Stellate cell expression of SPARC-related modular calcium-binding protein 2 is associated with human non-alcoholic fatty liver disease severity

Histological assessment of liver biopsies is the gold standard for diagnosis of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), despite its well-established limitations. Therefore, non-invasive biomarkers that can offer an integrated view of t...

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Published in:	JHEP reports Vol. 5; no. 2; p. 100615
Main Authors:	Larsen, Frederik T., Hansen, Daniel, Terkelsen, Mike K., Bendixen, Sofie M., Avolio, Fabio, Wernberg, Charlotte W., Lauridsen, Mette M., Grønkjaer, Lea L., Jacobsen, Birgitte G., Klinggaard, Ellen G., Mandrup, Susanne, Di Caterino, Tina, Siersbæk, Majken S., Chandran, Vineesh Indira, Graversen, Jonas H., Krag, Aleksander, Grøntved, Lars, Ravnskjaer, Kim
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-02-2023 Elsevier
Subjects:	hepatic stellate cells NAFLD NASH non-invasive biomarker SMOC2 transcriptomics NAS NAFLD hepatic stellate cells VSMCs SPARC non-invasive biomarker LSM AUROC NASH smFISH WGCNA ECM PCA SMOC2 SE qHSC transcriptomics HSC SAF aHSC MCP NAFL SP WGCNA, weighted gene co-expression network analysis ECM, extracellular matrix SAF, steatosis, activity, and fibrosis smFISH, single-molecule fluorescence in situ hybridisation NAS, NAFLD activity score PCA, principal component analysis NAFLD, non-alcoholic fatty liver disease SE, sensitivity SP, specificity LSM, liver stiffness measurement SPARC, secreted protein acidic and cysteine-rich AUROC, area under the receiver operating characteristic curve NAFL, non-alcoholic fatty liver aHSC, activated HSC VSMCs, vascular smooth muscle cells SMOC2, SPARC-related modular calcium-binding protein 2 qHSC, quiescent HSC HSC, hepatic stellate cells MCP, matricellular protein
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Summary:	Histological assessment of liver biopsies is the gold standard for diagnosis of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), despite its well-established limitations. Therefore, non-invasive biomarkers that can offer an integrated view of the liver are needed to improve diagnosis and reduce sampling bias. Hepatic stellate cells (HSCs) are central in the 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 histologically characterised cohort of obese patients (n = 30, BMI >35 kg/m2) 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 using 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 to no-NAFLD (p.adj <0.001). Single-cell RNA-sequencing data indicated that SMOC2 was primarily expressed by HSCs, which was validated using smFISH. Finally, plasma SMOC2 was elevated in NASH compared to no-NAFLD (p <0.001), with a predictive accuracy of AUROC 0.88. Increased SMOC2 in plasma appears to reflect HSC activation, a key cellular event associated with NASH progression, and may serve as a non-invasive biomarker of NASH. Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are the most common forms of chronic liver diseases. Currently, liver biopsies are the gold standard for diagnosing NAFLD. Blood-based biomarkers to complement liver biopsies for diagnosis of NAFLD are required. We found that activated hepatic stellate cells, a cell type central to NAFLD pathogenesis, upregulate expression of the secreted protein SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was elevated in blood samples from patients with NASH and may hold promise as a blood-based biomarker for the diagnosis of NAFLD. [Display omitted] •Hepatic expression of SMOC2 correlates with NAFLD severity.•SMOC2 is secreted by activated hepatic stellate cells/fibroblasts in the NASH liver.•Hepatic expression of SMOC2 shows good predictive performance for NAFLD severity.•SMOC2 is elevated in plasma from patients with NASH.•Plasma SMOC2 shows excellent predictive performance for NAFLD severity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2589-5559 2589-5559
DOI:	10.1016/j.jhepr.2022.100615