Hepatic and Extra-hepatic Metabolism in NAFLD and the Role of Hepatocyte Oxygen Sensing

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Holzner, Lorenz

Advisor dc:contributor.advisor

• Murray, Andrew

• Cardiac dysfunction
• Crosstalk
• HIF
• Hypoxia
• Kidney disease
• Metabolic dysfunction associated fatty liver disease
• Metabolism
• Non-alcoholic fatty liver disease
• Obesity

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cdaf2994-5249-436f-b09a-8c54a2dece26/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.112680

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/374721