TY - JOUR
T1 - MiRNA targeting of oxysterol-binding protein-like 6 regulates cholesterol trafficking and efflux
AU - Ouimet, Mireille
AU - Hennessy, Elizabeth J.
AU - Van Solingen, Coen
AU - Koelwyn, Graeme J.
AU - Hussein, Maryem A.
AU - Ramkhelawon, Bhama
AU - Rayner, Katey J.
AU - Temel, Ryan E.
AU - Perisic, Ljubica
AU - Hedin, Ulf
AU - Maegdefessel, Lars
AU - Garabedian, Michael J.
AU - Holdt, Lesca M.
AU - Teupser, Daniel
AU - Moore, Kathryn J.
N1 - Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - cholesterol
KW - cholesterol homeostasis
KW - lipids and lipoproteins
KW - macrophages
KW - microRNA
UR - http://www.scopus.com/inward/record.url?scp=84960157214&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84960157214&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.116.307282
DO - 10.1161/ATVBAHA.116.307282
M3 - Article
C2 - 26941018
AN - SCOPUS:84960157214
SN - 1079-5642
VL - 36
SP - 942
EP - 951
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 5
ER -