DsbA-L alleviates endoplasmic reticulum stress-induced adiponectin downregulation.
OBJECTIVE
Obesity impairs adiponectin expression, assembly, and secretion, yet the underlying mechanisms remain elusive. The aims of this study were 1) to determine the molecular mechanisms by which obesity impairs adiponectin multimerization and stability, and 2) to determine the potential role of disulfide-bond-A oxidoreductase-like protein (DsbA-L), a recently identified adiponectin interactive protein that promotes adiponectin multimerization and stability in obesity-induced endoplasmic reticulum (ER) stress and adiponectin downregulation.


METHODS
Tauroursodeoxycholic acid (TUDCA), a chemical chaperone that alleviates ER stress, was used to study the mechanism underlying obesity-induced adiponectin downregulation in db/db mice, high-fat diet-induced obese mice, and in ER-stressed 3T3-L1 adipocytes. The cellular levels of DsbA-L were altered by RNAi-mediated suppression or adenovirus-mediated overexpression. The protective role of DsbA-L in obesity- and ER stress-induced adiponectin downregulation was characterized.


RESULTS
Treating db/db mice and diet-induced obese mice with TUDCA increased the cellular and serum levels of adiponectin. In addition, inducing ER stress is sufficient to downregulate adiponectin levels in 3T3-L1 adipocytes, which could be protected by treating cells with the autophagy inhibitor 3-methyladenine or by overexpression of DsbA-L.


CONCLUSIONS
ER stress plays a key role in obesity-induced adiponectin downregulation. In addition, DsbA-L facilitates adiponectin folding and assembly and provides a protective effect against ER stress-mediated adiponectin downregulation in obesity.
Zhou
Lijun
L
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Liu
Meilian
M
Zhang
Jingjing
J
Chen
Hongzhi
H
Dong
Lily Q
LQ
Liu
Feng
F
D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008820:Mice, Obese / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology
D052242:Adiponectin; D007328:Insulin; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine