Hippo pathway activation causes multiple lipid derangements in a murine model of cardiomyopathy

Metabolic reprogramming occurs in cardiomyopathy and heart failure contributing to progression of the disease. Activation of cardiac Hippo pathway signaling has been implicated in mediating mitochondrial dysfunction and metabolic reprogramming in cardiomyopathy, albeit influence of Hippo pathway on lipid profile is unclear. Using a dual-omics approach, we determined alterations of cardiac lipids in a mouse model of cardiomyopathy due to enhanced Hippo signaling and explored molecular mechanisms. Lipidomic profiling discovered multiple alterations in lipid classes, notably reduction of triacylglycerol, diacylglycerol, phospholipids and ether lipids, and elevation of sphingolipids and lysophosphatidylcholine. Mechanistically, we found downregulated expression of PPARα and PGC-1α at mRNA and protein levels, and downregulated expression of PPARα-target genes, indicating attenuated transcriptional activity of PPARα/PGC-1α. Lipidomics-guided transcriptomic analysis revealed dysregulated expression of gene sets that were responsible for enhanced biosynthesis of ceramides, suppression of TG biosynthesis, storage, hydrolysis and mitochondrial fatty acid oxidation, and reduction of peroxisome-localized biosynthesis of ether lipids. Collectively, Hippo pathway activation with attenuated PPARα/PGC-1α signaling is the underlying mechanism for alterations in cardiac lipids in cardiomyopathy and failing heart.