| First Author | Zhao YC | Year | 2017 |
| Journal | Biochim Biophys Acta | Volume | 1863 |
| Issue | 8 | Pages | 1991-2000 |
| PubMed ID | 27825849 | Mgi Jnum | J:255907 |
| Mgi Id | MGI:6104950 | Doi | 10.1016/j.bbadis.2016.10.029 |
| Citation | Zhao YC, et al. (2017) Nuclear receptor retinoid-related orphan receptor alpha deficiency exacerbates high-fat diet-induced cardiac dysfunction despite improving metabolic abnormality. Biochim Biophys Acta 1863(8):1991-2000 |
| abstractText | Retinoid-related orphan receptor alpha (RORalpha), a member of the metabolic nuclear receptor superfamily, plays a vital regulatory role in circadian rhythm and metabolism. Here, we investigated the role of RORalpha in high-fat diet (HFD)-induced cardiac impairments and the underlying mechanisms involved. RORalpha-deficient stagger mice (sg/sg) and wild type (WT) littermates were fed with either standard diet or HFD. At 20weeks after HFD treatment, RORalpha 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, RORalpha deficiency impaired mitochondrial biogenesis and function. Additionally, RORalpha deficiency resulted in inhibition of the AMPK-PGC1alpha signaling pathway. In contrast, cardiomyocyte-specific RORalpha overexpression ameliorated myocardial hypertrophy, fibrosis and dysfunction by restoring AMPK-PGC1alpha signaling, and subsequently normalizing mitochondrial biogenesis. These findings demonstrated for the first time that nuclear receptor RORalpha deficiency aggravated HFD-induced myocardial dysfunction at least in part by impairing mitochondrial biogenesis in association with disrupting AMPK-PGC1alpha 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. |
