Perturbation of energy and lipid homeostasis plays a central role in the pathogenesis of heart disease.Primary and/or secondary alterations of lipid metabolism pathways in various pathological conditions can lead to cardiac hypertrophy and heart failure due to bioenergetic defect and lipotoxicity.Therefore, to maintain optimal myocardial energy and lipid metabolism can be an effective therapeutic target in treating cardiac disorders.Ligand activated nuclear receptors such as peroxisome proliferator-activated receptors (PPARα, β/δ and γ) and liver X receptors (LXRα and β) have emerged as key transcriptional regulators of lipid and energy homeostasis.We have investigated the cardiac specific roles of these nuclear receptors using conditional gene targeting and transgenic approaches.Cardiac-specific knockout of either PPARδ or PPARγin mice led to cardiac hypertrophy and heart failure with perturbed myocardial lipid metabolism.In contrast, transgenic overexpression of a constitutively active form of PPARδ led to enhance both lipid and glucose metabolism and improved cardiac performance in mice.More importantly, our data demonstrated that both PPARδ and PPARγ play an important role regulating expression of key endogenous antioxidants.Furthermore, mice with cardiac-specific knockout of LXRα also showed disturbed myocardial lipid and glucose metabolism, impaired cardiac performance and cardiac remodeling.Therefore, nuclear receptors such as PPARs and LXRs may be novel therapeutic targets for the treatment and prevention of cardiac disorders.