Papel de p53 en el metabolismo hepático

El objetivo de esta tesis es el estudio del papel de p53 en el metabolismo lipídico hepático. La ausencia de p53 provoca una disminución de peso corporal y de masa grasa debido a la activación de la termogénesis en el tejido adiposo marrón. Observamos que p53 es fundamental para la acción adipogénica de la ghrelina en el tejido adiposo blanco y en el hígado. La disminución total o específica de los niveles de p53 en el hígado, provocan un incremento de la grasa hepática. Esta acción está mediada por TAp63alfa; su sobreexpresión produce esteatosis a través de la activación IKKbeta y del estrés del retículo endoplasmático. Encontramos niveles elevados de TAp63alfa, IKKbeta y XBP1 en el hígado de pacientes con esteatosis y esteatohepatitis

Parabrachial Interleukin-6 reduces body weight and food intake and increases thermogenesis to regulate energy metabolism

Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6This research was funded by the Swedish Research Council ( 2014-2945 to K.P.S.; 2017-00792 to I.W.A.; and 2013-7107 to Patrik Rorsman), the Novo Nordisk Foundation Excellence project grant (to K.P.S. and I.W.A.), the Ragnar Söderberg Foundation (to K.P.S.), Harald Jeanssons Stiftelse and Greta Jeanssons Stiftelse (to K.P.S.), Magnus Bergvalls Stiftelse (to K.P.S.), the Wallenberg Foundation and the Center for Molecular and Translational Medicine (to K.P.S.), postdoctoral stipendium from The Swedish Brain Foundation (to D.M.), the ERC ( BFU2015-70664-R and StG-281408 ) (to R.N.), and the NIH ( DK-21397 ) (to H.J.G.)S

Absence of Intracellular Ion Channels TPC1 and TPC2 Leads to Mature-Onset Obesity in Male Mice, Due to Impaired Lipid Availability for Thermogenesis in Brown Adipose Tissue

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Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis

One of the most common types of fibrotic liver occurs in patients with non-alcoholic fatty liver disease (NAFLD), which may develop into non-alcoholic steatohepatitis (NASH). Hepatic stellate cells (HSCs) are the primary fibrogenic cell type activated following liver injury, moving from a quiescent phenotype rich in vitamin A into activated myofibroblast-like cells with proliferative and migratory properties.This work has been supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (DS and LH: SAF2017-83813-C3-1-R; MLMC: RTC2019-007125-1; CD: BFU2017-87721; ML: RTI2018–101840-B-I00; RN: RTI2018-099413-B-I00 and RED2018-102379-T; MLMC: SAF2017-87301-R; TCD: RTI2018-096759-A-100), Xunta de Galicia (ML: 2016-PG068; RN: 2015-CP080 and 2016-PG057), Fundación BBVA (RN and MLM), Proyectos Investigación en Salud (MLMC: DTS20/00138), Sistema Universitario Vasco (PA: IT971-16); Fundacion Araucaria (ML and RN), Gilead Sciences International Research Scholars Program in Liver Disease (MVR), Marató TV3 Foundation (DS: 201627), Government of Catalonia (DS: 2017SGR278) and European Foundation for the Study of Diabetes (RN). This research also received funding from the European Community’s H2020 Framework Programme (ERC Synergy Grant-2019-WATCH- 810331, to RN, VP and MS). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd). CIBERobn and CIBERehd are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644)S