THE ROLE OF LIPID PHOSPHATE PHOSPHATASE 3 IN CARDIAC ENERGY METABOLISM

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid that is generated by autotaxin (ATX) in circulation and is implicated in obesity induced cardiomyopathy. LPA signaling is terminated by lipid phosphate phosphatase 3 (LPP3) through dephosphorylation to monoacylglycerol (MAG). Plasma LPA increases with obesity and contributes to cardiovascular complications. Prior data from our lab show that heterozygous whole body ATX knockout mice are partially protected from diet-induced obesity and cardiomyocyte contractile dysfunction. We hypothesized that reducing LPA signaling in cardiomyocytes by selectively overexpressing LPP3 in the heart protects from obesity-induced cardiomyopathy. In mice with cardiomyocyte-specific LPP3 overexpression (LPP3OE) plasma LPA levels were reduced by 57% and 41% in low fat diet fed (LFD) males and females, respectively, compared to the LFD control group, which was associated with enhanced pyruvate-linked mitochondrial respiration in LPP3OE hearts. After 20 weeks of high fat diet (HFD) feeding, female LPP3OE mice showed reduced body weight gain and protection from impaired insulin sensitivity and cardiac dysfunction, which was paralleled by reduced plasma LPA levels and enhanced pyruvate linked mitochondrial respiration in cardiac myofibers compared to HFD-fed control mice. Female LPP3OE mice were also protected from HFD-induced cardiac hypertrophy. Interestingly, this cardiometabolic protective effect was not observed in HFD-fed male LPP3OE mice. Taken together, my thesis work identified LPP3 in cardiomyocytes as a regulator of circulating LPA levels, mitochondrial metabolism, and cardiac function. This work also suggests that targeting the LPA-LPP3 signaling pathway could be explored as a therapeutic strategy to treat obesity-induced cardiomyopathy, particularly in women.