Genome-scale modeling reveals regulation of human metabolism by the histone deacetylase SIRT1

Genome-scale metabolic models are powerful tools for predicting metabolic fluxes, yet regulatory mechanisms are typically outside their scope. Here, we present a genome-scale modeling framework that integrates transcriptional regulation by the histone deacetylase SIRT1 into human metabolism. By combining a curated regulatory network with the Recon3D metabolic reconstruction, we developed a continuous modeling framework that simulates graded regulatory influences on metabolic fluxes. The model captures known metabolic effects of SIRT1, including enhanced fatty acid oxidation and gluconeogenesis and suppressed glycolysis, across various tissues and dietary conditions. Through cell culture experiments, we quantified the dose-dependent inhibition of SIRT1 by butyrate, a microbiome-derived metabolite. After, incorporating this relationship into the model and found good agreement between experimental metabolomics measurements and in silico predictions. This is the first model to integrate a histone deacetylase and its inhibitor into a genome-scale metabolic framework, enabling simulation of host-microbiome regulatory crosstalk. Our approach provides a dynamic, systems-level tool to explore the regulation of human metabolism and offers insights into how diet and microbial activity influence host metabolic states.