title: Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis.
abstract: Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Under conditions of excess cholesterol, LXR activation induces the expression of several genes involved in cholesterol efflux, facilitates cholesterol esterification by promoting fatty acid synthesis, and inhibits cholesterol uptake by the low-density lipoprotein receptor. The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways are incompletely understood. Here we show that ligand activation of LXRs in mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as a mediator of this effect. Hepatic LeXis expression is robustly induced in response to a Western diet (high in fat and cholesterol) or to pharmacological LXR activation. Raising or lowering LeXis levels in the liver affects the expression of genes involved in cholesterol biosynthesis and alters the cholesterol levels in the liver and plasma. LeXis interacts with and affects the DNA interactions of RALY, a heterogeneous ribonucleoprotein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the mouse liver. These findings outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.|Department of Medicine, Division of Cardiology, University of California, Los Angeles, California 90095, USA.
authors.forename: Tamer
authors.initials: T
authors.lastname: Sallam
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Marius C
authors.initials: MC
authors.lastname: Jones
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gilliland
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.|Department of Medicine, Division of Cardiology, University of California, Los Angeles, California 90095, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.affiliation: Departement of Human Genetics, University of California, Los Angeles, California 90095, USA.
authors.forename: Ascia
authors.initials: A
authors.lastname: Eskin
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Sandhu
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: David
authors.initials: D
authors.lastname: Casero
authors.affiliation: Department of Medicine, Division of Cardiology, University of California, Los Angeles, California 90095, USA.
authors.forename: Thomas Q de Aguiar
authors.initials: TQ
authors.lastname: Vallim
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California 92008, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Katz
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California 92008, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lee
authors.affiliation: Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Whitelegge
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D066273:Diet, Western; D004041:Dietary Fats / Q000494:pharmacology; D005786:Gene Expression Regulation; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D062085:RNA, Long Noncoding; C484219:Raly protein, mouse; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol