Modulating SERCA Function to Improve Flux Dysregulation in Cardiometabolic Disease

Abstract

Cardiometabolic disease is characterized by metabolic dysregulations in several tissues throughout the body that increase the risk of developing cardiovascular disease. In fat-laden hepatocytes, mitochondrial metabolic fluxes are increased, linked to mitochondrial calcium accumulation from the inhibition of endoplasmic reticulum (ER) calcium reuptake. ER calcium reuptake is accomplished by sarco/endoplasmic reticulum calcium ATPase (SERCA). In the liver, the primary hepatic isoform, SERCA2b, is inhibited by allregulin (ALN), but little is known about the role of ALN in hepatic lipotoxicity, nor the role of SERCA activation to improve systemic cardiometabolic health. Using 13C tracer methodology and mathematical modeling, we were able to determine metabolic fluxes within cells and several tissues of interest. We generated ALN knockdown (KD) hepatocytes, finding that the ALN KD protected hepatocytes from lipotoxicity-induced cell death by restoring intracellular calcium compartmentation and reducing mitochondrial calcium. This led to the restoration of mitochondrial metabolic fluxes, with protection similar to that conferred by CDN1163. SERCA activation with CDN1163 alleviates the increase in hepatic fluxes in vivo and improves markers of systemic metabolic health in a mouse model of obesity. However, this improvement occurred independent of decreased food intake, suggesting a role for extrahepatic metabolism and shifts to energy balance to improve cardiometabolic health. We found that SERCA activation increases body temperature, resulting in a substrate switch to nonglycolytic sources for mitochondrial metabolism in the brown adipose tissue and gastrocnemius. Finally, due to the improvements in systemic metabolic health, we also studied the impact of SERCA activation on the heart itself, where SERCA2a dysfunction is linked to heart failure and disease. A greater fraction of mitochondrial acetyl‐coenzyme A was obtained from nonglycolytic sources to sustain citric acid cycle flux, corresponding to an increase in mitochondrial activity, without any impairments to basal cardiac function. In summary, this dissertation shows that activating SERCA has metabolically protective effects on mitochondrial flux in the liver, while increasing mitochondrial fluxes in thermogenic tissues and restoring substrate utilization in the heart. By shifting the burden of overnutrition away from the liver and onto the periphery, SERCA activation improves cardiometabolic health.