Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis

The aim of this study is to characterize cell type-specific transcriptional signatures in non-alcoholic steatohepatitis (NASH) to improve our understanding of the disease. We performed single-cell RNA sequencing on liver biopsies from 10 patients with NASH. We applied weighted gene co-expression network analysis and validated our findings using a publicly available RNA sequencing data set derived from 160 patients with non-alcoholic fatty liver disease (NAFLD) and 24 controls with normal liver histology. Our study provides a comprehensive single-cell analysis of NASH pathology in humans, describing 19,627 single-cell transcriptomes from biopsy-proven NASH patients. Our data suggest that the previous notion of NASH-associated macrophages can be explained by an up-regulation of normally existing subpopulations of liver macrophages. Similarly, we describe two distinct populations of activated hepatic stellate cells, associated with the level of fibrosis. Finally, we find that the expression of several circulating markers of NAFLD are co-regulated in hepatocytes together with predicted effector genes from NAFLD genome-wide association studies (GWAS), coupled to abnormalities in the complement system. In sum, our single-cell transcriptomic data set provides insights into novel cell type-specific and general biological processes associated with inflammation and fibrosis, emphasizing the importance of studying cell type-specific biological processes in human NASH.

Automated summary

This study aims to identify specific transcriptional patterns in non-alcoholic steatohepatitis (NASH) to enhance our understanding of the disease. By performing single-cell RNA sequencing on liver biopsies from 10 NASH patients, the study provides comprehensive insights into the pathology of NASH in humans. The findings suggest that previously identified NASH-associated macrophages are actually subpopulations of liver macrophages that are up-regulated. Additionally, the study identifies two distinct populations of activated hepatic stellate cells associated with the level of fibrosis. Furthermore, the study reveals co-regulation of circulating markers of NAFLD with predicted effector genes from NAFLD genome-wide association studies (GWAS), as well as abnormalities in the complement system in hepatocytes.