Objective - Cholesterol homeostasis is fundamental to human health and is, thus, tightly regulated. MicroRNAs exert potent effects on biological pathways, including cholesterol metabolism, by repressing genes with related functions. We reasoned that this mode of pathway regulation could be exploited to identify novel genes involved in cholesterol homeostasis. Approach and Results - Here, we identify oxysterol-binding protein-like 6 (OSBPL6) as a novel target of 2 miRNA hubs regulating cholesterol homeostasis: miR-33 and miR-27b. Characterization of OSBPL6 revealed that it is transcriptionally regulated in macrophages and hepatocytes by liver X receptor and in response to cholesterol loading and in mice and nonhuman primates by Western diet feeding. OSBPL6 encodes the OSBPL-related protein 6 (ORP6), which contains dual membrane- and endoplasmic reticulum-targeting motifs. Subcellular localization studies showed that ORP6 is associated with the endolysosomal network and endoplasmic reticulum, suggesting a role for ORP6 in cholesterol trafficking between these compartments. Accordingly, knockdown of OSBPL6 results in aberrant clustering of endosomes and promotes the accumulation of free cholesterol in these structures, resulting in reduced cholesterol esterification at the endoplasmic reticulum. Conversely, ORP6 overexpression enhances cholesterol trafficking and efflux in macrophages and hepatocytes. Moreover, we show that hepatic expression of OSBPL6 is positively correlated with plasma levels of high-density lipoprotein cholesterol in a cohort of 200 healthy individuals, whereas its expression is reduced in human atherosclerotic plaques. Conclusions - These studies identify ORP6 as a novel regulator of cholesterol trafficking that is part of the miR-33 and miR-27b target gene networks that contribute to the maintenance of cholesterol homeostasis.
|Number of pages||10|
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|State||Published - May 1 2016|
Bibliographical noteFunding Information:
Support for this work came from the National Institutes of Health (R01HL108182 to K.J. Moore; R01HL119047 to K.J. Moore and K.J. Rayner; R01HL117226 to M.J. Garabedian, R00HL088528 to R.E. Temel; T32HL098129 to E.J. Hennessy, and T32AI07180 to M.A. Hussein), the German Research Foundation (DFG) as part of the CRC 1123 (Project B1; L.M. Holdt and D. Teupser), the American Heart Association (13POST14490016 to B. Ramkhelawon; 14POST20180018 to C. van Solingen), and Canadian Institutes of Health Research (M. Ouimet). The Biobank of Karolinska Endarterectomies (BiKE) study was conducted with support from the Swedish Heart and Lung Foundation, the Swedish Research Council, Uppdrag Besegra Stroke, the Strategic Cardiovascular Programs of Karolinska Institutet and Stockholm County Council, the Stockholm County Council, the Foundation for Strategic Research, and the European Commission (CarTarDis, AtheroRemo, VIA, and AtheroFlux projects).
© 2016 American Heart Association, Inc.
- cholesterol homeostasis
- lipids and lipoproteins
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine