title: Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXRα expression and cholesterol homeostasis.
abstract: Aberrant regulation of cholesterol homeostasis is associated with obesity as well as multiple types of cancer. However, the mechanism behind these is largely missing. Here, we show that microRNA (miRNA)-128-2 is not only a pro-apoptotic microRNA but it also alters the expression of genes involved in cellular cholesterol homeostasis. Cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1) is a mechanism for cells to eliminate excess cholesterol and prevent cellular cholesterol accumulation. The regulation of these pathways is complex with transcriptional regulation by sterol-regulatory element-binding protein (SREBP) and liver X receptor/retinoid X receptor (RXR) transcription factors but poorly understood at the post-transcriptional levels. MiR-128-2 increases the expression of SREBP2 and decreases the expression of SREBP1 in HepG2, MCF7 and HEK293T cells independent of sirtuin 1 (SIRT1) status. MiR-128-2 inhibits the expression of ABCA1, ABCG1 and RXRα directly through a miR-128-2-binding site within their respective 3'untranslated regions. The administration of miR-128-2 leads to decline in the protein and mRNA levels of ABCA1, ABCG1 and RXRα. Conversely, anti-miRNA treatment leads to increased ABCA1, ABCG1 and RXRα expression. The inverse correlation between miR-128-2 and its targets viz. ABCA1 and ABCG1 was also established during high-fat diet in different mice tissues. Our data show that cholesterol efflux is attenuated by miR-128-2 overexpression and, conversely, stimulated by miR-128-2 silencing. Further, we also observed the induction of ER stress response by miR-128-2. In this study, we provide the first evidence of miR-128-2 to be a new regulator of cholesterol homeostasis. Our study shows dual role of miR-128-2, as a pro-apoptotic molecule as well as a regulator of cholesterol homeostasis.
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Delhi, India.
authors.forename: Y K
authors.initials: YK
authors.lastname: Adlakha
authors.forename: S
authors.initials: S
authors.lastname: Khanna
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.forename: V P
authors.initials: VP
authors.lastname: Singh
authors.forename: A
authors.initials: A
authors.lastname: Agrawal
authors.forename: N
authors.initials: N
authors.lastname: Saini
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism*; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; C550324:Mirn128 microRNA, mouse; D047490:Retinoid X Receptor alpha; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D056564:Sirtuin 1