Abstract
Aquaporin-11 (AQP11) is expressed in human adipocytes, but its functional role remains unknown. Since AQP11 is an endoplasmic reticulum (ER)-resident protein that transports water, glycerol, and hydrogen peroxide (H2O2), we hypothesized that this superaquaporin is involved in ER stress induced by lipotoxicity and inflammation in human obesity. AQP11 expression was assessed in 67 paired visceral and subcutaneous adipose tissue samples obtained from patients with morbid obesity and normal-weight individuals. We found that obesity and obesity-associated type 2 diabetes increased (p < 0.05) AQP11 mRNA and protein in visceral adipose tissue, but not subcutaneous fat. Accordingly, AQP11 mRNA was upregulated (p < 0.05) during adipocyte differentiation and lipolysis, two biological processes altered in the obese state. Subcellular fractionation and confocal microscopy studies confirmed its presence in the ER plasma membrane of visceral adipocytes. Proinflammatory factors TNF-α, and particularly TGF-β1, downregulated (p < 0.05) AQP11 mRNA and protein expression and reinforced its subcellular distribution surrounding lipid droplets. Importantly, the AQP11 gene knockdown increased (p < 0.05) basal and TGF-β1-induced expression of the ER markers ATF4 and CHOP. Together, the downregulation of AQP11 aggravates TGF-β1-induced ER stress in visceral adipocytes. Owing to its “peroxiporin” properties, AQP11 overexpression in visceral fat might constitute a compensatory mechanism to alleviate ER stress in obesity.
Highlights
Aquaporins (AQPs) are membrane channels that facilitate the movement of water across biological membranes [1]
A third subfamily of AQPs, unorthodox or “superaquaporins” (AQP11 and AQP12), exhibit unique Asn-Pro-Cys (NPC) motifs in AQP11 and Asn-Pro-Thr (NPT) in AQP12, and are located in the membranes of intracellular organelles [6,7,8]. This archetypical classification based on the transporting properties has been recently blurred because AQP11 is permeated by water [8], glycerol [9], and hydrogen peroxide (H2 O2 ) [10]
Differentiated adipocytes grown on glass coverslips were fixed with 4% formaldehyde for 15 min at room temperature (RT), incubated with PBS containing 0.3% saponin and 1% bovine serum albumin (BSA) for 1 h at RT, and exposed to rabbit polyclonal anti-human AQP11 antibody (HPA042879, Sigma) diluted 1:100 in PBS containing 0.3%
Summary
Aquaporins (AQPs) are membrane channels that facilitate the movement of water across biological membranes [1]. AQP structure is composed of six transmembrane α-helices and two reentrant loops with two asparagine–proline–alanine (NPA) signature motifs, which create the aperture of a water channel pore-forming a tridimensional “hourglass” structure in the lipid bilayer [2]. A third subfamily of AQPs, unorthodox or “superaquaporins” (AQP11 and AQP12), exhibit unique Asn-Pro-Cys (NPC) motifs in AQP11 and Asn-Pro-Thr (NPT) in AQP12, and are located in the membranes of intracellular organelles [6,7,8] This archetypical classification based on the transporting properties has been recently blurred because AQP11 is permeated by water [8], glycerol [9], and hydrogen peroxide (H2 O2 ) [10]. This ability to transport H2 O2 is observed in several orthodox AQPs (AQP5 and AQP8) [11,12] and aquaglyceroporins (AQP3 and AQP9) [13,14] that, together with superaquaporin AQP11 [10], are collectively termed “peroxiporins”
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