Calamita, G. (Giuseppe)

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    Aquaporin-11 contributes to TGF-β1-Induced endoplasmic reticulum stress in human visceral adipocytes: role in obesity-associated inflammation
    (MDPI, 2020) Balaguer, I. (Inmaculada); Valenti, V. (Víctor); Calamita, G. (Giuseppe); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Malagon, M.M. (María M.); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia); Méndez-Giménez-de-los-Galanes, L. (Leire)
    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.
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    Liver glycerol permeability and aquaporin-9 are dysregulated in a murine model of non-alcoholic fatty liver disease
    (Public Library of Science, 2013) Fanelli, E. (Elena); Svelto, M. (Maria); Calamita, G. (Giuseppe); Gena, P. (Patrizia); Portincasa, P. (Piero); Mastrodonato, M. (Maria); Mentino, D. (Donatella); Frühbeck, G. (Gema); Marinelli, R.A. (Raúl A.); Brenner, C. (Catherine); Rodriguez, A. (Amaia)
    One form of liver steatosis, namely Non-Alcoholic Fatty Liver Disease (NAFLD), is a worrisome health problem worldwide characterized by intrahepatic triacylglycerol (TG) overaccumulation. NAFLD is a common feature of metabolic syndrome being often associated with obesity, dyslipidemia and diabetes and mostly closely linked to insulin resistance. The mechanism of NAFLD pathogenesis is object of intense investigation especially regarding complex systems ultimately resulting in excessive TG deposition in hepatocytes. However, scarce is the attention about the relevance of hepatic import of glycerol, the other primary source (as glycerol-3-phosphate) of increased TG in hepatocytes. Obese leptin-deficient (ob/ob) mice, an animal model of NAFLD, were used to evaluate the functional involvement of Aquaporin-9 (AQP9), the major pathway of liver glycerol entry, in hepatosteatosis. By RT-PCR and qPCR, the level of Aqp9 mRNA in the liver of starved obese mice was comparable with the corresponding control lean littermates. By immunoblotting, the AQP9 protein at the hepatocyte sinusoidal plasma membrane of obese mice was markedly lower (33%) than lean mice, a finding fully confirmed by immunohistochemistry. By stopped-flow light scattering, the liver glycerol permeability of ob/ob mice was significantly lower (53%) than lean mice, a finding consistent with both the observed down-regulation of AQP9 protein and increased level of plasma glycerol characterizing obese mice. In summary, our results suggest implication of AQP9 in liver steatosis. The reduction of hepatocyte AQP9 and, consequently, glycerol permeability might be a defensive mechanism to counteract further fat infiltration in liver parenchyma.