Open AccessCardiac LXR α protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization
Author(s) -
Can Megan V,
Silljé Herman HW,
Sijbesma Jürgen WA,
VreeswijkBaudoin Inge,
Ciapaite Jolita,
van der Sluis Bart,
van Deursen Jan,
Silva Gustavo JJ,
de Windt Leon J,
Gustafsson JanÅke,
van der Harst Pim,
van Gilst Wiek H,
de Boer Rudolf A
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404669
Subject(s) - liver x receptor , biology , medicine , endocrinology , lipid metabolism , cardiac fibrosis , atrial natriuretic peptide , fibrosis , microbiology and biotechnology , transcription factor , nuclear receptor , biochemistry , gene
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 ( LXR s), which are key regulators of glucose and lipid metabolism, in cardiac hypertrophic pathogenesis. Using a transgenic approach in mice, we show that overexpression of LXR α 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 LXR α. Functionally, LXR α 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 LXR α‐deficient mice. Transcriptional changes induced by LXR α overexpression promoted energy‐independent utilization of glucose via the hexosamine biosynthesis pathway, resulting in O‐Glc NA c modification of GATA 4 and Mef2c and the induction of cytoprotective natriuretic peptide expression. Our results identify LXR α as a key cardiac transcriptional regulator that helps orchestrate an adaptive metabolic response to chronic cardiac stress, and suggest that modulating LXR α may provide a unique opportunity for intervening in myocyte metabolism.