Related Experiment Video
Updated: Mar 6, 2026
Incorporation of a Survivable Liver Biopsy Procedure in Mice to Assess Non-alcoholic Steatohepatitis NASH Resolution
Published on: April 16, 2019
GalNAc-conjugated siRNA targeting C/EBPβ reverses metabolic dysfunction and restores liver homeostasis in a murine
Shirin Elizabeth Khorsandi1,2,3, Daniel Vasconcelos1,4, Roman Nicholas1
1Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
Abstract:
CCAAT/enhancer-binding protein beta (C/EBPβ) is a master regulator of hepatic metabolism, inflammation, and fibrosis, making it an attractive but underexploited target for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we demonstrate that GalNAc-conjugated small interfering RNA (siRNA) targeting C/EBPβ (GalNAc-siCEBPβ) significantly improves liver function and metabolic parameters in a high fat diet (HFD) murine model. In vitro, GalNAc-siCEBPβ achieved dose-dependent C/EBPβ mRNA silencing (∼80% knockdown at 0.1 μM) in primary mouse hepatocytes. In vivo, subcutaneous administration (10 mg/kg) reduced hepatic C/EBPβ expression by 45% (p < 0.01), concomitant with a marked reduction in liver steatosis and improved metabolic profile (15% less weight gain, 20% lower glucose, 25% reduced triglycerides), and restored liver function (18% higher albumin, 22% lower bilirubin)-all without hepatotoxicity (ALT/AST unchanged). Notably, these effects occurred despite continued HFD feeding, suggesting disease-modifying potential. By leveraging the precision of RNAi and hepatocyte-specific GalNAc delivery, GalNAc-siCEBPβ addresses key limitations of current MASLD therapies by targeting both metabolism and fibrosis. Our findings support clinical translation for MASLD and its complications, including hepatocellular carcinoma.
Insights
GalNAc-conjugated siRNA targeting CCAAT/enhancer-binding protein beta (C/EBPβ) effectively treats metabolic dysfunction-associated steatotic liver disease (MASLD) in mice. This novel RNAi therapy improves liver function and metabolic health, offering potential for clinical translation.
Area of Science:
- Hepatology
- RNA Therapeutics
- Metabolic Diseases
Background:
- CCAAT/enhancer-binding protein beta (C/EBPβ) is a key regulator of liver metabolism, inflammation, and fibrosis.
- C/EBPβ is an underexploited therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD).
Purpose of the Study:
- To evaluate the efficacy of GalNAc-conjugated small interfering RNA (siRNA) targeting C/EBPβ (GalNAc-siCEBPβ) in a high-fat diet (HFD)-induced murine model of MASLD.
- To assess the impact of GalNAc-siCEBPβ on liver steatosis, metabolic parameters, liver function, and potential hepatotoxicity.
Main Methods:
- In vitro validation of GalNAc-siCEBPβ for dose-dependent C/EBPβ mRNA knockdown in primary mouse hepatocytes.
- In vivo subcutaneous administration of GalNAc-siCEBPβ (10 mg/kg) in HFD-fed mice.
- Assessment of hepatic C/EBPβ expression, liver steatosis, body weight, glucose levels, triglyceride levels, albumin, bilirubin, ALT, and AST.
Main Results:
- GalNAc-siCEBPβ achieved significant C/EBPβ mRNA knockdown in vitro (∼80% at 0.1 μM).
- In vivo treatment reduced hepatic C/EBPβ expression by 45% (p < 0.01), decreased liver steatosis, and improved metabolic profile (reduced weight gain, glucose, and triglycerides).
- Restored liver function (increased albumin, decreased bilirubin) without inducing hepatotoxicity (unchanged ALT/AST) despite continued HFD feeding.
Conclusions:
- GalNAc-siCEBPβ demonstrates significant therapeutic potential for MASLD by targeting C/EBPβ.
- This RNAi-based approach improves liver health and metabolic parameters, addressing limitations of current MASLD therapies.
- The findings support the clinical translation of GalNAc-siCEBPβ for MASLD and associated complications like hepatocellular carcinoma.
