ATGL-Catalyzed Lipolysis Regulates SIRT1 to Control PGC-1α/PPAR-α Signaling

Sirtuin 1 (SIRT1), an NAD(+)-dependent protein deacetylase, regulates a host of target proteins, including peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 alpha (PGC-1 alpha), a transcriptional coregulator that binds to numerous transcription factors in response to deacetylation to promote mitochondrial biogenesis and oxidative metabolism. Our laboratory and others have shown that adipose triglyceride lipase (ATGL) increases the activity of the nuclear receptor PPAR-alpha, a PGC-1 alpha binding partner, to promote fatty acid oxidation. Fatty acids bind and activate PPAR-alpha; therefore, it has been presumed that fatty acids derived from ATGL-catalyzed lipolysis act as PPAR-alpha ligands. We provide an alternate mechanism that links ATGL to PPAR-alpha signaling. We show that SIRT1 deacetylase activity is positively regulated by ATGL to promote PGC-la signaling. In addition, ATGL mediates the effects of beta-adrenergic signaling on SIRT1 activity, and PGC-1 alpha and PPAR-alpha target gene expression independent of changes in NAD(+). Moreover, SIRT1 is required for the induction of PGC-1 alpha/PPAR-alpha target genes and oxidative metabolism in response to increased ATGL-mediated lipolysis. Taken together, this work identifies SIRT1 as a critical node that links p-adrenergic signaling and lipolysis to changes in the transcriptional regulation of oxidative metabolism.