Back to Search
Start Over
Unconventional Secretion of Adipocyte Fatty Acid Binding Protein 4 Is Mediated By Autophagic Proteins in a Sirtuin-1-Dependent Manner.
- Source :
-
Diabetes [Diabetes] 2019 Sep; Vol. 68 (9), pp. 1767-1777. Date of Electronic Publication: 2019 Jun 06. - Publication Year :
- 2019
-
Abstract
- Fatty acid binding protein 4 (FABP4) is a leaderless lipid carrier protein primarily expressed by adipocytes and macrophages that not only functions intracellularly but is also secreted. The secretion is mediated via unconventional mechanism(s), and in a variety of species, metabolic dysfunction is correlated with elevated circulating FABP4 levels. In diabetic animals, neutralizing antibodies targeting serum FABP4 increase insulin sensitivity and attenuate hepatic glucose output, suggesting the functional importance of circulating FABP4. Using animal and cell-based models, we show that FABP4 is secreted from white, but not brown, adipose tissue in response to lipolytic stimulation in a sirtuin-1 (SIRT1)-dependent manner via a mechanism that requires some, but not all, autophagic components. Silencing of early autophagic genes such as Ulk1/2 , Fip200 , or Beclin-1 or chemical inhibition of ULK1/2 or VPS34 attenuated secretion, while Atg5 knockdown potentiated FABP4 release. Genetic knockout of Sirt1 diminished secretion, and serum FABP4 levels were undetectable in Sirt1 knockout mice. In addition, blocking SIRT1 by EX527 attenuated secretion while activating SIRT1 by resveratrol-potentiated secretion. These studies suggest that FABP4 secretion from adipocytes is regulated by SIRT1 and requires early autophagic components.<br /> (© 2019 by the American Diabetes Association.)
- Subjects :
- Adipose Tissue metabolism
Animals
Autophagy-Related Protein-1 Homolog genetics
Autophagy-Related Protein-1 Homolog metabolism
Autophagy-Related Proteins genetics
Autophagy-Related Proteins metabolism
Beclin-1 genetics
Beclin-1 metabolism
Gene Silencing
Insulin Resistance physiology
Mice
Mice, Knockout
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Sirtuin 1 genetics
Adipocytes metabolism
Autophagy physiology
Fatty Acid-Binding Proteins metabolism
Sirtuin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 68
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 31171562
- Full Text :
- https://doi.org/10.2337/db18-1367