Hepatic stellate cells specific liposomes with the Toll-like receptor 4 shRNA attenuates liver fibrosis.

Abstract

The hepatic stellate cells (HSCs) play a significant role in the onset of liver fibrosis, which can be treated by the inhibition and reversal of HSC activation. The RNA interference-mediated TLR4 gene silencing might be a potential therapeutic approach for liver fibrosis. The crucial challenge in this method is the absence of an efficient delivery system for the RNAi introduction in the target cells. HSCs have an enhanced capacity of vitamin A intake as they contain retinoic acid receptors (RARs). In the current study, we developed cationic liposomes modified with vitamin A to improve the specificity of delivery vehicles for HSCs. The outcome of this study revealed that the VitA-coupled cationic liposomes delivered the TLR4 shRNA to aHSCs more efficiently, as compared to the uncoupled cationic liposomes, both in the in vitro and in vivo conditions. Besides, as evident from the outcome of this study, the TLR4 gene silencing inhibited the HSCs activation and attenuated the liver fibrosis via the NF-κB transcriptional inactivation, pro-inflammatory cytokines secretion and reactive oxygen species (ROS) synthesis. Thus, the VitA-coupled liposomes encapsulated with the TLR4-shRNA might prove as an efficient therapeutic agent for liver fibrosis.

• Authors: Yuwei Zhang, Yang Li, Tong Mu, Nanwei Tong, Ping Cheng
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 2 Pg. 1299-1313 (01 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 33336563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Cytokines
• Inflammation Mediators
• Lipopolysaccharides
• Liposomes
• NF-kappa B
• RNA, Small Interfering
• Reactive Oxygen Species
• Toll-Like Receptor 4
• Vitamin A
• DNA
• NADPH Oxidases

Topics

• Animals
• Cytokines (metabolism)
• DNA (metabolism)
• Disease Progression
• Extracellular Matrix (metabolism)
• Female
• Gene Silencing
• Hepatic Stellate Cells (metabolism)
• Inflammation Mediators (metabolism)
• Lipopolysaccharides
• Liposomes
• Liver Cirrhosis (pathology, therapy)
• Mice, Inbred C57BL
• Mitochondria (metabolism)
• NADPH Oxidases (metabolism)
• NF-kappa B (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Reactive Oxygen Species (metabolism)
• Tissue Distribution
• Toll-Like Receptor 4 (metabolism)
• Transcription, Genetic
• Vitamin A (metabolism, pharmacokinetics)