Impact of the ACLY-inhibitor bempedoic acid on the hepatic epigenetic and transcriptional landscapes

• Applicant: Bilal Sheikh, Ph.D.
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511049882

Cardiovascular disease is the most common cause of death worldwide, accounting for over 27% of all deaths. One of the leading risk factors of cardiovascular disease is high levels of LDL-cholesterol and lipids. Consistently, pharmaceutical lowering of cholesterol levels is a highly successful strategy for improving metabolic health and reducing the risk of cardiovascular disorders. Approved for clinical use in the EU and USA in 2020, bempedoic acid (BA) is novel, first-in-class inhibitor that is increasingly being administered to metabolically unhealthy patients to reduce cholesterol levels. BA is a pro-drug that is specifically activated in the liver. BA inhibits the citrate lyase (ACLY) enzyme, which converts citrate to acetyl-CoA. As acetyl-CoA could be used in cholesterol production, inhibition of ACLY via BA is thought to directly reduce cholesterol synthesis. However, considerable quantities of ACLY and acetyl-CoA are also found in the nucleus, where they are thought to impact the epigenetic landscape. Indeed, around 80% of cellular acetyl-groups are stored on chromatin. Whether BA impacts the hepatic epigenetic and transcriptional landscapes is unknown and will be addressed in this study. Our preliminary data has revealed that ACLY is indeed present in the nuclear compartment of the liver. Through chromatin immunoprecipitation (ChIP)-seq analyses, we have uncovered that ACLY binds to the promoters of transcriptionally active genes, with metabolic genes showing the strongest enrichment. Consistently, we have uncovered that ACLY inhibition via BA globally reprograms the epigenetic state of hepatocytes. As gene transcription is governed by the epigenetic landscape, our preliminary data suggest that BA reprograms the transcriptional landscape of hepatocytes to rewire hepatic metabolism. To address our hypothesis, we will employ state-of-the-art transcriptomic, epigenetic and metabolic assays to systematically address how BA-driven molecular pathways reprogram hepatic transcription and metabolism. Furthermore, we will uncover the molecular mechanisms that recruit ACLY to chromatin, as well as the epigenetic complexes that interact and collaborate with ACLY to maintain the epigenetic and transcriptional landscapes. Through expression of organelle-specific variants of ACLY in primary hepatocytes, we will reveal the relative contribution of nuclear ACLY to maintaining metabolism at the transcriptional level. Through our multidisciplinary and mechanistic experimental approach, our work promises to reveal how BA drives epigenetic and transcriptional changes to reprogram hepatic metabolism. Given the increasing clinical use of BA, this study will provide timely insights that could guide the clinical use of BA in metabolically unhealthy patients and lead to a much clearer understanding of the molecular mode of its action.

• DFG Programme: Research Grants