6-methylcoumarin/miR-122 suppresses hepatic Sortilin-mediated ApoB-100 secretion to attenuate aortic atherosclerosis.

Autor: Ming X; People's Hospital of Shaodong of Internship Teaching Base of Guilin Medical University & Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China., Chen S; People's Hospital of Shaodong of Internship Teaching Base of Guilin Medical University & Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China., Li H; People's Hospital of Shaodong of Internship Teaching Base of Guilin Medical University & Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China., Wang Y; People's Hospital of Shaodong of Internship Teaching Base of Guilin Medical University & Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China., Zeng H; People's Hospital of Shaodong of Internship Teaching Base of Guilin Medical University & Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China. Electronic address: 572409875@qq.com., Lv Y; People's Hospital of Shaodong of Internship Teaching Base of Guilin Medical University & Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China. Electronic address: anthony0723@163.com.
Jazyk: angličtina
Zdroj: Cellular signalling [Cell Signal] 2024 Dec; Vol. 124, pp. 111384. Date of Electronic Publication: 2024 Sep 05.
DOI: 10.1016/j.cellsig.2024.111384
Abstrakt: This study aimed to investigate the effects of hepatic microRNA-122 (miR-122) on Sortilin-mediated apolipoprotein B100 (apoB-100) secretion, and on aortic lipid deposition and atherosclerosis (AS) lesions and to clarify the antiatherosclerotic mechanism of 6-methylcoumarin (6-MC) via the modulation of miR-122. Bioinformatics analysis revealed that miR-122 was putatively overexpressed in a liver-specific manner and was downregulated in steatotic livers. miR-122 was shown to suppress the expression of Sortilin by complementarily pairing to the 3'-untranslated region (3'-UTR) of Sortilin mRNA via bioinformatics and dual-luciferase reporter assays, impeding Sortilin-mediated apoB-100 secretion from HepG2 cells. Administration of 6-MC significantly upregulated hepatocellular miR-122 levels, reducing Sortilin expression and apoB-100 secretion in HepG2 cells. The miR-122 mimic vigorously enhanced 6-MC-depressed Sortilin expression, while miR-122 inhibitor repealed the inhibitory effect of 6-MC on Sortilin expression to some extent in HepG2 cells. After internal intervention with the miR-122 precursor, and 6-MC supplementation alone or in combination with the miR-122 sponge led to the reduction in blood triglyceride (TG) levels, low-density lipoprotein-cholesterol (LDL-C) and apoB-100 and a reduction in aortic lipid deposition and AS lesions in apolipoprotein E-deficient (ApoE -/- ) mice fed a high fat diet (HFD). The hepatic levels of Sortilin and apoB-100 expression were also decreased in these treated mice. In conclusion, miR-122 suppresses Sortilin expression and Sortilin-mediated apoB-100 secretion to resist circulating LDL production and aortic AS development, which is enhanced by 6-MC-upregulated miR-122 in the liver.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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