Transcriptional Dynamics of Hepatic Sinusoid-Associated Cells After Liver Injury
Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are the hepatic manifestations of metabolic syndrome. Histological assessment of liver biopsies is the gold standard for diagnosis of NASH. A Liver biopsy is resource heavy, can lead to complications such as bleeding, and does not fully capture tissue heterogeneity of the fibrotic liver. Therefore, non-invasive biomarkers that can reflect an integrated state of the liver are highly needed to improve diagnosis and sampling bias. Hepatic stellate cells (HSCs) are central in development of hepatic fibrosis, a hallmark of NASH. Secreted HSC-specific proteins may, therefore, reflect disease state in the NASH liver and serve as non-invasive diagnostic biomarkers. We performed RNA-sequencing on liver biopsies from a histological characterised cohort of obese patients to identify and evaluate HSC-specific genes encoding secreted proteins. Bioinformatics was used to identify potential biomarkers and their expression at single-cell resolution. We validated our findings by single-molecule fluorescence in situ hybridisation (smFISH) and ELISA to detect mRNA in liver tissue and protein levels in plasma, respectively. Hepatic expression of SPARC-related modular calcium-binding protein 2 (SMOC2) was increased in NASH compared no-NAFLD and elevated in blood samples from NASH patients and may hold promise as a blood-based biomarker for NAFLD diagnosis.
