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Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are two common liver disorders characterized by abnormal lipid accumulation. Our study found reduced levels of GTPase-activating protein-binding protein1（G3BP1）in patients with MASLD and MASH, suggesting its involvement in these liver disorders. Hepatocyte-specific G3BP1 knockout (G3BP1 HKO) mice had more severe MASLD and MASH than their corresponding controls. Intriguingly, the G3BP1 HKO MASLD model mice exhibit dysregulated autophagy, and biochemical analyses demonstrated that G3BP1 promotes autophagosome-lysosome fusion through direct interactions with the SNARE proteins STX17 and VAMP8. We also show that hepatic knockout of G3BP1 promotes de novo lipogenesis, and ultimately found that G3BP1 is required for the nuclear translocation of the well-known liver-lipid-regulating transcription factor TFE3. Taken together, our results suggest that G3BP1 should be investigated as a potential target for developing medical interventions to treat MASLD and MASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE304454 | GEO | 2025/08/06

REPOSITORIES: GEO

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Project description:Background & Aims Obesity is a major risk factor for metabolic associated steatotic liver disease (MASLD) which can progress from metabolic associated steatotic liver (MASL) to metabolic associated steatohepatitis (MASH). There are currently no effective and validated screening tools to stratify obese patients with a greater risk for MASH, independent of liver fibrosis, at a population level. We aimed to characterise the highly abundant and small protein plasma proteomes of worsening MASLD and overlay the liver-secreted proteome to generate a predictive model to stratify patients with and without MASH. Methods Venous blood and liver wedge biopsies were taken from 160 patients undergoing bariatric surgery. MASLD severity was assessed histologically. Liver biopsies from a subset of 96 patients were precision-cut and cultured to assess liver-secreted proteins. Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry on the plasma and the incubation medium cutoff the liver slices. Results Current non-invasive scores failed to stratify MASH in our cohort. The top200 plasma proteome exhibited mild changes in patients with MASH compared to those with No pathology, while the SPEA approach identified substantial differences in plasma proteins of patients with MASH compared to those without MASH. Liver-secreted proteins were remodelled in MASH compared to MASL and individuals with No pathology. There were no significant changes in the liver-secreted proteins and plasma proteome when comparing MASL to those with No pathology. The APASHA model, comprised of APOF, PCSK9, AFM, and S100A6, HbA1c % and AZGP1 stratified MASH in the discovery (AUROC: 0.887, p<0.0001) and validation cohorts (AUROC:0.7673, p=0.0002) and outcompeted other non-invasive scores. Conclusions These proteomic investigations provide a detailed description of liver-secreted and plasma proteome with worsening MASLD. MASH remodels plasma and liver-secreted proteins. Plasma proteomics generated the APASHA model validated in two Australian bariatric cohorts. Further investigation is warranted to interrogate the utility of the APASHA model as a non-invasive risk prediction model in additional cohorts. Lay Summary: Metabolic-associated steatohepatitis (MASH), a more advanced form of metabolic-associated steatotic liver disease (MASLD), alters the levels of many proteins secreted by the liver and in the blood and those. The APASHA model, which is based on proteins that change in the blood or are secreted by the liver in cases of MASH, could potentially be developed into a simple blood test to predict MASH in high-risk groups.

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Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease

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