title: Cardiac LXRα protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization.
abstract: Pathological cardiac hypertrophy is characterized by a shift in metabolic substrate utilization from fatty acids to glucose, but the molecular events underlying the metabolic remodeling remain poorly understood. Here, we investigated the role of liver X receptors (LXRs), which are key regulators of glucose and lipid metabolism, in cardiac hypertrophic pathogenesis. Using a transgenic approach in mice, we show that overexpression of LXRα acts to protect the heart against hypertrophy, fibrosis, and dysfunction. Gene expression profiling studies revealed that genes regulating metabolic pathways were differentially expressed in hearts with elevated LXRα. Functionally, LXRα overexpression in isolated cardiomyocytes and murine hearts markedly enhanced the capacity for myocardial glucose uptake following hypertrophic stress. Conversely, this adaptive response was diminished in LXRα-deficient mice. Transcriptional changes induced by LXRα overexpression promoted energy-independent utilization of glucose via the hexosamine biosynthesis pathway, resulting in O-GlcNAc modification of GATA4 and Mef2c and the induction of cytoprotective natriuretic peptide expression. Our results identify LXRα as a key cardiac transcriptional regulator that helps orchestrate an adaptive metabolic response to chronic cardiac stress, and suggest that modulating LXRα may provide a unique opportunity for intervening in myocyte metabolism.
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Megan V
authors.initials: MV
authors.lastname: Cannon
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Herman H W
authors.initials: HH
authors.lastname: Silljé
authors.affiliation: Department of Nuclear Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jürgen W A
authors.initials: JW
authors.lastname: Sijbesma
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Vreeswijk-Baudoin
authors.affiliation: Department Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jolita
authors.initials: J
authors.lastname: Ciapaite
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van der Sluis
authors.affiliation: Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: van Deursen
authors.affiliation: Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Gustavo J J
authors.initials: GJ
authors.lastname: Silva
authors.affiliation: Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: de Windt
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX, USA Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands r.a.de.boer@umcg.nl.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control*; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism; D000071518:Liver X Receptors; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D005947:Glucose
keywords: O‐GlcNAcylation; glucose metabolism; left ventricular hypertrophy; liver X receptor; nuclear receptor