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Manganese supplementation increases adiponectin secretion by upregulating disulfide bond A‐like protein in endothelial cells and Zucker diabetic fatty rats (767.13)
Author(s) -
Burlet Elodie,
Jain Sushil
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.767.13
Subject(s) - adiponectin , medicine , endocrinology , chemistry , protein disulfide isomerase , endoplasmic reticulum , lipoprotein , insulin , insulin resistance , cholesterol , biochemistry
Adiponectin is an insulin sensitizer that plays a role in the regulation of lipid and glucose homeostasis and has anti atherosclerotic effects. It is synthesized as a single polypeptide and is then assembled in the endoplasmic reticulum into different multimers. An adiponectin‐interacting protein named disulfide bond A‐like protein (DsbA‐L) was recently found to play an important role in multimerization of adiponectin; impairment in DsbA‐L is associated with diabetes and low adiponectin levels. Manganese (Mn) levels have been found to be low in atherosclerotic and diabetic patients. Previous studies in our lab have shown that Mn supplementation can lower blood cholesterol and ICAM‐1 levels in ZDF rats and reduce MCP‐1 secretion and monocyte adhesion to endothelial cells in HUVECs model (J. Biol. Chem, 2013 Mar 1; 288 (9):6409‐16). This study investigates the hypothesis that Mn supplementation affects DsbA‐L expression levels, and thereby adiponectin levels, in ZDF rats and endothelial cells (HUVECs). Results show that diabetic rats supplemented with Mn (gavaged daily with 16 mg/kg BW for seven weeks, n=5) have higher plasma adiponectin levels (41%, p=0.007) and higher DsbA‐L expression in the liver compared to control diabetic rats (n=6). Similarly, pre‐treatment with Mn (with 5 or 10 μM for 24 h) prevented the decrease in DsbAL expression and adiponectin levels in HUVECs and 3T3L1 adipocyte cells exposed to high glucose and MCP‐1. We further investigated the role of DsbA‐L protein by knocking down its expression in HUVECs. Preliminary studies with DsbA‐L siRNA show that beneficial effects of Mn supplementation on NOX4 expression and other biomarkers of vascular inflammation were abolished in DsbA‐L knocked down cells. Thus, this study demonstrates that DsbA‐L mediates the beneficial effects of Mn on adiponectin and provides a novel mechanism by which Mn supplementation reduces biomarkers of vascular inflammation in diabetes.