Metabolic impairment in response to early induction of C/EBPβ leads to compromised cardiac function during pathological hypertrophy.

Chronic pressure overload-induced left ventricular hypertrophy in heart is preceded by a metabolic perturbation that prefers glucose over lipid as substrate for energy requirement. Here, we establish C/EBPβ (CCAAT/enhancer-binding protein β) as an early marker of the metabolic derangement that triggers the imbalance in fatty acid (FA) oxidation and glucose uptake with increased lipid accumulation in cardiomyocytes during pathological hypertrophy, leading to contractile dysfunction and endoplasmic reticulum (ER) stress. This is the first study that shows that myocardium-targeted C/EBPβ knockdown prevents the impaired cardiac function during cardiac hypertrophy led by maladaptive metabolic response with persistent hypertrophic stimuli, whereas its targeted overexpression in control increases lipid accumulation significantly compared to control hearts. A new observation from this study was the dual and opposite transcriptional regulation of the alpha and gamma isoforms of Peroxisomal proliferator activated receptors (PPARα and PPARγ) by C/EBPβ in hypertrophied cardiomyocytes. Before the functional and structural remodeling sets in the diseased myocardium, C/EBPβ aggravates lipid accumulation with the aid of the increased FA uptake involving induced PPARγ expression and decreased fatty acid oxidation (FAO) by suppressing PPARα expression. Glucose uptake into cardiomyocytes was greatly increased by C/EBPβ via PPARα suppression. The activation of mammalian target of rapamycin complex-1 (mTORC1) during increased workload in presence of glucose as the only substrate was prevented by C/EBPβ knockdown, thereby abating contractile dysfunction in cardiomyocytes. Our study thus suggests that C/EBPβ may be considered as a novel cellular marker for deranged metabolic milieu before the heart pathologically remodels itself during hypertrophy. Unlabelled Image • Myocardium-targeted knockdown of C/EBPβ prevents cardiac hypertrophy. • C/EBPβ induction precedes metabolic deregulation during cardiac hypertrophy. • Stress-induced C/EBPβ promotes substrate switch from lipid to glucose in heart. • C/EBPβ induces PPARγ expression leading to excess lipid accumulation and ER stress. • C/EBPβ modulates glucose metabolism via PPARα, activating mTORC1. [ABSTRACT FROM AUTHOR]