Lipid Nanoparticle-Mediated Delivery of CRISPR-Cas9 Against Rubicon Ameliorates NAFLD by Modulating CD36 Along with Glycerophospholipid Metabolism

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2024 Jun 19

PMID 38894572

Authors

Yu Bai

Yanyang Nan

Tao Wu

An Zhu

Xinlei Xie

Yun Sun

Yong Deng

Zihan Dou

Xiaozhi Hu

Rongrui Zhou

Shuwen Xu

Yuanzhen Zhang

Jiajun Fan

Dianwen Ju

Affiliations

Soon will be listed here.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of various chronic metabolic hepatic diseases with limited therapeutics. Rubicon, an essential regulator in lysosomal degradation, is reported to exacerbate hepatic steatosis in NAFLD mice and patients, indicating its probability of being a therapeutic target for NAFLD treatment. In this study, the therapeutic potential of Rubicon blockage is investigated. Lipid nanoparticles carrying Rubicon-specific CRISPR-Cas9 components exhibited liver accumulation, cell internalization, and Rubicon knockdown. A single administration of the nanoparticles results in attenuated lipid deposition and hepatic steatosis, with lower circulating lipid levels and decreased adipocyte size in NAFLD mice. Furthermore, the increase of phosphatidylcholine and phosphatidylethanolamine levels can be observed in the NAFLD mice livers after Rubicon silencing, along with regulatory effects on metabolism-related genes such as CD36, Gpcpd1, Chka, and Lpin2. The results indicate that knockdown of Rubicon improves glycerophospholipid metabolism and thereby ameliorates the NAFLD progression, which provides a potential strategy for NAFLD therapy via the restoration of Rubicon.

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Lipid Nanoparticle-Mediated Delivery of CRISPR-Cas9 Against Rubicon Ameliorates NAFLD by Modulating CD36 Along with Glycerophospholipid Metabolism.

Bai Y, Nan Y, Wu T, Zhu A, Xie X, Sun Y Adv Sci (Weinh). 2024; 11(31):e2400493.

PMID: 38894572 PMC: 11336963. DOI: 10.1002/advs.202400493.

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