Nuclear receptor retinoid-related orphan receptor α deficiency exacerbates high-fat diet-induced cardiac dysfunction despite improving metabolic abnormality.
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 20weeks 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.
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Yi-Chao
YC
Zhao
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Long-Wei
LW
Xu
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Song
S
Ding
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Qing-Qi
QQ
Ji
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Nan
N
Lin
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Qing
Q
He
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Ling-Chen
LC
Gao
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China.
Yuan-Yuan
YY
Su
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China. Electronic address: pujun310@hotmail.com.
Jun
J
Pu
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 PuJian Road, Shanghai 200127, China. Electronic address: heben1025@hotmail.com.
Ben
B
He
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000172:deficiency*; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D004041:Dietary Fats; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C539739:Rora protein, mouse; D055372:AMP-Activated Protein Kinases
Mitochondrial biogenesis; Myocardial hypertrophy; PGC1α; RORα