title: β-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation.
abstract: Hormone-stimulated lipolysis is a rapid way to mobilize fat from its storage depot for use in peripheral tissues. By convention, activation of cytosolic lipases via the β-adrenergic receptor (ADRB2)-cAMP signaling pathway is the only molecular mechanism considered to liberate fatty acids from triglycerides stored in lipid droplets (LDs) of cells. Herein, we provide evidence that, aside from the activation of cytosolic lipases, autophagy contributes to this hormone-stimulated lipolysis. The ADRB2-stimulated lipolysis was reduced after inhibition of early or late autophagy using either pharmacological inhibitors or shRNA-mediated autophagic gene knockdown. ADRB2 stimulation has caused a marked increase in the autophagy-targeted LDs for lysosomal degradation, which is dependent on the LD-associated RAB7 as evidenced by the use of both shRNA-mediated RAB7 knockdown and a dominant-negative RAB7 mutant. In addition, RAB7 is involved in unstimulated (basal) lipolysis, and mediates the enhanced basal lipolysis in PLIN1/perilipin 1 knockdown fat cells. In conclusion, our results showed a contribution of lipophagy to both basal and hormone-stimulated lipolysis and that RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid degradation in fat cells.
authors.affiliation: Taiwan International Graduate Program; Graduate Institute of Life Science; National Defense Medical Center and Academia Sinica;; Laboratory of Molecular Pathology; Institute of Molecular Biology, Academia Sinica; Taipei, Taiwan.
authors.forename: Analyn
authors.initials: A
authors.lastname: Lizaso
authors.forename: Kien-Thiam
authors.initials: KT
authors.lastname: Tan
authors.forename: Ying-Hue
authors.initials: YH
authors.lastname: Lee
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D008066:Lipolysis; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D002352:Carrier Proteins; D000070778:Perilipin-1; D010750:Phosphoproteins; C000602979:Plin1 protein, mouse; D011943:Receptors, Adrenergic, beta; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D000242:Cyclic AMP; D020691:rab GTP-Binding Proteins
keywords: 3T3-L1; RAB7; autolysosome-mediated lipid degradation; lipolysis; lipophagy