Abstract
Our study aimed to explore the function of circRNA_0001805 in the pathogenesis of NAFLD and the underlying mechanism. A nanodrug system (GA-RM/GZ/PL) was constructed to overexpress circRNA_0001805 specifically in hepatocytes for the treatment of NAFLD. Fat droplet accumulation in cultured cells and mouse hepatic tissues was detected using Oil Red O or H&E staining. The relative expression of circRNAs, genes associated with lipogenesis was quantified by qRT-PCR. Interactions between circRNA_0001805 and miR-106a-5p/miR-320a, between miR-106a-5p/miR-320a and ABCA1/CPT1 were confirmed by dual-luciferase reporter assay. A novel metalorganic framework nanocarrier (GZ) was prepared from glycyrrhizic acid and zinc ions (Zn2+), and this nanocarrier was loaded with the circRNA_0001805 plasmid to construct a nanocore (GZ/PL). Then, this GZ/PL was coated with a galactose-modified RBC membrane (GA-RM) to generate GA-RM/GZ/PL. CircRNA_0001805 expression was downregulated in FFA-challenged primary hepatocytes, HFD-fed mice and NAFLD patients. Overexpressed circRNA_0001805 attenuated NAFLD development by suppressing lipid metabolism disorder and inflammation. CircRNA_0001805 targeted miR-106a-5p/miR-320a, which served as an upstream inhibitor of ABCA1/CPT1 and collaboratively regulated NAFLD progression. GA-RM/GZ/PL targeted hepatocytes, overexpressed circRNA_0001805, released glycyrrhizic acid to reduce the accumulation of lipids in the liver and played a synergistic role against NAFLD-induced lipid metabolism disorder.Graphical
Highlights
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic hepatic diseases, and more than 20% of the world’s population is affected [1]
NAFLD is a disorder characterized by excess fat deposition in the liver that is not caused by alcohol consumption, and NAFLD may further progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC) due to chronic inflammation [2]
CircRNA_0001805 expression was downregulated in NAFLD The onset and development of NAFLD are often closely associated with the aberrant expression of hepatic genes, and a recent study by Guo et al reported that the expression of a total of 357 circRNAs was dysregulated in a hepatic steatosis cellular model; of these circRNAs, 154 were upregulated and 203 were downregulated
Summary
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic hepatic diseases, and more than 20% of the world’s population is affected [1]. NAFLD is mainly characterized by the accumulation of fatty acids and triglycerides in the liver, which increase the infiltration of macrophages and the expression level of inflammatory factors, such as TNF-α and IL-6 [8]. After activation by inflammatory factors (TNF-α and IL-6), IκB is phosphorylated by IK kinase (IKKβ) and dissociates from NF-κB, disinhibiting its activity [9]. NF-κB enters the nucleus and effectively induces the expression of inflammatory cytokines (TNF-α and IL-6), which play a cascading role in amplifying the inflammatory response [10]. The NF-κB signaling pathway plays a vital role in regulating NAFLD progression and represents a promising therapeutic target [11]
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