Efecto de la hipertermia sobre la proliferación de células CC531 in vitro

El cáncer colorrectal (CCR) es un problema mundial, con una incidencia anual de aproximadamente un millón de casos, y una mortalidad anual de más de 500.000. Así, el CCR es la segunda causa de mortalidad por cáncer entre hombres y mujeres. Además, se prevé que el número absoluto de casos aumentará en las próximas dos décadas como resultado del envejecimiento y la expansión de las poblaciones, tanto en los países desarrollados como en los países en desarrol lo (1, 2). Gran parte de los carcinomas colorrectales son adenocarcinomas glandulares, caracterizados por la invasión de tejidos o estructuras circundantes y por su potencial de metastatizar, por vía linfática o vascular. De hecho, alrededor del 50% de los pacientes con cáncer de colon desarrollan metástasis hepáticas, bien en la presentación del tumor o en la recidiva de la enfermedad. Por este motivo, las metástasis hepáticas del CCR constituyen un problema clínico de primera magnitud. En la última década , la cirugía ha aumentado sus indicaciones desde pacientes con no más de tres metástasis , hasta pacientes con una masa tumoral hepática inicialmente no resecable, pero susceptibles de reducir el volumen tumoral mediante quimioterapia o de incrementar la m asa hepática remanente hasta proporciones compatibles con la supervivencia del enfermo (embolizaciones, ligadura de vasos portales, etc.). Hoy por hoy, la técnica curativa indiscutida es la resección quirúrgica del parénquima hepático invadido por tumor; s in embargo, solo una pequeña parte de los pacientes que presentan metástasis hepáticas son aptos para someterse a resección quirúrgica

Atorvastatin Provides a New Lipidome Improving Early Regeneration After Partial Hepatectomy in Osteopontin Deficient Mice

Osteopontin (OPN), a multifunctional cytokine that controls liver glycerolipid metabolism, is involved in activation and proliferation of several liver cell types during regeneration, a condition of high metabolic demands. Here we investigated the role of OPN in modulating the liver lipidome during regeneration after partial-hepatectomy (PH) and the impact that atorvastatin treatment has over regeneration in OPN knockout (KO) mice. The results showed that OPN deficiency leads to remodeling of phosphatidylcholine and triacylglycerol (TG) species primarily during the first 24 h after PH, with minimal effects on regeneration. Changes in the quiescent liver lipidome in OPN-KO mice included TG enrichment with linoleic acid and were associated with higher lysosome TG-hydrolase activity that maintained 24 h after PH but increased in WT mice. OPN-KO mice showed increased beta-oxidation 24 h after PH with less body weight loss. In OPN-KO mice, atorvastatin treatment induced changes in the lipidome 24 h after PH and improved liver regeneration while no effect was observed 48 h post-PH. These results suggest that increased dietary-lipid uptake in OPN-KO mice provides the metabolic precursors required for regeneration 24 h and 48 h after PH. However, atorvastatin treatment offers a new metabolic program that improves early regeneration when OPN is deficient.This work was supported by IT-336-10 (Gobierno Vasco) (to PA) and SAF2015-64352-R (to PA), SAF2017-87301-R (to MLM-C) and EITB Maratoia BIO15/CA/014 (to MLM-C). MNG and DM were recipients of a predoctoral fellowship from the University of Basque Country UPV/EHU and BG-S and DS were recipients for predoctoral fellowships from the Basque Goverment. We thank technical support from Jose Antonio Lopez Gomez

Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease

[EN] Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of agerelated hepatosteatosis.This work was supported by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971‐16 to P.A.), MINECO‐FEDER (SAF2017‐87301‐R to M.L.M‐Ch) MCIU/AEI/FEDER, UE (RTI2018‐095134‐B‐100 to P.A. and RTI2018‐099413‐B‐I00 to RN, Asociación Española contra el Cáncer, Canceres raros (M.L.M‐Ch), La Caixa Foundation (to M.L.M‐Ch), Ayudas Fundación BBVA a equipos de Investigación Científica 2018 (to M.L.M‐Ch), Xunta de Galicia (RN: 2015‐CP080 and 2016‐ PG057), Fundación BBVA (RN), and European Foundation for the Study of Diabetes (RN). ISCIII‐FEDER PI17/00535 (to C.G‐M.), ISCIII‐FEDER CP14/00181 and PI16/00823 (to A.G‐ R.), and Francisco Cobos Foundation (to A.G‐R.). CiC bioGUNE thanks MINECO for the Severo Ochoa Excellence Accreditation (SEV‐2016‐ 0644

Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis

Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis. High methionine and S-adenosylmethionine serum levels are related with obesity. Here the authors show that knockdown of methionine adenosyltransferase by using antisense oligonucleotides provides beneficial effects in obesity and comorbidities.This work was supported by Ayudas para apoyar grupos de investigacion del sistema Universitario Vasco (IT971-16) and MCIU/AEI/FEDER, UE (RTI2018-095134-B-100) (to P.A.), (RTI2018-099413-B-I00 and RED2018-102379-T) (to R.N.), PID2020119486RB-100 (to M.V.R.) and (RTI2018-096759-A-100) (to T.C.D). EFSD/Lilly European Diabetes Research Program, MICIU (PID2019-104399RB-I00), Fundacion AECC PROYE19047SABI, and Comunidad de Madrid IMMUNOTHERCAN-CM B2017/BMD-3733 (to G.S.). La CAIXA Foundation LCF/PR/HP17/52190004, MINECO-FEDER SAF2017-87301-R, AYUDAS FUNDACION BBVA A EQUIPOS DE INVESTIGACION CIENTIFICA UMBRELLA 2018 and AECC Scientific Foundation, grant name: Rare Cancers 2017 (to M.L.M.-C.). AECC Scientific Foundation (to T.C.D.). Xunta de Galicia 2020-PG015 (to R.N.) Gilead Sciences International Research Scholars Program in Liver Disease (to M.V.R.). Personal fellows: E.P.F. was awarded with Juan de la Cierva-Formacion, FJC2018-035449-I. C.F. was awarded with Sara Borrell (CD19/00078). CIC bioGUNE thanks MCIU for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). The authors thank Dr. Manuel Lafitas laboratory (Getxo, Bizkaia, Spain) for his valuable help in the analysis of biochemical parameters

Efecto de la hipertermia sobre la proliferación de células CC531 in vitro

El cáncer colorrectal (CCR) es un problema mundial, con una incidencia anual de aproximadamente un millón de casos, y una mortalidad anual de más de 500.000. Así, el CCR es la segunda causa de mortalidad por cáncer entre hombres y mujeres. Además, se prevé que el número absoluto de casos aumentará en las próximas dos décadas como resultado del envejecimiento y la expansión de las poblaciones, tanto en los países desarrollados como en los países en desarrol lo (1, 2). Gran parte de los carcinomas colorrectales son adenocarcinomas glandulares, caracterizados por la invasión de tejidos o estructuras circundantes y por su potencial de metastatizar, por vía linfática o vascular. De hecho, alrededor del 50% de los pacientes con cáncer de colon desarrollan metástasis hepáticas, bien en la presentación del tumor o en la recidiva de la enfermedad. Por este motivo, las metástasis hepáticas del CCR constituyen un problema clínico de primera magnitud. En la última década , la cirugía ha aumentado sus indicaciones desde pacientes con no más de tres metástasis , hasta pacientes con una masa tumoral hepática inicialmente no resecable, pero susceptibles de reducir el volumen tumoral mediante quimioterapia o de incrementar la m asa hepática remanente hasta proporciones compatibles con la supervivencia del enfermo (embolizaciones, ligadura de vasos portales, etc.). Hoy por hoy, la técnica curativa indiscutida es la resección quirúrgica del parénquima hepático invadido por tumor; s in embargo, solo una pequeña parte de los pacientes que presentan metástasis hepáticas son aptos para someterse a resección quirúrgica