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Sphingosine kinase 2 (SphK2) knockout alters metabolic gene expression in an early MASH mouse model

ABSTRACT: Sphingosine kinase 2 (SphK2) knockout alters metabolic gene expression in an early MASH mouse model

PROVIDER: PRJNA1176455 | ENA |

REPOSITORIES: ENA

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Sphingosine kinase 2 (SphK2) knockout alters metabolic gene expression in an early MASH mouse model

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Sphingosine kinase 2 (SphK2) knockout increases liver inflammation in an early MASH mouse model

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Serum Protein Risk Stratification Score for Diagnostic Evaluation of Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Project description:Reliable non-invasive tools to diagnose at risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high risk MASH patients (NAFLD Activity Score (NAS) >4 and fibrosis score >2). In this three-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease (MASLD), we first developed a multi-protein predictor for discriminating NAS>4 based on SOMAscan proteomics quantifying 1,305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N=168), and enhanced by adding clinical variables to create the 9-feature MASH Dx Score which predicted MASH and also high risk MASH (F2+). The MASH Dx Score was validated in two independent, external cohorts from Germany (N=139) and Brazil (N=177). The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of four proteins (THBS2, GDF15, SELE, IGFBP7) was verified by ELISA in the expanded discovery and independently in the two external cohorts. MASH Dx Score incorporated these proteins with established MASH risk factors (age, BMI, ALT, diabetes, hypertension) to achieve good discrimination between MASH and MASLD without MASH (AUC:0.87- discovery; 0.83- pooled external validation cohorts), with similar performance when evaluating high risk MASH F2-4 (vs. MASH F0-1 and MASLD without MASH). The MASH Dx Score offers the first reliable non-invasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high risk MASH in patient cohorts from the US, Brasil and Europe.

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Sphingosine kinase 1 regulates the pulmonary vascular immune response

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Sphingosine kinase 2 in stromal fibroblasts creates a hospitable tumor microenvironment in breast cancer

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