Adipose Triglyceride Lipase Mediated Regulation Of Sirtuin1 And Lipophagy

Thumbnail Image

Persistent link to this item

View Statistics

Journal Title

Journal ISSN

Volume Title


Adipose Triglyceride Lipase Mediated Regulation Of Sirtuin1 And Lipophagy

Published Date




Thesis or Dissertation


An over-accumulation of triacylglycerol (TAG) within the liver results in non-alcoholic fatty liver disease (NAFLD), which may progress to more severe states including cirrhosis and fibrosis, finally leading to liver injury and death. In most cases, the etiology of NAFLD is not completely understood but has been primarily linked to the occurrence of insulin resistance, which often accompanies obesity, dyslipidemia and Type 2 Diabetes. Previously, our laboratory discovered that adipose triglyceride lipase (ATGL) catalyzes TAG hydrolysis in the liver and partitions the hydrolyzed fatty acids to oxidative pathways. Additionally, ATGL promotes fatty acid oxidation in part through its induction of peroxisome proliferator activated receptor-α (PPAR-α) and its co-activator PPAR-γ coactivator-1α (PGC-1α) signaling. The objective of this work is to further elucidate the mechanisms underlying ATGL’s effects on lipid metabolism and signaling. Herein, we show that ATGL activates the protein deacetylase sirtuin 1 (SIRT1) which subsequently deacetylates and activates PGC1-α and PPAR-α to promote transcriptional regulation of mitochondrial biogenesis and FA oxidation. ATGL preferentially cleaves FA oleate from TAG to induce SIRT1 enzyme activity in a dose-dependent manner; other FA species had no effect. Moreover, ATGL requires SIRT1 for the induction of PGC-1α/PPAR-α target genes and oxidative metabolism. ATGL also mediates the effect of β-adrenergic signaling on SIRT1 activity and PGC-1α and PPAR-α target gene expression. This work is the first to identify an endogenous activator of SIRT1 that couples β-adrenergic signaling and lipolysis activation to enhanced transcriptional regulation of oxidative metabolism. In addition to increased SIRT1 activity and downstream oxidative metabolism, our research reveals that ATGL activation induces a cellular recycling process called autophagy. In particular, ATGL requires functional autophagy to mediate its effects on lipid depletion in a SIRT1 dependent manner. In addition, ATGL requires SIRT1 to exert its effects on TAG turnover via autophagy. In addition, we show that ATGL mediates FA secretion via the lysosome, as confirmed in both in vitro and in vivo models, in response to fasting. Interestingly, these effluxed FAs undergo a reuptake process before being oxidized or reesterified into existing TAG depots. Overall, these data challenge the current dogma of hepatic lipid metabolism and advance our understanding of lipid droplet biology.



University of Minnesota Ph.D. dissertation. August 2016. Major: Nutrition. Advisor: Douglas Mashek. 1 computer file (PDF); viii, 155 pages.

Related to




Series/Report Number

Funding information

Isbn identifier

Doi identifier

Previously Published Citation

Suggested citation

Sathyanarayan, Aishwarya. (2016). Adipose Triglyceride Lipase Mediated Regulation Of Sirtuin1 And Lipophagy. Retrieved from the University Digital Conservancy,

Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.