Cardiac LXRα protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization.
Cardiac LXRα protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization.
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DOI：
10.15252/emmm.201404669
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发表时间：
2015-09
影响因子：
11.1
通讯作者：
de Boer RA
中科院分区：
文献类型：
--
作者：
Cannon MV;Silljé HH;Sijbesma JW;Vreeswijk-Baudoin I;Ciapaite J;van der Sluis B;van Deursen J;Silva GJ;de Windt LJ;Gustafsson JÅ;van der Harst P;van Gilst WH;de Boer RA
病理性心脏肥大的特点是代谢底物利用从脂肪酸转向葡萄糖，但代谢重塑背后的分子事件仍然知之甚少。在这里，我们研究了肝脏 X 受体 (LXR) 在心脏肥大发病机制中的作用，肝脏 X 受体是葡萄糖和脂质代谢的关键调节因子。通过在小鼠中进行转基因方法，我们发现 LXRα 的过度表达可以保护心脏免受肥大、纤维化和功能障碍的影响。基因表达谱研究表明，调节代谢途径的基因在 LXRα 升高的心脏中存在差异表达。从功能上讲，LXRα在离体心肌细胞和小鼠心脏中的过度表达显着增强了肥厚应激后心肌葡萄糖摄取的能力。相反，这种适应性反应在 LXRα 缺陷小鼠中减弱。 LXRα 过表达诱导的转录变化通过己糖胺生物合成途径促进葡萄糖的能量独立利用，导致 GATA4 和 Mef2c 的 O-GlcNAc 修饰，并诱导细胞保护性利钠肽表达。我们的结果确定 LXRα 是一种关键的心脏转录调节因子，有助于协调对慢性心脏应激的适应性代谢反应，并表明调节 LXRα 可能为干预心肌细胞代谢提供独特的机会。
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.