Hepatic ATGL manipulation regulates lipid metabolism through altered autophagy

Abstract

Adipose triglyceride lipase (ATGL) catalyzes the rate‐limiting step of triacylglycerol (TAG) hydrolysis in multiple tissues. Our laboratory has previously shown that hepatic ATGL preferentially channels hydrolyzed fatty acids (FAs) to β‐oxidation with a concomitant induction of peroxisome proliferator activated receptor‐α (PPAR‐α), independent of a FA carrier. Additionally, our work describes a novel signaling axis involving cAMP/PKA, ATGL‐catalyzed lipolysis and sirtuin1 (SIRT1) activation that governs transcriptional regulation of oxidative metabolism and mitochondrial biogenesis. Recent studies have also shown SIRT1 promotes autophagy, which also contributes to lipid droplet catabolism (lipophagy). Thus, the objective of these studies is to determine the effects of ATGL on autophagy in the liver. Hepatic ATGL overexpression promotes the expression of autophagy genes, whereas ATGL knockdown reduces the expression of the same genes. ATGL regulates autophagosome biogenesis and lysosomal levels through alterations in the microtubule‐associated protein 1A/1B‐light chain 3 (LC3), sequestome1 (p62) and lysosomal‐associated membrane protein 1 (LAMP1). Use of a chemical inhibitor of ATGL, ATGListatin (Astat) in hepatocytes shows a marked suppression of autophagy, similar to the effects observed with ATGL knockdown in vivo. Finally, ATGL requires SIRT1 to govern its effects on autophagy as evidenced by studies showing that ATGL overexpression in liver‐specific SIRT1 KO mice is unable to induce autophagy. Thus, our findings identify ATGL‐mediated lipolysis as an important and potent regulator of autophagy that could have important implications for NAFLD etiology and its comorbidities.Support or Funding InformationFunding sources include the NIDDK (DK085008 to DGM) and the Minnesota Obesity Center (DK050456).