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ATGL‐catalyzed lipolysis regulates SIRT1 to control PGC‐1 a /PPAR‐ a signaling
Author(s) -
Sathyanarayan Aishwarya,
Khan Salmaan,
Mashek Mara,
Mashek Douglas
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.885.24
Subject(s) - sirtuin 1 , mitochondrial biogenesis , adipose triglyceride lipase , peroxisome proliferator activated receptor , microbiology and biotechnology , coactivator , chemistry , lipolysis , peroxisome , transcription factor , receptor , biology , adipose tissue , biochemistry , downregulation and upregulation , mitochondrion , gene
Ample research has shown that adipose triacylglycerol lipase (ATGL) increases the activity of the nuclear receptor peroxisome proliferator‐activated receptor‐a (PPAR‐α), a PPAR‐γ coactivator‐1a (PGC‐1α) binding partner, to promote fatty acid (FA) oxidation. Since FAs bind and activate PPAR‐a, it has been presumed that FAs derived from ATGL‐catalyzed lipolysis act as PPAR‐a ligands. However, our laboratory has shown that administration of fenofibrate, a PPAR‐α ligand, was unable to rescue PPAR‐α target gene expression in the absence of ATGL suggesting an alternate mechanism must exist. Sirtuin 1 (SIRT1) is a NAD + dependent protein deacetylase that regulates deacetylation of a host of target proteins including PGC‐1a, a transcriptional co‐regulator that binds numerous transcription factors to promote oxidative metabolism and mitochondrial biogenesis. Thus, given the importance of SIRT1 in regulating PGC‐1a and subsequently PPAR‐a, we investigated if ATGL manipulations altered SIRT1 activity thus regulating the expression of oxidative genes. We show that SIRT1 deacetylase activity is positively regulated by ATGL to promote PGC‐1a signaling. In addition, ATGL mediates the effects of b‐adrenergic signaling on SIRT1 activity and downstream PGC‐1a/PPAR‐a target gene expression. Furthermore, we demonstrate that SIRT1 is required for induction of PGC‐1a/PPAR‐a target genes and oxidative metabolism in response to increased ATGL‐mediated lipolysis. Taken together, our work describes a novel signaling axis involving b‐adrenergic signaling, ATGL‐catalyzed lipolysis and SIRT1 activation that governs transcriptional regulation of oxidative metabolism and mitochondrial biogenesis. Funding sources include: NIDDK (DK085008 to DGM) and Minnesota Obesity Center (DK050456).