title: Negative feedback regulation between microRNA let-7g and the oxLDL receptor LOX-1.
abstract: Lectin-like oxidized LDL receptor-1 (LOX-1) is a surface scavenger receptor for oxidized low-density lipoprotein (oxLDL). Several transcription factors have been reported to regulate LOX-1 expression. MicroRNAs are small noncoding RNAs that control gene expression, but there have been no reports of LOX-1 expression being regulated by microRNAs. Because the microRNA let-7g has been predicted to bind to LOX-1 mRNA, we investigated whether let-7g can regulate LOX-1 expression. Our experiments first demonstrated that oxLDL can reduce let-7g expression. We later confirmed that there is a let-7g binding site on the 3'-untranslated region of LOX-1 mRNA. We showed that intracellular Ca(2+)-activated protein kinase C is involved in the oxLDL-LOX-1-let-7g pathway. Bioinformatics predicted that the let-7g promoter has a binding site for the transcriptional repressor OCT-1. We used a promoter assay and chromatin immunoprecipitation to confirm this binding. Consequently, knockdown of OCT-1 was found to increase let-7g expression. Transfection of let-7g inhibited oxLDL-induced LOX-1 and OCT-1 expression, cell proliferation and migration. Mice fed with a high-fat diet showed a decrease in let-7g and an increase in LOX-1 and OCT-1. A study on humans showed the serum levels of let-7g are lower in subjects with hypercholesterolemia compared with normal controls. Our findings identify a negative feedback regulation between let-7g and LOX-1, and indicate that let-7g could be a target to treat cardiovascular disease.
authors.affiliation: Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung,  Taiwan.
authors.forename: Ku-Chung
authors.initials: KC
authors.lastname: Chen
authors.forename: I-Chung
authors.initials: IC
authors.lastname: Hsieh
authors.forename: Edward
authors.initials: E
authors.lastname: Hsi
authors.forename: Yung-Song
authors.initials: YS
authors.lastname: Wang
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Dai
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Chou
authors.forename: Suh-Hang Hank
authors.initials: SH
authors.lastname: Juo
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D061251:Primary Cell Culture; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014945:Wound Healing
chemical_list: D008077:Lipoproteins, LDL; D035683:MicroRNAs; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E; C487931:mirnlet7 microRNA, human; C099252:oxidized low density lipoprotein