Nuclear receptor retinoid-related orphan receptor α deficiency exacerbates high-fat diet-induced cardiac dysfunction despite improving metabolic abnormality.
Nuclear receptor retinoid-related orphan receptor α deficiency exacerbates high-fat diet-induced cardiac dysfunction despite improving metabolic abnormality.
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尽管改善了代谢异常，但核受体视黄醇相关的孤儿受体α缺乏却加剧了高脂肪饮食引起的心脏功能障碍。
DOI：
10.1016/j.bbadis.2016.10.029
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
He B
中科院分区：
文献类型：
--
作者：
Gao LC;Su YY;Pu J;He B
类维生素A相关孤儿受体α（RORα）是代谢核受体超家族的成员，对昼夜节律和代谢起着重要的调节作用。在此，我们研究了RORα在高脂饮食（HFD）诱导的心脏损伤中的作用及其相关机制。RORα缺陷型交错小鼠（sg/sg）和野生型（WT）同窝小鼠饲喂标准饲料或HFD。在HFD治疗后20周，与WT对照组相比，RORα缺乏导致体重增加显著降低，血脂异常改善，胰岛素抵抗改善（通过血液生化和葡萄糖/胰岛素耐量试验评估）。然而，与HFD处理的WT小鼠相比，HFD处理的sg/sg小鼠表现出显著增加的心肌肥大、心脏纤维化（麦胚凝集素、马森三色和天狼星红染色）和心功能不全（超声心动图和血流动力学）。RORα缺乏会损害线粒体的生物发生和功能。此外，RORα缺陷导致AMPK-PGC 1 α信号通路的抑制。相比之下，心肌细胞特异性RORα过表达通过恢复AMPK-PGC 1 α信号传导，随后使线粒体生物合成正常化，从而改善心肌肥大、纤维化和功能障碍。这些研究结果首次证明，核受体RORα缺陷至少部分通过损害线粒体生物合成以及破坏AMPK-PGC 1 α信号转导来加重HFD诱导的心肌功能障碍。这篇文章是特刊的一部分，题为：心力衰竭的遗传和表观遗传控制-由Jun Ren和Megan Yingmei Zhang编辑。
Retinoid-related orphan receptor α (RORα), a member of the metabolic nuclear receptor superfamily, plays a vital regulatory role in circadian rhythm and metabolism. Here, we investigated the role of RORα in high-fat diet (HFD)-induced cardiac impairments and the underlying mechanisms involved. RORα-deficient stagger mice (sg/sg) and wild type (WT) littermates were fed with either standard diet or HFD. At 20 weeks after HFD treatment, RORα deficiency resulted in significantly decreased body weight gain, improved dyslipidemia and ameliorated insulin resistance (evaluated by blood biochemical and glucose/insulin tolerance tests) compared with WT control. However, compared with HFD-treated WT mice, HFD-treated sg/sg mice exhibited significantly augmented myocardial hypertrophy, cardiac fibrosis (wheat germ agglutinin, masson trichrome and sirius red staining) and cardiac dysfunction (echocardiography and hemodynamics). Mechanistically, RORα deficiency impaired mitochondrial biogenesis and function. Additionally, RORα deficiency resulted in inhibition of the AMPK-PGC1α signaling pathway. In contrast, cardiomyocyte-specific RORα overexpression ameliorated myocardial hypertrophy, fibrosis and dysfunction by restoring AMPK-PGC1α signaling, and subsequently normalizing mitochondrial biogenesis. These findings demonstrated for the first time that nuclear receptor RORα deficiency aggravated HFD-induced myocardial dysfunction at least in part by impairing mitochondrial biogenesis in association with disrupting AMPK-PGC1α signaling. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren and Megan Yingmei Zhang.
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DOI：
10.1007/978-3-319-77525-8_100075
发表时间：
2018-12
期刊：
Encyclopedia of Big Data Technologies
影响因子：
--
作者：
通讯作者：
--
影响因子：
3
作者：
通讯作者：
--
DOI：
10.1210/jcem.85.1.6229
发表时间：
2000
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1109/icmas.2000.858517
发表时间：
2000-07
期刊：
Proceedings Fourth International Conference on MultiAgent Systems
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.4
作者：
Jones OD;Schall JD;Shen FX
通讯作者：
Shen FX