Abstract 813: Exercise Attenuates Heart failure in Cardiac Lipoprotein Lipase/CD36 Double Knockout Mice
The adult heart derives 70% of its ATP from fatty acids (FA), many of which are delivered via lipoprotein lipase (LpL) mediated hydrolysis of lipoproteins, followed by diffusion or uptake through FAT/CD36. In heart failure, metabolism shifts towards increased glucose utilization and less FA oxidation. Mechanisms by which exercise improves heart function in heart failure are not fully understood. We hypothesized that exercise mediated improvements in heart function require improved substrate uptake via induction of LpL and CD36. We created 4 groups of mice (n=9 –10/group): control, CD36 Knockout (Cd36−/−), cardiac LpL Knockout (hLpL0), and Double Knockout (DKO, hLpL0/Cd36−/−). Heart lipid uptake, measured using radiolabeled human VLDL and mouse chylomicrons, showed a significant reduction in cardiac VLDL-TG uptake in hLpL0 (49±23%), Cd36−/− (64±17%) and DKO (76±5%; p<0.05) compared to controls. This reduction tended to be higher in DKO compared to hLpL0 and Cd36−/− mice, but was not statistically significant. Reduced uptake of chylomicron TG-derived FA however, was only found in DKO. Interestingly, loss of cardiac LpL reduced cardiac VLDL-cholesteryl ester (CE) uptake in hLpL0 (81%) and DKO (73%) (p<0.05), but not in CD36−/− mice. Similarly, vitamin A (RE) uptake was reduced in both hLpL0 and DKO mice but not in CD36−/−. Mice were assigned to sedentary or exercise (swimming) groups at 14 weeks. Cardiac function, assessed by echocardiography, was reduced in sedentary DKO mice (%fractional shortening (%FS) 26.6 vs 37.6 in controls; p<0.05), and tended to decrease %FS in hLpL0 mice (%FS=33.9; p=0.35), but was normal in Cd36−/− mice. Surprisingly, exercise training in DKO mice led to an improvement in %FS (33.6; p=0.09) and normalization of heart failure gene expression (p<0.05). Exercise also improved heart function in hLpL0 mice (%FS=40.9; p<0.05). In summary, LpL and CD36 work in conjunction to contribute to TG-derived cardiac FA uptake but only loss of LpL reduces CE and RE uptake and causes heart dysfunction. Exercise training attenuates heart failure in DKO mice and improves cardiac function in hLpL0 mice. We postulate that exercise induces glucose uptake pathways that compensate for defective lipid delivery in these models.