{"id":{"repo_id":"wfu","oai_identifier":"oai:wakespace.lib.wfu.edu:10339/39014"},"canonical_url":"https://search.dev.ndltd.org/etd/wfu/oai:wakespace.lib.wfu.edu:10339/39014","repository":{"repo_id":"wfu","name":"Wake Forest University","base_url":"https://wakespace.lib.wfu.edu/oai/request"},"display":{"title":"IMPACT OF HEPATIC APOLIPOPROTEIN A-IV EXPRESSION ON VLDL PARTICLE EXPANSION, TRIGLYCERIDE SECRETION, AND STEATOSIS","abstract":"Several apolipoproteins (apo) can impact triglyceride (TG) transport by modulating VLDL assembly and secretion. Here we explore the impact of apoA-IV on VLDL particle expansion. Previous studies demonstrated that apoA-IV expression promotes apoB lipoprotein-mediated TG secretion in transfected enterocytes and hepatoma cells. We therefore examined the impact of apoA-IV expression on VLDL particle dynamics in stably transfected McA-RH7777 hepatoma cells. Expression of apoA-IV caused an increase in TG secretion that was attributed to 10.1 nm increase in VLDL1 particle diameter. While these data suggest that apoA-IV can directly impact VLDL particle expansion, there is no current evidence indicating that apoA-IV can promote lipid transport by this or any other mechanisms, in vivo. To explore the role of apoA-IV in vivo, we assessed the impact of both apoA-IV deficiency and overexpression on hepatic VLDL-mediated lipid efflux in two different mouse models of hepatic steatosis. Hepatic steatosis induced by either a high fat diet or enhanced de novo lipogenesis, caused by transgenic overexpression of a constitutively active form of SREBP-1a (SREBP-1aTg), was associated with a robust induction (up to 43-fold) of hepatic apoA-IV mRNA and protein levels. In both models, a positive linear correlation between hepatic TG content and apoA-IV mRNA abundance was observed (r2 = 0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1aTg mice were crossed with apoA-IV knock out mice (A4KO). With Triton blockade of peripheral lipolysis, SREBP-1aTg/A4KO mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1aTg controls, but no change in apoB production. Negative stain electron microscopy revealed a 33% decrease in the abundance of secreted large VLDL particles with diameters ≥120 nm. Conversely, mice infected with a recombinant human apoA-IV adenovirus demonstrated a 38% increase in hepatic TG secretion rate and a 39% reduction in liver TG content relative to LacZ controls, associated with a 43% increase in large diameter VLDL particles and no change in apoB secretion. In conclusion, hepatic steatosis in mice induces hepatic apoA-IV expression, which, in turn, promotes lipoprotein particle expansion and reduces hepatic lipid burden without increasing the number of secreted atherogenic apoB-containing lipoprotein particles.","abstract_html":"Several apolipoproteins (apo) can impact triglyceride (TG) transport by modulating VLDL assembly and secretion. Here we explore the impact of apoA-IV on VLDL particle expansion. Previous studies demonstrated that apoA-IV expression promotes apoB lipoprotein-mediated TG secretion in transfected enterocytes and hepatoma cells. We therefore examined the impact of apoA-IV expression on VLDL particle dynamics in stably transfected McA-RH7777 hepatoma cells. Expression of apoA-IV caused an increase in TG secretion that was attributed to 10.1 nm increase in VLDL1 particle diameter. While these data suggest that apoA-IV can directly impact VLDL particle expansion, there is no current evidence indicating that apoA-IV can promote lipid transport by this or any other mechanisms, in vivo. To explore the role of apoA-IV in vivo, we assessed the impact of both apoA-IV deficiency and overexpression on hepatic VLDL-mediated lipid efflux in two different mouse models of hepatic steatosis. Hepatic steatosis induced by either a high fat diet or enhanced de novo lipogenesis, caused by transgenic overexpression of a constitutively active form of SREBP-1a (SREBP-1a<super>Tg</super>), was associated with a robust induction (up to 43-fold) of hepatic apoA-IV mRNA and protein levels. In both models, a positive linear correlation between hepatic TG content and apoA-IV mRNA abundance was observed (r2 = 0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1a<super>Tg</super> mice were crossed with apoA-IV knock out mice (A4KO). With Triton blockade of peripheral lipolysis, SREBP-1a<super>Tg</super>/A4KO mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1a<super>Tg</super> controls, but no change in apoB production. Negative stain electron microscopy revealed a 33% decrease in the abundance of secreted large VLDL particles with diameters ≥120 nm. Conversely, mice infected with a recombinant human apoA-IV adenovirus demonstrated a 38% increase in hepatic TG secretion rate and a 39% reduction in liver TG content relative to LacZ controls, associated with a 43% increase in large diameter VLDL particles and no change in apoB secretion. In conclusion, hepatic steatosis in mice induces hepatic apoA-IV expression, which, in turn, promotes lipoprotein particle expansion and reduces hepatic lipid burden without increasing the number of secreted atherogenic apoB-containing lipoprotein particles.","abstract_has_math":false,"creators":["VerHague, Melissa"],"institution":"Wake Forest University","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013","date_published":"2013","updated_at":"2026-07-27T22:01:39Z","subjects":["apoa-iv"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10339/39014","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["VerHague, Melissa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2013-08-23T08:35:14Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2015-08-23T08:30:10Z"]},{"key":"dc:date.issued","label":"Date","values":["2013"]},{"key":"dc:publisher","label":"Institution","values":["Wake Forest University"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["apoa-iv"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10339/39014"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Several apolipoproteins (apo) can impact triglyceride (TG) transport by modulating VLDL assembly and secretion. Here we explore the impact of apoA-IV on VLDL particle expansion. Previous studies demonstrated that apoA-IV expression promotes apoB lipoprotein-mediated TG secretion in transfected enterocytes and hepatoma cells. We therefore examined the impact of apoA-IV expression on VLDL particle dynamics in stably transfected McA-RH7777 hepatoma cells. Expression of apoA-IV caused an increase in TG secretion that was attributed to 10.1 nm increase in VLDL1 particle diameter. While these data suggest that apoA-IV can directly impact VLDL particle expansion, there is no current evidence indicating that apoA-IV can promote lipid transport by this or any other mechanisms, in vivo. To explore the role of apoA-IV in vivo, we assessed the impact of both apoA-IV deficiency and overexpression on hepatic VLDL-mediated lipid efflux in two different mouse models of hepatic steatosis. Hepatic steatosis induced by either a high fat diet or enhanced de novo lipogenesis, caused by transgenic overexpression of a constitutively active form of SREBP-1a (SREBP-1aTg), was associated with a robust induction (up to 43-fold) of hepatic apoA-IV mRNA and protein levels. In both models, a positive linear correlation between hepatic TG content and apoA-IV mRNA abundance was observed (r2 = 0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1aTg mice were crossed with apoA-IV knock out mice (A4KO). With Triton blockade of peripheral lipolysis, SREBP-1aTg/A4KO mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1aTg controls, but no change in apoB production. Negative stain electron microscopy revealed a 33% decrease in the abundance of secreted large VLDL particles with diameters ≥120 nm. Conversely, mice infected with a recombinant human apoA-IV adenovirus demonstrated a 38% increase in hepatic TG secretion rate and a 39% reduction in liver TG content relative to LacZ controls, associated with a 43% increase in large diameter VLDL particles and no change in apoB secretion. In conclusion, hepatic steatosis in mice induces hepatic apoA-IV expression, which, in turn, promotes lipoprotein particle expansion and reduces hepatic lipid burden without increasing the number of secreted atherogenic apoB-containing lipoprotein particles."]},{"key":"dc:title","label":"Title","values":["IMPACT OF HEPATIC APOLIPOPROTEIN A-IV EXPRESSION ON VLDL PARTICLE EXPANSION, TRIGLYCERIDE SECRETION, AND STEATOSIS"]}]}],"canonical_facts":{"dc:creator":["VerHague, Melissa"],"dc:date.accessioned":["2013-08-23T08:35:14Z"],"dc:date.available":["2015-08-23T08:30:10Z"],"dc:date.issued":["2013"],"dc:description.abstract":["Several apolipoproteins (apo) can impact triglyceride (TG) transport by modulating VLDL assembly and secretion. Here we explore the impact of apoA-IV on VLDL particle expansion. Previous studies demonstrated that apoA-IV expression promotes apoB lipoprotein-mediated TG secretion in transfected enterocytes and hepatoma cells. We therefore examined the impact of apoA-IV expression on VLDL particle dynamics in stably transfected McA-RH7777 hepatoma cells. Expression of apoA-IV caused an increase in TG secretion that was attributed to 10.1 nm increase in VLDL1 particle diameter. While these data suggest that apoA-IV can directly impact VLDL particle expansion, there is no current evidence indicating that apoA-IV can promote lipid transport by this or any other mechanisms, in vivo. To explore the role of apoA-IV in vivo, we assessed the impact of both apoA-IV deficiency and overexpression on hepatic VLDL-mediated lipid efflux in two different mouse models of hepatic steatosis. Hepatic steatosis induced by either a high fat diet or enhanced de novo lipogenesis, caused by transgenic overexpression of a constitutively active form of SREBP-1a (SREBP-1aTg), was associated with a robust induction (up to 43-fold) of hepatic apoA-IV mRNA and protein levels. In both models, a positive linear correlation between hepatic TG content and apoA-IV mRNA abundance was observed (r2 = 0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1aTg mice were crossed with apoA-IV knock out mice (A4KO). With Triton blockade of peripheral lipolysis, SREBP-1aTg/A4KO mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1aTg controls, but no change in apoB production. Negative stain electron microscopy revealed a 33% decrease in the abundance of secreted large VLDL particles with diameters ≥120 nm. Conversely, mice infected with a recombinant human apoA-IV adenovirus demonstrated a 38% increase in hepatic TG secretion rate and a 39% reduction in liver TG content relative to LacZ controls, associated with a 43% increase in large diameter VLDL particles and no change in apoB secretion. In conclusion, hepatic steatosis in mice induces hepatic apoA-IV expression, which, in turn, promotes lipoprotein particle expansion and reduces hepatic lipid burden without increasing the number of secreted atherogenic apoB-containing lipoprotein particles."],"dc:identifier.uri":["http://hdl.handle.net/10339/39014"],"dc:language.iso":["en"],"dc:publisher":["Wake Forest University"],"dc:subject":["apoa-iv"],"dc:title":["IMPACT OF HEPATIC APOLIPOPROTEIN A-IV EXPRESSION ON VLDL PARTICLE EXPANSION, TRIGLYCERIDE SECRETION, AND STEATOSIS"],"dc:type":["Dissertation"]},"updated_at":"2026-07-27T22:01:39Z"}