Liver-specific inactivation of Cideb improves metabolic profiles and ameliorates steatohepatitis and fibrosis in animal models for MASH
Germline mutations of CIDEB, a lipid droplets (LDs)-associated protein, confer protection against various liver diseases in humans. It remains to be determined whether liver-specific inhibition of CIDEB will bring clinical benefits. We aim to establish pharmacological proof of concept by testing Gal...
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
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| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000891 |
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| Summary: | Germline mutations of CIDEB, a lipid droplets (LDs)-associated protein, confer protection against various liver diseases in humans. It remains to be determined whether liver-specific inhibition of CIDEB will bring clinical benefits. We aim to establish pharmacological proof of concept by testing GalNAc-conjugated Cideb surrogate siRNAs in respective animal models of obesity and MASH and to develop siRNA drug candidates for clinical investigations. Surrogate siRNAs targeting mouse Cideb were designed and evaluated via a panel of assays. Concurrently, humanized CIDEB knock-in mice were generated as a research tool to facilitate human therapeutic siRNA discovery. In vivo administration of the surrogate siRNAs was conducted in the diet-induced obesity (DIO) model and CDAA-HFD model of MASH. In the DIO model, Cideb knockdown led to significant reductions of serum total cholesterol (TC) and triglyceride (TG) levels, a significant decrease in hepatic macro-steatosis and notable weight loss. In the CDAA-HFD model, Cideb siRNA treatment significantly reduced liver TC and TG levels. Furthermore, remarkable reductions of hepatic steatosis and the composite NAS score were observed with a concomitant amelioration of liver fibrosis. Transcriptome analyses revealed that integrin pathways may contribute to the major pharmacological activities upon Cideb inactivation beyond lipid metabolism. CIDEB exhibits significant potential as a therapeutic target for the treatment of MASH. Liver-targeting siRNA candidates are under development for therapeutic hypothesis testing in humans. |
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| ISSN: | 1096-1186 |