PPARδ activation improves cardiac mitochondrial homeostasis in desmin deficient mice but does not alleviate systolic dysfunction.

Peroxisome proliferator-activated receptor (PPAR) δ is a major transcriptional regulator of cardiac energy metabolism with pleiotropic properties, including anti-inflammatory, anti-oxidative and cardioprotective action. In this study, we sought to investigate whether pharmacological activation of PPARδ via intraperitoneal administration of the selective ligand GW0742 could ameliorate heart failure and mitochondrial dysfunction that have been previously reported in a characterized genetic model of heart failure, the desmin null mice (Des-/-). Our studies demonstrate that treatment of Des-/- mice with the PPARδ agonist attenuated cardiac inflammation, fibrosis and cardiac remodeling. In addition, PPARδ activation alleviated oxidative stress in the failing myocardium as evidenced by decreased ROS levels. Importantly, PPARδ activation stimulated mitochondrial biogenesis, prevented mitochondrial and sarcoplasmic reticulum vacuolar degeneration and improved the mitochondrial intracellular distribution. Finally, PPARδ activation alleviated the mitochondrial respiratory dysfunction, prevented energy depletion and alleviated excessive autophagy and mitophagy in Des-/- hearts. Nevertheless, improvement of all these parameters did not suffice to overcome the significant structural deficiencies that desmin deletion incurs in cardiomyocytes and cardiac function did not improve significantly. In conclusion, pharmacological PPARδ activation in Des-/- hearts exerts protective effects during myocardial degeneration and heart failure by preserving the function and quality of the mitochondrial network. These findings implicate PPARδ agonists as a supplemental constituent of heart failure medications.

Partial validation of a six-month high-fat diet and fructose-glucose drink combination as a mouse model of nonalcoholic fatty liver disease.

PURPOSE: The need to investigate the pathogenesis and treatment of nonalcoholic fatty liver disease (NAFLD) has led to the development of multiple mouse models. The aim of this study was to validate a fast food diet (FFD) mouse model that is introduced as being close to the human disease. METHODS: Eight to nine weeks old male and female C57BL/6 J mice were randomly allocated to a FFD group or to a chow diet (CD) group. Every four weeks, mice were weighed, and blood samples were collected for the measurement of glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TGs) and total cholesterol. After 25 weeks, mice were sacrificed, and liver tissue was histologically evaluated. RESULTS: FFD mice gained more weight (p = 0.049) and presented a higher liver-to-body weight ratio (p < 0.001) compared to CD mice. FFD group presented with greater steatosis, hepatocellular ballooning and NAFLD activity score (NAS), whereas lobular inflammation and fibrosis were not significantly different compared to CD. When stratified by sex, NAS was different between FFD and CD groups in both male and female mice. Group by time interaction was significant for weight, ALT and cholesterol, but not for glucose, AST and TGs. CONCLUSION: FFD mice presented with morphologic and biochemical features of NAFLD and with greater hepatic steatosis, hepatocellular ballooning and NAS, but not lobular inflammation and fibrosis, compared to CD mice. These results only partly validate the FFD mouse model for NAFLD, at least for a 6-month feeding period.