Unconventional secretion of adipocyte fatty acid binding protein 4 is mediated by autophagic proteins in a sirtuin-1-dependent manner

Ajeetha Josephrajan, Ann M Hertzel, Ellie K. Bohm, Michael W. McBurney, Shin Ichiro Imai, Douglas Mashek, Do Hyung Kim, David A Bernlohr

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1767-1777
Number of pages11
JournalDiabetes
Volume68
Issue number9
DOIs
StatePublished - Sep 1 2019

Fingerprint

Sirtuin 1
Fatty Acid-Binding Proteins
Adipocytes
Proteins
Blood Proteins
Brown Adipose Tissue
Neutralizing Antibodies
Knockout Mice
Insulin Resistance
Carrier Proteins
Macrophages
Lipids
Glucose

Cite this

Unconventional secretion of adipocyte fatty acid binding protein 4 is mediated by autophagic proteins in a sirtuin-1-dependent manner. / Josephrajan, Ajeetha; Hertzel, Ann M; Bohm, Ellie K.; McBurney, Michael W.; Imai, Shin Ichiro; Mashek, Douglas; Kim, Do Hyung; Bernlohr, David A.

In: Diabetes, Vol. 68, No. 9, 01.09.2019, p. 1767-1777.

Research output: Contribution to journalArticle

Josephrajan, Ajeetha ; Hertzel, Ann M ; Bohm, Ellie K. ; McBurney, Michael W. ; Imai, Shin Ichiro ; Mashek, Douglas ; Kim, Do Hyung ; Bernlohr, David A. / Unconventional secretion of adipocyte fatty acid binding protein 4 is mediated by autophagic proteins in a sirtuin-1-dependent manner. In: Diabetes. 2019 ; Vol. 68, No. 9. pp. 1767-1777.
@article{fda418609dae4d2e9adeee2d49115e17,
title = "Unconventional secretion of adipocyte fatty acid binding protein 4 is mediated by autophagic proteins in a sirtuin-1-dependent manner",
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.",
author = "Ajeetha Josephrajan and Hertzel, {Ann M} and Bohm, {Ellie K.} and McBurney, {Michael W.} and Imai, {Shin Ichiro} and Douglas Mashek and Kim, {Do Hyung} and Bernlohr, {David A}",
year = "2019",
month = "9",
day = "1",
doi = "10.2337/db18-1367",
language = "English (US)",
volume = "68",
pages = "1767--1777",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "9",

}

TY - JOUR

T1 - Unconventional secretion of adipocyte fatty acid binding protein 4 is mediated by autophagic proteins in a sirtuin-1-dependent manner

AU - Josephrajan, Ajeetha

AU - Hertzel, Ann M

AU - Bohm, Ellie K.

AU - McBurney, Michael W.

AU - Imai, Shin Ichiro

AU - Mashek, Douglas

AU - Kim, Do Hyung

AU - Bernlohr, David A

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85071434460&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071434460&partnerID=8YFLogxK

U2 - 10.2337/db18-1367

DO - 10.2337/db18-1367

M3 - Article

C2 - 31171562

AN - SCOPUS:85071434460

VL - 68

SP - 1767

EP - 1777

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -