Targeting bile acid metabolism for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma

Nikolaos Nikolaou, University of Oxford

 

Aims

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. It is a spectrum of disease ranging from lipid accumulation within hepatocytes, and eventually progressing to cirrhosis and hepatocellular carcinoma (HCC). Bile acids (BAs), synthesised in liver, are established endocrine regulators of metabolic and proliferative phenotype. Crucially, in patients with NAFLD as well HCC, BA synthesis is dysregulated, and composition of the BA pool is altered.

Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms in BA-metabolising genes associated with decreased circulating triglyceride levels. Endorsing this, my pilot data reveal that genetic knockdown of these BA-metabolising enzymes beneficially alters metabolic and proliferative gene expression in human hepatocytes, inferring decreased triglyceride-synthesis, enhanced insulin sensitivity, and cell cycle arrest. 

I am an early-career researcher trying to establish my research independence, and have recently applied for postdoctoral fellowships (Wellcome Trust Sir Henry) to pursue the above project. Whilst the reviewers regarded my application highly, additional pilot data, including BA-metabolome profiling of control and knockdown hepatocytes, were requested. With this grant, I request money to profile the BA metabolome in my hepatocyte models, enabling me to address the reviewers' comments and submit a revised proposal within the next 6-9 months.  

 

Grant awarded: £5,063.00