YAP mediates activation of the serine synthesis pathway in the heart during pressure overload

Activation of YAP during the acute phase of pressure overload induces compensatory cardiac hypertrophy by activating aerobic glycolysis. One potential mechanism mediating the salutary action of YAP is an accumulation of serine, which provides building blocks essential for the growth and survival of cardiomyocytes. We investigated the molecular mechanism through which YAP promotes serine accumulation in the heart during the acute phase of pressure overload. Overexpression of YAP upregulated PHGDH, PSAT1, PSPH, components of the serine synthesis pathway (SSP), and SHMT1, but not SHMT2, an enzyme involved in interconversion between serine and glycine, in cardiomyocytes at both the mRNA and protein levels. Upregulation of these enzymes during transverse aortic constriction (TAC) was abolished in cardiac specific Yap knockout (Yap-chKO) mice. Downregulation of Phgdh attenuated YAP-induced increases in SSP metabolites, including phospho-serine, serine, glycine and S-adenosylmethionine, in cultured cardiomyocytes. YAP also upregulated ASC-1, a serine transporter, in cardiomyocytes, and YAP-induced increases in serine content in cardiomyocytes were decreased in the presence of Asc-1 knock-down. YAP-induced increases in cardiomyocyte cell size were inhibited in the presence of siRNA targeting Phgdh, Psat1, Psph, Shmt1 or Asc-1, suggesting that the increase in serine content plays an important role in mediating YAP-induced hypertrophy in cardiomyocytes. TAC increased binding of YAP and TEAD1 to the promoters of the SSP genes, whereas YAP-induced upregulation of PHGDH and PSAT1 was inhibited in the presence of TEAD1 downregulation. These results suggest that YAP directly promotes expression of genes involved in serine synthesis and uptake in cardiomyocytes, and that upregulation of the serine content plays an important role in mediating YAP-induced cardiac hypertrophy.