PEDF promotes nuclear degradation of ATGL through COP1

Abstract

Adipose triglyceride lipase (ATGL) plays a compelling role in hepatic lipid turnover and in the pathophysiology of non-alcoholic fatty liver disease. Hepatic ATGL is post-transcriptionally regulated by E3 ubiquitin ligase constitutive photomorphogenic1 (COP1) through polyubiquitylation and proteasomal degradation. However the physiological cue for COP1-mediated hepatocellular degradation of ATGL remained unknown. Here we checked for the role of pigment epithelium-derived factor (PEDF), a moonlighting hepatokine and the so-called ligand of ATGL for its stability in hepatocytes. We show that PEDF diminishes ATGL protein stability by promoting its proteasomal degradation in COP1-dependent manner. Despite being a secretory glycoprotein, PEDF is also sequestered in the nuclear compartment so as COP1. Interestingly, PEDF enhances nuclear import of predominantly cytosolic ATGL protein for its subsequent proteasomal degradation in the nucleus. PEDF also controls cell autonomous hepatocyte lipid accumulation and mobilization through COP1-ATGL axis, thereby unraveling a novel pathway for hepatic lipid metabolism.