Guzmán-Ruiz, R. (Rocío)
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- 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.
- 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.