immunity","inflammasome","caspase","inflammation","fibrosis","stellate cell","kupffer cell","hepatocyte","steatosis."],"dc:title":["The role of caspase-1 in liver and adipose tissue during metabolic dysregulation in mouse models on NASH"],"dc:type":["Electronic Thesis or Dissertation"],"thesis:degree_discipline":["Molecular Medicine"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["Case Western Reserve University School of Graduate Studies"]},"updated_at":"2026-07-24T03:35:52Z"}