Malagon, M.M. (María M.)
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- Ghrelin Reduces TNF-α-Induced Human Hepatocyte Apoptosis, Autophagy, and Pyroptosis: Role in Obesity-Associated NAFLD(Oxford University Press, 2019) Valenti, V. (Víctor); Ezquerro-Ezquerro, S. (Silvia); Colina, I. (Inmaculada); Catalan, V. (Victoria); Guzmán-Ruiz, R. (Rocío); Becerril, S. (Sara); Frühbeck, G. (Gema); Malagon, M.M. (María M.); Mugueta, C. (Carmen); Mocha, F. (Fátima); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)Context: Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death. Objective: The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated. Design, settings, and participants: Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes. Results: Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR. Conclusions: Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.
- 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.
- The caveolae-associated coiled-coil protein, NECC2, regulates insulin signalling in Adipocytes(Wiley, 2018) Gasman, S. (Stéphane); Vitale, N. (Nicolas); Rabanal-Ruiz, Y. (Yoana); Tinahones, F.J. (Francisco J.); Catalan, V. (Victoria); Díaz-Ruiz, A. (Alberto); Guzmán-Ruiz, R. (Rocío); Jiménez-Gómez, Y. (Yolanda); Frühbeck, G. (Gema); Malagon, M.M. (María M.); Molero-Murillo, L. (Laura); López-Alcalá, J. (Jaime); Trávez, A. (Andrés); Rodriguez, A. (Amaia)Adipocyte dysfunction in obesity is commonly associated with impaired insulin sig-nalling in adipocytes and insulin resistance. Insulin signalling has been associatedwith caveolae, which are coated by large complexes of caveolin and cavin proteins,along with proteins with membrane‐binding and remodelling properties. Here, weanalysed the regulation and function of a component of caveolae involved in growthfactor signalling in neuroendocrine cells, neuroendocrine long coiled‐coil protein‐2(NECC2), in adipocytes. Studies in 3T3‐L1 cells showed that NECC2 expressionincreased during adipogenesis. Furthermore, NECC2 co‐immunoprecipitated withcaveolin‐1 (CAV1) and exhibited a distribution pattern similar to that of the compo-nents of adipocyte caveolae, CAV1, Cavin1, the insulin receptor and cortical actin.Interestingly, NECC2 overexpression enhanced insulin‐activated Akt phosphoryla-tion, whereas NECC2 downregulation impaired insulin‐induced phosphorylation ofAkt and ERK2. Finally, an up‐regulation ofNECC2in subcutaneous and omental adi-pose tissue was found in association with human obesity and insulin resistance. Thiseffect was also observed in 3T3‐L1 adipocytes exposed to hyperglycaemia/hyperin-sulinemia. Overall, the present study identifies NECC2 as a component of adipocytecaveolae that is regulated in response to obesity and associated metabolic complica-tions, and supports the contribution of this protein as a molecular scaffold modulat-ing insulin signal transduction at these membrane microdomains.
- The L-[alpha]-lysophosphatidylinositol/GPR55 system and its potential role in human obesity(American Diabetes Association, 2012-02) Vazquez-Martinez, R. (Rafael); Nogueiras, R. (Rubén); Rotellar, F. (Fernando); Diaz-Arteaga, A. (Adenis); Catalan, V. (Victoria); Pulido, M.R. (Marina R.); Frühbeck, G. (Gema); Malagon, M.M. (María M.); Ross, R.A. (Ruth A.); Dieguez, C. (Carlos); Moreno-Navarrete, J. (José); Gomez-Ambrosi, J. (Javier); Imbernon, M. (Mónica); Russel, W.R. (Wendy R.); Whyte, L. (Lauren); Fernandez-Real, J.M. (José Manuel); Guzman, R. (Rocío)GPR55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. We investigated 1) whether GPR55 is expressed in fat and liver; 2) the correlation of both GPR55 and LPI with several metabolic parameters; and 3) the actions of LPI on human adipocytes. We analyzed CB1, CB2, and GPR55 gene expression and circulating LPI levels in two independent cohorts of obese and lean subjects, with both normal or impaired glucose tolerance and type 2 diabetes. Ex vivo experiments were used to measure intracellular calcium and lipid accumulation. GPR55 levels were augmented in the adipose tissue of obese subjects and further so in obese patients with type 2 diabetes when compared with nonobese subjects. Visceral adipose tissue GPR55 correlated positively with weight, BMI, and percent fat mass, particularly in women. Hepatic GPR55 gene expression was similar in obese and type 2 diabetic subjects. Circulating LPI levels were increased in obese patients and correlated with fat percentage and BMI in women. LPI increased the expression of lipogenic genes in visceral adipose tissue explants and intracellular calcium in differentiated visceral adipocytes. These findings indicate that the LPI/GPR55 system is positively associated with obesity in humans.