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Liver-specific inactivation of Cideb improves metabolic profiles and ameliorates steatohepatitis and fibrosis in animal models for MASH

ABSTRACT: Background and Aims: Germline mutations in CIDEB, a lipid droplet (LD)-associated protein, confer protection against various liver diseases in humans. Whether liver-specific inhibition of CIDEB will bring clinical benefits remains to be determined. We aim to establish preclinical proof of concept by testing GalNac-conjugated Cideb siRNAs in animal models for obesity and MASH and to develop siRNA drug candidates for clinical investigations. Method: Surrogate siRNAs targeting mouse Cideb were designed and evaluated via a panel of assays. In vivo administration of the surrogate siRNAs was conducted in diet-induced obesity model and CDAA-HFD model for MASH. Plasma and liver lipid levels were measured, and liver histopathological features were analyzed. RNA-Seq analysis of liver tissues was performed to gain a comprehensive mechanistic understanding of Cideb target biology. Concurrently, humanized CIDEB knock-in mice were generated as a research tool to aid human therapeutic siRNAs discovery and development. Results: Single administration of a potent surrogate siRNA resulted in more than 80% target knockdown up to two weeks. In the DIO model, Cideb knockdown led to significant reductions of plasma total cholesterol (TC) and triglyceride (TG) levels, a significant decrease in hepatic macro-steatosis and notable body weight loss. In the CDAA-HFD model, Cideb siRNA treatment significantly reduced liver weight as well as liver TC and TG levels. Furthermore, remarkable reductions of hepatic steatosis and total NAS score were observed with a concomitant amelioration of liver fibrosis. Transcriptome analyses revealed key mechanisms upon Cideb inactivation beyond lipid metabolism. Conclusion: CIDEB exhibits significant potential as a therapeutic target for the treatment of MASH. Liver-targeting siRNA candidates are being developed to test the therapeutic hypothesis in humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE279351 | GEO | 2025/04/12

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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Liver-specific inactivation of Cideb improves metabolic profiles and ameliorates steatohepatitis and fibrosis in animal models for MASH

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