KLF7 Alleviates Atherosclerotic Lesions and Inhibits Glucose Metabolic Reprogramming in Macrophages by Regulating HDAC4/miR-148b-3p/NCOR1.

Atherosclerosis (AS) remains a major contributor to death worldwide. This study sought to explore the role of Krüppel-like factor 7 (KLF7) in AS lesions via regulating glucose metabolic reprogramming (GMR) in macrophages.AS mouse and cell models were established via high-fat-diet feeding and oxidized low-density lipoprotein (ox-LDL) induction. KLF7, histone deacetylase 4 (HDAC4), miR-148b-3p, and nuclear receptor corepressor 1 (NCOR1) expressions in aortic tissue and cells were detected via reverse transcription quantitative polymerase chain reaction or Western blotting. Parameters of AS lesions and mouse metabolism were detected via hematoxylin-eosin, oil red O, and Masson staining, assay kits, glucose tolerance test, and enzymatic analysis. Peritoneal macrophages of mice were isolated and cellular metabolism was detected via Seahorse metabolic flux analysis, assay kits, ELISA, and Western blotting. Bindings among KLF7, HDAC4, microRNA (miR)-148b-3p, and NCOR1 were testified via the dual-luciferase assay and chromatin immunoprecipitation assay.KLF7 was poorly expressed in AS mice and ox-LDL-induced RAW264.7 cells. KLF7 overexpression attenuated AS lesions and rescued metabolic abnormities in AS mice, and reduced glucose intake and GMR in ox-LDL-induced RAW264.7 cells. Mechanically, KLF7 bound to the HDAC4 promoter to activate HDAC4. HDAC4 reduced H3 and H4 acetylation levels in the miR-148b promoter to inhibit miR-148b-3p and promote NCOR1 transcription. HDAC4 downregulation abolished the protective role of KLF7 overexpression in AS mice and ox-LDL-induced RAW264.7 cells via the miR-148b-3p/NCOR1 axis.KLF7 bound to the HDAC4 promoter to activate HDAC4, inhibit miR-148b-3p via reducing acetylation level, and promote NCOR1 transcription, thereby limiting GMR in macrophages and alleviating AS lesions.© 2022 S. Karger AG, Basel.

Citation

Fangyuan Chen, Juanli Li, Tao Zheng, Tao Chen, Zuyi Yuan. KLF7 Alleviates Atherosclerotic Lesions and Inhibits Glucose Metabolic Reprogramming in Macrophages by Regulating HDAC4/miR-148b-3p/NCOR1. Gerontology. 2022 Apr 19:1-20

PMID: 35439761

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