Cardiomyocyte-Restricted Deletion of PPARβ/δin PPARα-Null Mice Causes Impaired Mitochondrial Biogenesis and Defense, but No Further Depression of Myocardial Fatty Acid Oxidation

It is well documented that PPAR α and PPAR β / δ share overlapping functions in regulating myocardial lipid metabolism. However, previous studies demonstrated that cardiomyocyte-restricted PPAR β / δ deficiency in mice leads to severe cardiac pathological development, whereas global PPAR α knockout shows a benign cardiac phenotype. It is unknown whether a PPAR α -null background would alter the pathological development in mice with cardiomyocyte-restricted PPAR β / δ deficiency. In the present study, a mouse model with long-term PPAR β / δ deficiency in PPAR α -null background showed a comparably reduced cardiac expression of lipid metabolism to those of single PPAR-deficient mouse models. The PPAR α -null background did not rescue or aggravate the cardiac pathological development linked to cardiomyocyte-restricted PPAR β / δ deficiency. Moreover, PPAR α -null did not alter the phenotypic development in adult mice with the short-term deletion of PPAR β / δ in their hearts, which showed mitochondrial abnormalities, depressed cardiac performance, and cardiac hypertrophy with attenuated expression of key factors in mitochondrial biogenesis and defense. The present study demonstrates that cardiomyocyte-restricted deletion of PPAR β / δ in PPAR α -null mice causes impaired mitochondrial biogenesis and defense, but no further depression of fatty acid oxidation. Therefore, PPAR β / δ is essential for maintaining mitochondrial biogenesis and defense in cardiomyocytes independent of PPAR α .