The impact of cholesterol lowering drugs on metabolism and epigenetics

Abstract

Background and Aims : Cardiovascular diseases (CVDs) are the leading cause of death globally. In patients with CVDs, treatment with cholesterol lowering drugs has been shown to reduce cardiovascular events. Bempedoic acid is a novel drug for lowering low-density lipoprotein cholesterol that has recently been approved for clinical use. Bempedoic acid specifically inhibits ATP citrate lyase (ACLY) in the liver, an enzyme that converts citrate to acetyl-CoA and acts at the interface of carbohydrate and lipid metabolism. ACLY is not only cytoplasmic, but is also found in the nucleus, where it regulates histone acetylation levels. Yet, it is unknown if and how bempedoic acid impacts ACLYs regulatory function in the nucleus.Methods: By combining chromatin immunoprecipitation sequencing, transcriptomics, tracer metabolomics and mass-spectrometry based histone post-translational modification analysis in primary human hepatocytes, we systematically investigate the impact of bempedoic acid on ACLY at different regulatory levels.Results: Our data from mouse liver tissue revealed binding of ACLY to promoter regions of metabolic genes. Consistently, gene expression analyses in primary human hepatocytes showed reduced expression of ACLY bound metabolic genes in response to bempedoic acid. Furthermore, histone modification analysis via mass spectrometry and ChIP-seq profiles displayed a highly specific loss of H3K9ac, a promoter-based histone modification known to stimulate gene transcription, upon bempedoic acid treatment. Metabolite profiling revealed reduction in lipid metabolism following bempedoic acid administration.Conclusions: Taken together, these data suggest that bempedoic acid's mechanism of action involves reprogramming of the epigenetic and transcriptional landscape of ACLY associated genes, together with a reduction in lipid production in hepatocytes. Background and Aims : Cardiovascular diseases (CVDs) are the leading cause of death globally. In patients with CVDs, treatment with cholesterol lowering drugs has been shown to reduce cardiovascular events. Bempedoic acid is a novel drug for lowering low-density lipoprotein cholesterol that has recently been approved for clinical use. Bempedoic acid specifically inhibits ATP citrate lyase (ACLY) in the liver, an enzyme that converts citrate to acetyl-CoA and acts at the interface of carbohydrate and lipid metabolism. ACLY is not only cytoplasmic, but is also found in the nucleus, where it regulates histone acetylation levels. Yet, it is unknown if and how bempedoic acid impacts ACLYs regulatory function in the nucleus. Methods: By combining chromatin immunoprecipitation sequencing, transcriptomics, tracer metabolomics and mass-spectrometry based histone post-translational modification analysis in primary human hepatocytes, we systematically investigate the impact of bempedoic acid on ACLY at different regulatory levels. Results: Our data from mouse liver tissue revealed binding of ACLY to promoter regions of metabolic genes. Consistently, gene expression analyses in primary human hepatocytes showed reduced expression of ACLY bound metabolic genes in response to bempedoic acid. Furthermore, histone modification analysis via mass spectrometry and ChIP-seq profiles displayed a highly specific loss of H3K9ac, a promoter-based histone modification known to stimulate gene transcription, upon bempedoic acid treatment. Metabolite profiling revealed reduction in lipid metabolism following bempedoic acid administration. Conclusions: Taken together, these data suggest that bempedoic acid's mechanism of action involves reprogramming of the epigenetic and transcriptional landscape of ACLY associated genes, together with a reduction in lipid production in hepatocytes.