Valenti, V. (Víctor)
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- Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD(Elsevier, 2023) Valenti, V. (Víctor); Colina, I. (Inmaculada); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Fernández-Sáez, E.M. (Eva M.); Losarcos, M. (Maite); Burrell, M.A. (María Ángela); Martín, M. (Mariana); Moncada, R. (Rafael); Mugueta, C. (Carmen); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Escalada, J. (Javier)Background: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery. Methods: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions. Results: Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial β-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced β-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-β1 stimulation. Conclusions: Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.
- Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD(2020) Sánchez-Infantes, D. (David); Bartrons, R. (Ramon); Valenti, V. (Víctor); Domínguez-Castellano, M. (María); Weber, M. (Minéia); Frühbeck, G. (Gema); Zorzano, A. (Antonio); Fucho, R. (Raquel); Casals, N. (Núria); Llorente-Cortes, V. (Vicenta); Mera, P. (Paula); Soler-Vázquez, M.C. (M. Carmen); Serra, D. (Dolors); Herrero, L. (Laura); Mir, J.F. (Joan Francesc); Rodriguez, A. (Amaia); Sebastián, D. (David); Montironi, C. (Carla); Casas, J. (Josefina); Alonso, S. (Sergio); Recalde, S. (Sandra); Escola-Gil, J.C. (Joan Carles)The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.
- Increased expression levels of netrin-1 in visceral adipose tissue during obesity favour colon cancer cell migration(2023) Neira, G. (Gabriela); Valenti, V. (Víctor); Ferro, A. (Alberto); Baixauli-Fons, J. (Jorge); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Mentxaka, A. (Amaia); Becerril, S. (Sara); Frühbeck, G. (Gema); Burrell, M.A. (María Ángela); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Claro, V. (Vasco)Simple Summary Netrin-1 (NTN-1) regulates obesity-associated low-grade inflammation, being also involved in the control of cell migration and proliferation. We aim to study whether excess visceral adipose tissue in patients with obesity and colon cancer is associated with increased NTN1 and the expression levels of its main receptors, promoting an inflammatory microenvironment that favours colon cancer development. Increased expression levels of NTN1 and its receptor NEO1 in the visceral adipose tissue from patients with obesity and colon cancer together with elevated DCC and UNC5B mRNA levels in patients with colon cancer were found. Moreover, the treatment of colorectal cancer cells with NTN-1 and with the adipocyte-derived secretome obtained from patients with obesity increased the migration of colorectal cancer cells. These results suggest that NTN-1 plays an important role in obesity-associated colon cancer development. Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.
- Cirugía bariátrica laparoscópica: bypass gástrico proximal(Gobierno de Navarra. Departamento de Salud, 2005) Valenti, V. (Víctor); Pastor, C. (Carlos); Rotellar, F. (Fernando); Poveda, I. (Ignacio); Baixauli-Fons, J. (Jorge); Gil, A. (Aurora); Marti-Cruchaga, P. (Pablo)The spectacular increase in the prevalence of obesity in our society and the significant complications and comorbidities that it gives rise to have stimulated the interest of scientists and public in this pathology. Surgical treatment is at present the only efficient and lasting treatment for morbid obesity and in many cases it appreciably improves, and even definitively cures, associated complications such as the case of diabetes or hypertension. Amongst the different techniques of bariatric surgery, the gastric bypass (GBP) seems to be definitively establishing itself, since it offers an excellent balance between loss of weight (>70% of the excess), surgical risk and subsequent quality of life. The possibility of carrying out this technique employing a laparoscopic approach has improved its acceptance by doctors and patients while it has made it possible to reduce morbidity and mortality, length of hospital stay and costs. Proximal GBP is carried on those patients with an BMI <60 Kg/m2; for BMI >60 Kg/m2 the GBP employed is denominated distal. Between October 2003 and November 2005, our centre performed 55 laparoscopic proximal Roux-en-Y gastric bypasses via laparoscopy. These involved 42 women and 13 males with an average age of 44 years. The average BMI was 43.5 (35-55.8). The average basal weight was 116.15 Kg. There was no peroperative mortality, nor reinterventions. The BMI after 12 months was 28.4. The average basal weight was 74.2 Kg. Laparoscopic Roux-en-Y proximal gastric bypass is a safe and efficient technique for the treatment of morbid obesity.
- Cirugía laparoscópica hepática y pancreática(Gobierno de Navarra. Departamento de Salud, 2005) Valenti, V. (Víctor); Pastor, C. (Carlos); Rotellar, F. (Fernando); Poveda, I. (Ignacio); Pardo, F. (Fernando); Zozaya-Larequi, G. (Gabriel); Marti-Cruchaga, P. (Pablo)The development of laparoscopic surgery also includes the more complex procedures of abdominal surgery such as those that affect the liver and the pancreas. From diagnostic laparoscopy, accompanied by laparoscopic echography, to major hepatic or pancreatic resections, the laparoscopic approach has spread and today encompasses practically all of the surgical procedures in hepatopancreatic pathology. Without forgetting that the aim of minimally invasive surgery is not a better aesthetic result but the reduction of postoperative complications, it is undeniable that the laparoscopic approach has brought great benefits for the patient in every type of surgery except, for the time being, in the case of big resections such as left or right hepatectomy or resections of segments VII and VIII. Pancreatic surgery has undergone a great development with laparoscopy, especially in the field of distal pancreatectomy due to cystic and neuroendocrine tumours where the approach of choice is laparoscopic. Laparoscopy similarly plays an important role, together with echolaparoscopy, in staging pancreatic tumours, prior to open surgery or for indicating suitable treatment. In coming years, it is to be hoped that it will continue to undergo an exponential development and, together with the advances in robotics, it will be possible to witness a greater impact of the laparoscopic approach on the field of hepatic and pancreatic surgery.
- Relevance of leptin and other adipokines in obesity-associated cardiovascular risk(MDPI AG, 2019) Landecho, M.F. (Manuel F.); Valenti, V. (Víctor); Frühbeck, G. (Gema); Higuera, M. (Magdalena) de la; Tuero, C. (Carlota); Bilbao, I. (Idoia)Obesity, which is a worldwide epidemic, confers increased risk for multiple serious conditions including type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue only for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins, and growth and vasoactive factors, which are collectively called adipokines known to influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. This review describes the relevance of specific adipokines in the obesity-associated cardiovascular disease.
- Cirugía laparoscópica biliar(Gobierno de Navarra. Departamento de Salud, 2005) Valenti, V. (Víctor); Pastor, C. (Carlos); Rotellar, F. (Fernando); Poveda, I. (Ignacio); Zozaya-Larequi, G. (Gabriel); Marti-Cruchaga, P. (Pablo)The following article briefly sets out the possible new protocols that can be applied in biliary pathology, arising from the changes brought about by the appearance of new techniques of laparoscopic biliary surgery. It offers a synthesis of the latest and most novel articles on surgical technique and management in different biliary pathologies such as Choledocholithiasis and cholecystitis. It can be concluded that management will differ greatly, depending on the technical capacities of the centre that is called upon to deal with one of these pathologies. A standard protocol for everybody cannot thus be established at present. Teh differences between endoscopic retrograde cholangiopancreatography and intraoperative laparoscopic cholangiography have still to be demonstrated, it is not possible to make generalisations about whether one technique is more useful than the other. The same could be said about whether access to the main biliary path should be achieved through the cystic conduct or whether, on the contrary, a choledochotomy should be performed.
- Dermatopontin, a novel adipokine promoting adipose tissue extracellular matrix remodelling and inflammation in obesity(MDPI AG, 2020) Unamuno, X. (Xabier); Valenti, V. (Víctor); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)Compelling evidence suggests that dermatopontin (DPT) regulates collagen and fibronectin fibril formation, the induction of cell adhesion and the prompting of wound healing. We aimed to evaluate the role of DPT on obesity and its associated metabolic alterations as well as its impact in visceral adipose tissue (VAT) inflammation and extracellular matrix (ECM) remodelling. Samples obtained from 54 subjects were used in a case-control study. Circulating and VAT expression levels of DPT as well as key ECM remodelling- and inflammation-related genes were analysed. The effect of pro- and anti-inflammatory mediators on the transcript levels of DPT in visceral adipocytes was explored. The impact of DPT on ECM remodelling and inflammation pathways was also evaluated in cultured adipocytes. We show that obesity and obesity-associated type 2 diabetes (T2D) increased (p < 0.05) circulating levels of DPT. In this line, DPT mRNA in VAT was increased (p < 0.05) in obese patients with and without T2D. Gene expression levels of DPT were enhanced (p < 0.05) in human visceral adipocytes after the treatment with lipopolysaccharide, tumour growth factor (TGF)-β and palmitic acid, whereas a downregulation (p < 0.05) was detected after the stimulation with interleukin (IL)-4 and IL-13, critical cytokines mediating anti-inflammatory pathways. Additionally, we revealed that DPT increased (p < 0.05) the expression of ECM- (COL6A3, ELN, MMP9, TNMD) and inflammation-related factors (IL6, IL8, TNF) in human visceral adipocytes. These findings provide, for the first time, evidence of a novel role of DPT in obesity and its associated comorbidities by influencing AT remodelling and inflammation.
- Analysis of POSSUM score and postoperative morbidity in patients with rectal cancer undergoing surgery(American Medical Association, 2009) Valenti, V. (Víctor); Pastor, C. (Carlos); Martinez-Regueira, F. (Fernando); Baixauli-Fons, J. (Jorge); Aristu-Mendioroz, J.J. (José Javier); Álvarez-Cienfuegos, J. (Javier); Hernandez-Lizoain, J.L. (Jose Luis); Beunza, J.J. (Juan José)The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) and later modifications (P-POSSUM y CR-POSSUM) have been used to predict morbidity and mortality rates among patients with rectal cancer undergoing surgery. These calculations need some adjustment, however. The aim of this study was to assess the applicability of POSSUM to a group of patients with rectal cancer undergoing surgery, analysing surgical morbidity by means of several variables. METHODS: between January 1995 and December 2004, 273 consecutive patients underwent surgery for rectal cancer. Information was gathered about the patients, tumour and therapy. To assess the prediction capacity of POSSUM, subgroups for analysis were created according to variables related to operative morbidity and mortality. RESULTS: The global morbidity rate was 23.6% (31.2% predicted by POSSUM). The mortality rate was 0.7% (6.64, 1.95 and 2.08 predicted by POSSUM, P-POSSUM and CR-POSSUM respectively). POSSUM predictions may be more accurate for patients younger than 51 years, older than 70 years, with low anaesthetic risk (ASA I/II), DUKES stage C and D, surgery duration of less than 180 minutes and for those receiving neoadjuvant therapy. CONCLUSION: POSSUM is a good instrument to make results between different institutions and publication comparable. We found prediction errors for some variables related to morbidity. Modifications of surgical variables and specifications for neoadjuvant therapy as well as physiological variables including life style may improve future prediction of surgical risk. More research is needed to identify further potential risk factors for surgical complications.
- NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling(Nature Publishing Group, 2021) Unamuno, X. (Xabier); Valenti, V. (Víctor); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesity-associated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case-control study. The expression of different components of the inflammasome as well as their main effectors and inflammation- and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.