Unconventional Secretion of Adipocyte Fatty Acid Binding Protein (FABP4) by Adipocytes

Abstract

Fatty acid binding protein 4 (FABP4) is a cytoplasmic lipid carrier functioning in adipocytes to facilitate lipolysis. Genetic or pharmacologic depletion of the protein provides protection from insulin resistance, asthma, atherosclerosis and inflammation. Metabolic dysfunction has been considered due to the intracellular functions of the protein. However, recent literature has shown that serum FABP4 levels are elevated in patients with metabolic syndrome. FABP4 is a leaderless protein and the mechanism of its release from adipocytes is unknown. Although FABP4 secretion increased with increasing intracellular free fatty acid (FFA) levels and correlated positively with FFA efflux, the molar amount of FABP4 secreted is less than 1% of total molar FFA efflux implying that the protein does not mediate release of bulk lipid in response to lipolytic stimulation. To evaluate the mechanism of FABP4 secretion, we have used primary mouse adipocytes and the 3T3‐L1 adipocyte cell culture model. Results from inhibitor/activator studies showed requirement for some, but not all components of autophagy. For example, classical autophagic inhibitors such as 3‐methyl adenine or the Class III PI 3‐Kinase VPS34 specific inhibitor attenuated FABP4 secretion, while autophagic inducer N‐acetyl sphingosine induced FABP4 secretion. Moreover, FABP4 secretion was potentiated when lipophagy and lysosomal exocytosis were blocked using chemical inhibitors of lysosomal acid lipase or Bafilomycin A1, respectively. Consistent with these results, genetic knockdown of ATG13 or FIP200 (involved in early events of phagophore formation) attenuated secretion, whereas silencing of Atg5 had little effect on FABP4 secretion. Similar to the adipocyte secretion of eNAMPT, blocking SIRT1 by the chemical inhibitor EX527 attenuated secretion, while activating SIRT1 by resveratrol potentiated secretion. Our results show that FABP4 is secreted through autophagy mediated alternative secretion and regulated in part by SIRT1.Support or Funding InformationSupported by NIH DK053189 to DAB.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.