A genomics approach to study the non-parenchymal cell population of the liver

Obesity prevalence is increasing worldwide. It impacts virtually all tissues by inducing systemic metabolic imbalances. The liver is a major site for energy disposal in obesity leading to hepatosteatosisthat may further boost hepatic inflammation and fibrogenesis leading to non-alcoholic steatohepatitis(NASH). Insights into disease mechanisms are required for the development of novel therapies. Lipotoxic stress induce hepatocellular death and the release of proinflammatory cytokines that triggerimmune cell infiltration and activation of resident cell types. Moreover, dedifferentiation of liversinusoidal endothelial cells (LSECs) drives stellate cell activation in turn exaggerating fibrogenesis.In recent years we have obtained invaluable insight into cell type heterogeneity in NASH due to theexpansion of single cell transcriptomics. However, insight into the cis-regulatory genome serving asthe link between niche signals and gene expression outcome is lacking. We applied a diet-inducedmouse model of NASH to map the cis-regulatory regions (CRR) involved in NASH using singlenucleus ATAC sequencing and single nucleus RNA-sequencing combined with a genetic approachto deplete hepatocyte nuclei. We detected the expected repertoire of non-parenchymal cell types in aNASH context and confirmed the highly cell type-defining nature of the cis-regulatory genome as