{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/374721"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/374721","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Hepatic and Extra-hepatic Metabolism in NAFLD and the Role of Hepatocyte Oxygen Sensing","abstract":"Non-alcoholic fatty liver disease (NAFLD) is a growing healthcare challenge, affecting ~30% of the global population, however there are currently no specific treatments approved for the disease. A better understanding of pathophysiological mechanisms is required, including the close links between NAFLD and metabolic, cardiovascular and chronic kidney disease. Hypoxia-inducible factor 2α (HIF2α) accumulates in the livers of NAFLD patients and mouse models, and is a regulator of lipid metabolism. In this thesis, I investigated whether hepatocyte-specific deletion of *Epas1* (encoding HIF2α) protects against NAFLD, and whether this is associated with changes in mitochondrial and lipid metabolism. To investigate this, wild type mice and mice with a hepatocyte-specific deletion of *Epas1* were fed a high-fat, high-fructose, high-cholesterol diet (GAN diet) for 28 weeks and hepatic pathology and metabolism were assessed alongside measures of cardiac, renal and whole-body health and metabolism. Hepatic *Epas1* deletion did not protect against NAFLD, or GAN diet induced hyperglycaemia and hyperlipidaemia, but did ameliorate GAN induced hyperinsulinaemia. Moreover, hepatic *Epas1* deletion did alter hepatic mitochondrial respiration and expression of fatty acid oxidation (FAO) genes. Independent of diet, hepatic *Epas1* deletion was associated with accumulation of two specific sphingomyelin species, SM 41:1 and SM 42:2. GAN feeding also induced cardiac dysfunction, as assessed in Langendorff perfused hearts, as well as cardiac steatosis and accumulation of ceramides. Hepatic *Epas1* deletion did not protect against this, but was instead associated with cardiac dysfunction independent of diet, as well as accumulation of diacylglycerols, ceramides, and again, SM 41:1 and 42:2. Hepatic *Epas1* deletion did ameliorate cardiac sympathetic dominance in GAN fed mice. Similarly, GAN feeding induced renal steatosis, possibly due to lower FAO capacity and higher expression of renin. Again, hepatic *Epas1* deletion did not prevent this but may have worsened steatosis, and was associated with higher expression of angiotensin II type 1 receptor. Overall, hepatic *Epas1* deletion did not protect against NAFLD, but was instead associated with cardiac dysfunction and accumulation of potentially lipotoxic species, as well as higher renal expression of components of the renin-angiotensin system. Underlying mechanisms remain unclear, but programming by developmental anaemia in hepatic *Epas1* knockout mice may play a role.","abstract_html":"Non-alcoholic fatty liver disease (NAFLD) is a growing healthcare challenge, affecting ~30% of the global population, however there are currently no specific treatments approved for the disease. A better understanding of pathophysiological mechanisms is required, including the close links between NAFLD and metabolic, cardiovascular and chronic kidney disease. Hypoxia-inducible factor 2α (HIF2α) accumulates in the livers of NAFLD patients and mouse models, and is a regulator of lipid metabolism. In this thesis, I investigated whether hepatocyte-specific deletion of *Epas1* (encoding HIF2α) protects against NAFLD, and whether this is associated with changes in mitochondrial and lipid metabolism. To investigate this, wild type mice and mice with a hepatocyte-specific deletion of *Epas1* were fed a high-fat, high-fructose, high-cholesterol diet (GAN diet) for 28 weeks and hepatic pathology and metabolism were assessed alongside measures of cardiac, renal and whole-body health and metabolism. Hepatic *Epas1* deletion did not protect against NAFLD, or GAN diet induced hyperglycaemia and hyperlipidaemia, but did ameliorate GAN induced hyperinsulinaemia. Moreover, hepatic *Epas1* deletion did alter hepatic mitochondrial respiration and expression of fatty acid oxidation (FAO) genes. Independent of diet, hepatic *Epas1* deletion was associated with accumulation of two specific sphingomyelin species, SM 41:1 and SM 42:2. GAN feeding also induced cardiac dysfunction, as assessed in Langendorff perfused hearts, as well as cardiac steatosis and accumulation of ceramides. Hepatic *Epas1* deletion did not protect against this, but was instead associated with cardiac dysfunction independent of diet, as well as accumulation of diacylglycerols, ceramides, and again, SM 41:1 and 42:2. Hepatic *Epas1* deletion did ameliorate cardiac sympathetic dominance in GAN fed mice. Similarly, GAN feeding induced renal steatosis, possibly due to lower FAO capacity and higher expression of renin. Again, hepatic *Epas1* deletion did not prevent this but may have worsened steatosis, and was associated with higher expression of angiotensin II type 1 receptor. Overall, hepatic *Epas1* deletion did not protect against NAFLD, but was instead associated with cardiac dysfunction and accumulation of potentially lipotoxic species, as well as higher renal expression of components of the renin-angiotensin system. Underlying mechanisms remain unclear, but programming by developmental anaemia in hepatic *Epas1* knockout mice may play a role.","abstract_has_math":false,"creators":["Holzner, Lorenz"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Murray, Andrew"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-04-25","date_published":"2024-04-25","updated_at":"2026-07-22T22:24:04Z","subjects":["Cardiac dysfunction","Crosstalk","HIF","Hypoxia","Kidney disease","Metabolic dysfunction associated fatty liver disease","Metabolism","Non-alcoholic fatty liver disease","Obesity"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cdaf2994-5249-436f-b09a-8c54a2dece26/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.112680","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Murray, Andrew"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Wellcome Trust PhD Studentship 220033/Z/19/Z"]},{"key":"dc:creator","label":"Author","values":["Holzner, Lorenz"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2024-04-25"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/374721"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Cardiac dysfunction","Crosstalk","HIF","Hypoxia","Kidney disease","Metabolic dysfunction associated fatty liver disease","Metabolism","Non-alcoholic fatty liver disease","Obesity"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cdaf2994-5249-436f-b09a-8c54a2dece26/download","https://www.rioxx.net/licenses/all-rights-reserved/"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2025-10-10"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.112680"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/588ef484-f159-4bc4-9dda-e6231ddca4c8/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Non-alcoholic fatty liver disease (NAFLD) is a growing healthcare challenge, affecting ~30% of the global population, however there are currently no specific treatments approved for the disease. A better understanding of pathophysiological mechanisms is required, including the close links between NAFLD and metabolic, cardiovascular and chronic kidney disease. Hypoxia-inducible factor 2α (HIF2α) accumulates in the livers of NAFLD patients and mouse models, and is a regulator of lipid metabolism. In this thesis, I investigated whether hepatocyte-specific deletion of *Epas1* (encoding HIF2α) protects against NAFLD, and whether this is associated with changes in mitochondrial and lipid metabolism. To investigate this, wild type mice and mice with a hepatocyte-specific deletion of *Epas1* were fed a high-fat, high-fructose, high-cholesterol diet (GAN diet) for 28 weeks and hepatic pathology and metabolism were assessed alongside measures of cardiac, renal and whole-body health and metabolism. Hepatic *Epas1* deletion did not protect against NAFLD, or GAN diet induced hyperglycaemia and hyperlipidaemia, but did ameliorate GAN induced hyperinsulinaemia. Moreover, hepatic *Epas1* deletion did alter hepatic mitochondrial respiration and expression of fatty acid oxidation (FAO) genes. Independent of diet, hepatic *Epas1* deletion was associated with accumulation of two specific sphingomyelin species, SM 41:1 and SM 42:2. GAN feeding also induced cardiac dysfunction, as assessed in Langendorff perfused hearts, as well as cardiac steatosis and accumulation of ceramides. Hepatic *Epas1* deletion did not protect against this, but was instead associated with cardiac dysfunction independent of diet, as well as accumulation of diacylglycerols, ceramides, and again, SM 41:1 and 42:2. Hepatic *Epas1* deletion did ameliorate cardiac sympathetic dominance in GAN fed mice. Similarly, GAN feeding induced renal steatosis, possibly due to lower FAO capacity and higher expression of renin. Again, hepatic *Epas1* deletion did not prevent this but may have worsened steatosis, and was associated with higher expression of angiotensin II type 1 receptor. Overall, hepatic *Epas1* deletion did not protect against NAFLD, but was instead associated with cardiac dysfunction and accumulation of potentially lipotoxic species, as well as higher renal expression of components of the renin-angiotensin system. 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A better understanding of pathophysiological mechanisms is required, including the close links between NAFLD and metabolic, cardiovascular and chronic kidney disease. Hypoxia-inducible factor 2α (HIF2α) accumulates in the livers of NAFLD patients and mouse models, and is a regulator of lipid metabolism. In this thesis, I investigated whether hepatocyte-specific deletion of *Epas1* (encoding HIF2α) protects against NAFLD, and whether this is associated with changes in mitochondrial and lipid metabolism. To investigate this, wild type mice and mice with a hepatocyte-specific deletion of *Epas1* were fed a high-fat, high-fructose, high-cholesterol diet (GAN diet) for 28 weeks and hepatic pathology and metabolism were assessed alongside measures of cardiac, renal and whole-body health and metabolism. Hepatic *Epas1* deletion did not protect against NAFLD, or GAN diet induced hyperglycaemia and hyperlipidaemia, but did ameliorate GAN induced hyperinsulinaemia. Moreover, hepatic *Epas1* deletion did alter hepatic mitochondrial respiration and expression of fatty acid oxidation (FAO) genes. Independent of diet, hepatic *Epas1* deletion was associated with accumulation of two specific sphingomyelin species, SM 41:1 and SM 42:2. GAN feeding also induced cardiac dysfunction, as assessed in Langendorff perfused hearts, as well as cardiac steatosis and accumulation of ceramides. Hepatic *Epas1* deletion did not protect against this, but was instead associated with cardiac dysfunction independent of diet, as well as accumulation of diacylglycerols, ceramides, and again, SM 41:1 and 42:2. Hepatic *Epas1* deletion did ameliorate cardiac sympathetic dominance in GAN fed mice. Similarly, GAN feeding induced renal steatosis, possibly due to lower FAO capacity and higher expression of renin. Again, hepatic *Epas1* deletion did not prevent this but may have worsened steatosis, and was associated with higher expression of angiotensin II type 1 receptor. Overall, hepatic *Epas1* deletion did not protect against NAFLD, but was instead associated with cardiac dysfunction and accumulation of potentially lipotoxic species, as well as higher renal expression of components of the renin-angiotensin system. Underlying mechanisms remain unclear, but programming by developmental anaemia in hepatic *Epas1* knockout mice may play a role."],"dc:format.checksum.md5":["b73329a831cc9ad641f6498570595064","87eda9de84448d1f82354d60eee3eb5f"],"dc:identifier.doi":["https://doi.org/10.17863/CAM.112680"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/588ef484-f159-4bc4-9dda-e6231ddca4c8/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/374721"],"dc:rights":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cdaf2994-5249-436f-b09a-8c54a2dece26/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"dc:rights.embargodate":["2025-10-10"],"dc:rights.embargotype":["embargo"],"dc:subject":["Cardiac dysfunction","Crosstalk","HIF","Hypoxia","Kidney disease","Metabolic dysfunction associated fatty liver disease","Metabolism","Non-alcoholic fatty liver disease","Obesity"],"dc:title":["Hepatic and Extra-hepatic Metabolism in NAFLD and the Role of Hepatocyte Oxygen Sensing"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:04Z"}