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[EN]: Retinal diseases linked to inflammation, including diabetic retinopathy (DR), are often accompanied by resident macrophage/microglial cells activation. During DR, there are substantial changes in the polarization status of the microglia from the M2 (anti-inflammatory) to the M1 (pro-inflammatory) stage. However, the dynamics between M1 and M2 polarization of microglia during DR has not been investigated and it might be therapeutically useful. In this study, we have characterized the evolution of microglia polarizarion during the early stages of DR in the retina of diabetic db/db mice. Moreover, we have analyzed microglia polarization in response to pro-(bacterial lipopolysaccharide; LPS) or anti-(IL4/IL13 cytokines or the bicyclic nojirimycin derivative (1R)-1-dodecylsulfinyl-5N,6O-oxomethylidenenojirimycin (RDS-ONJ)) inflammatory stimuli. For this goal, we have performed in vitro experiments in Bv-2 murine microglial cells as well as ex vivo experiments in retinal explants from db/db mice. Treatment of Bv-2 cells with LPS together with IL4/IL13 or R-DS-ONJ switched the M1 response towards M2. In retinal explants from db/db mice, R-DS-ONJ induced a M2 response. In conclusion, the modulation of microglia polarization dynamics towards a M2 status at early stages of DR offers novel therapeutic interventions. ; [ES]: Las enfermedades retinianas, entre las que se encuentra la retinopatía diabética (RD), están vinculadas a un contexto inflamatorio en el cual existe una activación de los macrófagos residentes en la retina (microglia). Durante la retinopatía diabética se producen cambios de polarización de la microglia, definiéndose éstos como transiciones entre el estado M1 (proinflamatorio) y el estado M2 (anti-inflamatorio), estando aún por determinar los tiempos de aparición y actuación de la microglia en cada uno de ellos. La identificación espacio-temporal de la transición de la microglía de un estado a otro podría constituir una potente herramienta clínica para diferentes abordajes terapéuticos. En este trabajo se ha caracterizado el estado de polarización de la microgía en la retina durante las primeras fases de la RD en el modelo de ratón diabético db/db. Además, se ha estudiado la polarización de la microglia en presencia de estímulos pro-inflamatorios (lipopolisacárido bacteriano; LPS) o anti-inflamatorios (citoquinas IL4/IL13 o un compuesto natural derivado de la casternospermina, R-DS-ONJ). Para ello, se ha realizado un abordaje in vitro utilizando la línea celular de microglia murina Bv-2 y un abordaje ex vivo con explantes de retinas procedentes de ratones diabéticos db/db. El tratamiento de las células Bv-2 con LPS en combinación con IL4/IL13 o alternativamente con el compuesto R-DS-ONJ indujo la transición en la polarización de la microglia desde el estado proinflamatorio M1, inducido por el LPS, al estado antiinflamatorio M2. En los explantes de retinas de ratones db/db, el compuesto R-DS-ONJ indujo la respuesta M2 disminuyendo la respuesta M1. En conclusión, la polarización de la microglia hacía un estado M2 durante los estadíos tempranos de la RD ofrece una nueva ventana terapéutica de actuación. ; This work was supported by grants from the Spanish Ministry of Economy and Competitivity (SAF2015-65267-R and SAF2012-33283), Comunidad de Madrid S2010/BMD-2423 and S2010/BMD2439, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem, Instituto Carlos III, Spain), European Union (EUROCONDOR (FP7 HEALTH.2011.2.4.3.1.)). ; Peer Reviewed

[Purpose]: Insulin-like growth factor-I receptor (IGF-IR) signaling mediates retinal growth and survival and its failure may contribute to aggravate diabetic retinopathy (DR). Protein tyrosine phosphatase 1B (PTP1B) negatively modulates IGF-IR signaling, but its involvement in inflammation during DR remains unknown. We investigated whether PTP1B participates in the cross-talk between proinflammatory signaling pathways and IGF-IR–mediated signaling in the retina. [Methods]: 661W photoreceptors or mouse retinal explants were treated with TNFa, IL6, and IL1b. Insulin-like growth factor-I receptor signaling cascade was evaluated in the absence or presence of PTP1B. db/db mice were used to test a PTP1B inhibitor in retinal gliosis. [Results]: 661W retinal cells and retinal explants responded to IGF-I by inducing IGF-IR tyrosine (13-fold) and Akt phosphorylations (7- and 3-fold for serine 473 and threonine 308, respectively). Cytokines triggered early activation of stress kinases (c-jun [NH2] terminal kinase [JNK] and p38 MAPK), resulting in insulin receptor substrate 1 (IRS1) serine 307 phosphorylation that precedes its degradation. Pretreatment of 661W cells or retinal explants with cytokines upregulated PTP1B protein levels (1.45- and 4.5-fold, respectively), induced IRS1 degradation and decreased IGF-I–mediated IGF-IR/Akt phosphorylation. Silencing or deficiency in PTP1B ameliorated the negative effects of cytokines on IGF-IR signaling. Cytokines increased glial fibrillary acidic protein (GFAP) expression in retinal explants by 4.5- fold, this response being reduced by 2-fold with a PTP1B inhibitor. Protein tyrosine phosphatase 1B protein levels increased by 3-fold in retinas from db/db mice and its inhibition reduced gliosis. [Conclusions]: Targeting PTP1B might be useful for modulating IGF-I effects in retinal cells during DR. ; Supported by grants from Spanish Ministry of Economy and Competitivity (SAF2012-33283; Madrid, Spain), Comunidad de Madrid S2010/BMD-2423 (Madrid, Spain), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBEDEM, Instituto Carlos III, Madrid, Spain), and European Union (EUROCONDOR; FP7 HEALTH.2011.2.4.3.1.; Barcelona, Spain). ; Peer Reviewed

This is an open access article under the CC BY-NC-ND license.-- et al. ; [Objective]: SIRT1 has been proposed to be a key signaling node linking changes in energy metabolism to transcriptional adaptations. Although SIRT1 overexpression is protective against diverse metabolic complications, especially in response to high-fat diets, studies aiming to understand the etiology of such benefits are scarce. Here, we aimed to identify the key tissues and mechanisms implicated in the beneficial effects of SIRT1 on glucose homeostasis. [Methods]: We have used a mouse model of moderate SIRT1 overexpression, under the control of its natural promoter, to evaluate glucose homeostasis and thoroughly characterize how different tissues could influence insulin sensitivity. [Results]: Mice with moderate overexpression of SIRT1 exhibit better glucose tolerance and insulin sensitivity even on a low fat diet. Euglycemic-hyperinsulinemic clamps and in-depth tissue analyses revealed that enhanced insulin sensitivity was achieved through a higher brown adipose tissue activity and was fully reversed by housing the mice at thermoneutrality. SIRT1 did not influence brown adipocyte differentiation, but dramatically enhanced the metabolic transcriptional responses to β3-adrenergic stimuli in differentiated adipocytes. [Conclusions]: Our work demonstrates that SIRT1 improves glucose homeostasis by enhancing BAT function. This is not consequent to an alteration in the brown adipocyte differentiation process, but as a result of potentiating the response to β3-adrenergic stimuli. ; M.S. is funded by the CNIO and by grants from the MICINN (SAF), the Regional Government of Madrid, the European Research Council (CANCER&AGING; LS1, ERC-2008-AdG), the Botín Foundation, the Ramón Areces Foundation, and the AXA Foundation. P.J.F.M. is funded by the AECC. A.M.V. is funded by the following grant support: SAF2012-33283 (MINECO, Spain), Comunidad de Madrid S2010/BMD-2423, EFSD and Amylin Paul Langerhans Grant and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM, ISCIII, Barcelona, Spain). P.M.G.R. is funded by the following grant support: BFU2011-24679 (MINECO, Spain) and he is a recipient of a Ramon y Cajal contract: RYC-2009-05158(MINECO, Spain). ; Peer Reviewed

et al. ; Fasting is a physiological stress that elicits well-known metabolic adaptations, however, little is known about the role of stress-responsive tumor suppressors in fasting. Here, we have examined the expression of several tumor suppressors upon fasting in mice. Interestingly, p21 mRNA is uniquely induced in all the tissues tested, particularly in liver and muscle (>10 fold), and this upregulation is independent of p53. Remarkably, in contrast to wild-type mice, p21-null mice become severely morbid after prolonged fasting. The defective adaptation to fasting of p21-null mice is associated to elevated energy expenditure, accelerated depletion of fat stores, and premature activation of protein catabolism in the muscle. Analysis of the liver transcriptome and cell-based assays revealed that the absence of p21 partially impairs the transcriptional program of PPARα, a key regulator of fasting metabolism. Finally, treatment of p21-null mice with a PPARα agonist substantially protects them from their accelerated loss of fat upon fasting. We conclude that p21 plays a relevant role in fasting adaptation through the positive regulation of PPARα. ; E.L.-G. was recipient of a predoctoral contract from the Spanish Ministry of Education. P.J.F.-M. has been funded by the Spanish Association Against Cancer (aecc). Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (SAF project), the European Research Council (ERC Advanced Grant), the Regional Government of Madrid co-funded by the European Social Fund (ReCaRe project), the Botin Foundation and Banco Santander (Santander Universities Global Division), the Ramon Areces Foundation, and the AXA Foundation. ; Peer Reviewed

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. ; Sei1 is a positive regulator of proliferation that promotes the assembly of Cdk4-cyclin D complexes and enhances the transcriptional activity of E2f1. The potential oncogenic role of Sei1 is further suggested by its overexpression in various types of human cancers. To study the role of Sei1, we have generated a mouse line deficient for this gene. Sei1-null fibroblasts did not show abnormalities regarding proliferation or susceptibility to neoplastic transformation, nor did we observe defects on Cdk4 complexes or E2f activity. Sei1-null mice were viable, did not present overt pathologies, had a normal lifespan, and had a normal susceptibility to spontaneous and chemically-induced cancer. Pancreatic insulin-producing cells are known to be particularly sensitive to Cdk4-cyclin D and E2f activities, and we have observed that Sei1 is highly expressed in pancreatic islets compared to other tissues. Interestingly, Sei1-null mice present lower number of islets, decreased beta-cell area, impaired insulin secretion, and glucose intolerance. These defects were associated to nuclear accumulation of the cell-cycle inhibitors p21(Cip1) and p27(Kip1) in islet cells. We conclude that Sei1 plays an important role in pancreatic beta-cells, which supports a functional link between Sei1 and the core cell cycle regulators specifically in the context of the pancreas. ; Work in the laboratory of M.S. is funded by the Centro Nacional de Investigaciones Oncológicas (CNIO) and by grants from the Spanish Ministry of Science (SAF and CONSOLIDER), the Regional Government of Madrid (GsSTEM), the European Union (PROTEOMAGE), the European Research Council (ERC), and the ''Marcelino Botin'' Foundation. Work in the laboratory of A.M.V. was funded by the Ministry of Science (BFU2008-02420) and by the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). ; Peer reviewed

Retinal degenerative diseases are a group of heterogeneous diseases that include age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR). The progressive degeneration of the retinal neurons results in a severe deterioration of the visual function. Neuroinflammation is an early hallmark of many neurodegenerative disorders of the retina including AMD, RP and DR. Microglial cells, key components of the retinal immune defense system, are activated in retinal degenerative diseases. In the microglia the interplay between the proinflammatory/classically activated or antiinflammatory/alternatively activated phenotypes is a complex dynamic process that occurs during the course of disease due to the different environmental signals related to pathophysiological conditions. In this regard, an adequate transition from the proinflammatory to the anti-inflammatory response is necessary to counteract retinal neurodegeneration and its subsequent damage that leads to the loss of visual function. Insulin like-growth factor-1 (IGF-1) has been considered as a pleiotropic factor in the retina under health or disease conditions and several effects of IGF-1 in retinal immune modulation have been described. In this review, we provide recent insights of inflammation as a common feature of retinal diseases (AMD, RP and RD) highlighting the role of microglia, exosomes and IGF-1 in this process. ; The work of AIA and ÁMV has been funded by grants from European Union (project H2020-MSCA-ITN TREATMENT Grant Agreement number: 721236 and project EUROCONDOR FP7 Grant Agreement number 278040), grant from the Spanish Ministry of Economy and Competitiveness: SAF2015-65267-R (MINECO/FEDER) and grants from the Spanish ISCIII (CIBERdem) and INFLAMES (ISCIII PIE14/00045, co-funded by ERDF, Investing in your future). ; Peer Reviewed

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. ; [Purpose]: Many cellular and molecular studies in experimental animals and early retinal function tests in patients with diabetic retinopathy (DR) have shown that retinal neurodegeneration is an early event in the pathogenesis of the disease. Somatostatin (SST) is one of the most important neuroprotective factors synthesized by the retina: SST levels are decreased in parallel to retinal neurodegeneration in early stages of DR. In this study, we characterized the induction of apoptosis (programmed cell death) in a 661W photoreceptor-like cell line cultured under high glucose (HG) conditions and the effect of SST. [Methods]: A 661W photoreceptor-like cell line and retinal explants from 10-week-old male C57BL/6 mice were cultured under HG conditions and treated with SST. [Results]: Hyperglycemia significantly reduced the cellular viability by increasing the percentage of apoptotic cells, and this effect was ameliorated by SST (p˂0.05). Activation of caspase-8 by hyperglycemia was found in the 661W cells and retinal explants and decreased in the presence of SST (p˂0.05). Moreover, we detected activation of calpain-2 associated with hyperglycemia-induced cell death, as well as increased protein tyrosine phosphatase 1B (PTP1B) protein levels; both had a pattern of cleavage that was absent in the presence of SST (p˂0.05). Treatment of the 661W cells and retinal explants with SST for 24 h increased the phosphorylation of type 1 insulin-like growth factor receptor (IGF-IR; tyrosine 1165/1166) and protein kinase B (Akt; serine 473), suggesting this survival signaling is activated in the neuroretina by SST (p˂0.05). [Conclusions]: This study has provided new mechanistic insights first into the involvement of calpain-2 and PTP1B in the loss of cell survival and increased caspase-8-dependent apoptosis induced by hyperglycemia in photoreceptor cells and second, on the protective effect of SST against apoptosis by the enhancement of IGF-IR-mediated Akt phosphorylation. ; This work was supported by grants from European Union: (EUROCONDOR project grant agreement number 278,040) and FP7-People-2012-CIG (grant agreement number 333,594), Spanish Ministry of Economy and Competitivity: SAF2012-35562 and SAF2015-65267R cofunded by the Fondos Europeos de Desarrollo Regional de la Unión Europea [FEDER] and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem). ; Peer Reviewed

15 páginas, 7 figuras.-- et al. ; Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δMAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δpathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved. ; G. Sabio is an investigator of the Ramón y Cajal Program and a recipient of a Principe de Girona Impulsa award. R.J. Davis is an investigator of the Howard Hughes Medical Institute. Á. Verdugo is a recipient of a Madrid Regional Government fellowship. E. Manieri is a fellow of the La Caixa Foundation Á. González-Rodríguez was supported by CIBERDEM (ISCIII, Spain). This work was funded by the following grants: ERC 260464, EFSD 2030, MICINN SAF2010-19347, and Comunidad de Madrid S2010/BMD-2326 (to G. Sabio:); MICINN SAF2011-27330 (to P. Martin); and MICINN SAF2012-3328 (to Á. Valverde). The CNIC is supported by the Ministry of Economy and Competitiveness and the Pro-CNIC Foundation. ; Peer Reviewed

Neuroinflammation is an early event during diabetic retinopathy (DR) that impacts the dynamics of microglia polarization. Gliosis is a hallmark of DR and we have reported the beneficial effects of 1R-DSO-ONJ, a member of the sp2-iminosugar glycolipid (sp2-IGL) family, in targeting microglia and reducing gliosis in diabetic db/db mice. Herein, we analyzed the effect of DSO2-ONJ, another family compound incorporating a sulfone group that better mimics the phosphate group of phosphatidylinositol ether lipid analogues (PIAs), in Bv.2 microglial cells treated with bacterial lipopolysaccaride (LPS) and in retinal explants from db/db mice. In addition to decreasing iNOS and inflammasome activation, the anti-inflammatory effect of DSO2-ONJ was mediated by direct p38α MAPK activation. Computational docking experiments demonstrated that DSO2-ONJ binds to p38α MAPK at the same site where PIAs and the alkyl phospholipid perifosine activators do, suggesting similar mechanism of action. Moreover, treatment of microglial cells with DSO2-ONJ increased both heme-oxygenase (HO)-1 and Il10 expression regardless the presence of LPS. In retinal explants from db/db mice, DSO2-ONJ also induced HO-1 and reduced gliosis. Since IL-10-mediated induction of HO-1 expression is mediated by p38α MAPK activation, our results suggest that this molecular mechanism is involved in the anti-inflammatory effects of DSO2-ONJ in microglia. ; This work was supported by grants from the Spanish Ministry of Economy and Competitiveness: SAF2015-65267-R (MINECO/FEDER), SAF2016-76083-R (MINECO-FEDER), CTQ2015-64425-C2-1-R (MINECO-FEDER) and CTQ2014-53144-P and grants from the Spanish ISCIII (CIBERdem) and INFLAMES (ISCIII PIE14/00045, co-funded by ERDF, "Investing in your future"). We also acknowledge the European Union project H2020-MSCA-ITN TREATMENT Grant Agreement number: 721236. L.M. thanks the Universitat Autònoma de Barcelona-Banco Santander Program for financial support. ; Peer reviewed

Insulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1), present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1 mice. Tnfa and Il1bmRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1 mice compared to those in agematched Igf1 controls. In 6-month-old Igf1 retinas, increased mRNAlevelsofthe autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1) protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1 mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1 controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1 and Igf1 mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL), inner plexiform layer (IPL) and inner nuclear layer (INL), and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1 mice. Moreover, reactive gliosis was exclusively detected inthe retinas from 12-month-old blind Igf1 mice. In conclusion, this study provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during ageing. ; This work was supported by grants from the Spanish Ministerio de Economia y Competitividad [grant numbers SAF2015-65267-R MINECO/FEDER (to A.M.V.) and SAF2014-53979-R (I.V.-N.)]; Instituto de Salud Carlos III [grant number INFLAMES, PIE14/00045]; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem, Instituto Carlos III, Spain); and European Union and Marie Curie Industry-Academia Partnerships and Pathways (IAPP), TARGEAR [grant number FP7 PEOPLE 2013 IAPP-612261, http://cordis.europa.eu/project/rcn/110205_en.html (to I.V.-N.)]. ; Peer Reviewed

Aging in mammals is characterized by failure of the homeostatic mechanisms that regulate energy balance. Several mechanisms have been proposed such as the presence of a low-grade chronic inflammation in different tissues, as well as leptin and insulin resistance, but the primary alteration is not fully elucidated. The gut microbiota has recently emerged as a key player in a variety of metabolic and neurological disorders. A main concept in this context is the gut–brain axis that refers to alterations in the gut that mediate effects in the central nervous system, including those related with the control of energy balance. Using 16S rRNA analysis, we demonstrate that aged male Wistar rats have increased presence of mucin-degrading and lipopolysaccharide (LPS)-producing bacteria. In addition, old animals exhibit a lower number of neutral mucin secreting goblet cells, and a decrease of tight junctions and adherens junctions marker proteins, zonula occludens protein-1 (ZO-1) and β-catenin, respectively. These data are compatible with a thinner mucus layer and a weaker gut barrier in older animals that likely facilitate LPS leakage. Our data also show that cholecystokinin (CCK) satiating effect is impaired in aged rats, one of the expected effects of increased LPS leakage. In contrast, no overt signs of gut or systemic inflammation are observed. Changes in microbiota in old male Wistar rats present features of situations of increased adiposity, but different from those of obese animals. These could partly explain the increased adiposity and fat deposition in liver and heart as observed here. ; Spanish Government (grants BFU2008-04901-C03-01/BFI to J.M.C., BIO2016-76601-C3-2-R to M.F.-L., and RTI2018-094052-B-100 [MCI/AEI/FEDER, UE to A.M.V.] and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (Instituto de Salud Carlos III) and Comunidad de Madrid, Spain (grants S2010/BMD-2423 to J.M.C., F.E., L.G.G., and A.M.V. and S2017/BMD-3684 to F.E. and A.M.V.). C.R. was supported by a predoctoral aid from Spanish Government. The Centro de Biología Molecular is recipient of institutional aids from Banco de Santander and Ramón Areces Foundation.

[Objectives]: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). [Methods]: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2–7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. [Results]: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. [Conclusions]: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD. ; This work was funded by SAF2015-65267-R (MINECO/FEDER), CIBERdem (ISCIII, Spain), INFLAMES (ISCIII PIE14/00045, co-funded by ERDF, "Investing in your future") to A.M.V; IJCI-2014-19381 (MINECO/FEDER) to P.R and A.M.V; CP14/00181 and PI16/00823 (ISCIII/FEDER) and CIBERehd (ISCIII, Spain) to A.G-R; BFU2015-65937-R (MINECO/FEDER), 67-2015 (Department of Health, Navarra Government) and CIBERobn (ISCIII, Spain) to M.J.M; SAF2015-69145-R (MINECO/FEDER) to A.S. A.A. was recipient of a Marie Curie ESR contract from IT-LIVER (Marie Curie Action of the FP7-2012, grant agreement 316549). We also acknowledge the European Union, project H2020-MSCA-ITN TREATMENT Grant Agreement number: 721236. ; Peer Reviewed

[Objective] The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)b/d and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. [Methods] Studies were conducted in wild-type and Pparb/d-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. [Results] Increased VLDLR levels were observed in liver of Pparb/d-null mice and in Pparb/d-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2a (eIF2a) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARb/d mRNA abundance and DNA-binding activity compared with control subjects. [Conclusions]: Overall, these findings provide new mechanisms by which PPARb/d and FGF21 regulate VLDLR levels and influence hepatic steatosis development. ; This study was partly supported by funds from the Spanish Ministry of the Economy and Competitiveness (SAF2015-64146-R to MVC, SAF2014-55725 to FV, and SAF2015-65267-R to AMV) and European Union ERDF funds. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn) are Carlos III Health Institute projects. WW is supported by Start-Up Grants from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, and by the Région Midi-Pyrénées, France, and TQL is supported by a CONACyT (National Council for Science and Technology in Mexico) Ph.D. scholarship. ; Peer reviewed