It TAK(es) 1 to prevent steatohepatitis and tumorigenesis
Priya Handa
,
, Kris V. Kowdley
,
* Benaroya Research Institute, Seattle, Washington, USA, Liver Transplant Care Network, Swedish, Seattle, WA, USA
Read
773
Timeswas read the article
348
Total PDF
425
Total HTML
Share statistics
array:24 [ "pii" => "S1665268119309925" "issn" => "16652681" "doi" => "10.1016/S1665-2681(19)30992-5" "estado" => "S300" "fechaPublicacion" => "2014-11-01" "aid" => "70748" "copyright" => "Fundación Clínica Médica Sur, A.C." "copyrightAnyo" => "2014" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "nws" "cita" => "Ann Hepatol. 2014;13:847-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 90 "formatos" => array:3 [ "EPUB" => 12 "HTML" => 24 "PDF" => 54 ] ] "itemSiguiente" => array:19 [ "pii" => "S1665268119309937" "issn" => "16652681" "doi" => "10.1016/S1665-2681(19)30993-7" "estado" => "S300" "fechaPublicacion" => "2014-11-01" "aid" => "70749" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "simple-article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "mis" "cita" => "Ann Hepatol. 2014;13:849-50" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 58 "formatos" => array:3 [ "EPUB" => 15 "HTML" => 14 "PDF" => 29 ] ] "en" => array:7 [ "idiomaDefecto" => true "titulo" => "An Acknowledgement" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "849" "paginaFinal" => "850" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119309937?idApp=UINPBA00004N" "url" => "/16652681/0000001300000006/v1_201906150917/S1665268119309937/v1_201906150917/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268119309913" "issn" => "16652681" "doi" => "10.1016/S1665-2681(19)30991-3" "estado" => "S300" "fechaPublicacion" => "2014-11-01" "aid" => "70747" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "cor" "cita" => "Ann Hepatol. 2014;13:845-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 49 "formatos" => array:3 [ "EPUB" => 9 "HTML" => 17 "PDF" => 23 ] ] "en" => array:8 [ "idiomaDefecto" => true "titulo" => "Challenges in treating liver fibrosis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "845" "paginaFinal" => "846" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jorge L. Poo, Linda E. Muñoz" "autores" => array:2 [ 0 => array:3 [ "preGrado" => "M.D." "nombre" => "Jorge L." "apellidos" => "Poo" ] 1 => array:2 [ "nombre" => "Linda E." "apellidos" => "Muñoz" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119309913?idApp=UINPBA00004N" "url" => "/16652681/0000001300000006/v1_201906150917/S1665268119309913/v1_201906150917/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "It TAK(es) 1 to prevent steatohepatitis and tumorigenesis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "847" "paginaFinal" => "848" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Priya Handa, Kris V. Kowdley" "autores" => array:2 [ 0 => array:5 [ "preGrado" => "Ph.D." "nombre" => "Priya" "apellidos" => "Handa" "email" => array:1 [ 0 => "phanda@benaroyaresearch.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:5 [ "preGrado" => "M.D." "nombre" => "Kris V." "apellidos" => "Kowdley" "email" => array:1 [ 0 => "kris.kowdley@swedish.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0010" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Benaroya Research Institute, Seattle, Washington, USA, Liver Transplant Care Network, Swedish, Seattle, WA, USA" "etiqueta" => "*" "identificador" => "aff0005" ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0005">Article commented:</span><p id="p0005" class="elsevierStylePara elsevierViewall">TAKl-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. Inokuchi-Shimizu S, Park EJ, Roh YS, Yang L, Zhang B, Song J, Liang S, Pimienta M, Taniguchi K, Wu X, Asahina K, Lagakos W, Mackey MR, Akira S, Ellisman MH, Sears DD, Olefsky JM, Karin M, Brenner DA, Seki E. <span class="elsevierStyleItalic">J Clin Invest 2014;</span> 124(8): 3566-78.</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0010">Comment:</span><p id="p0010" class="elsevierStylePara elsevierViewall">TAK1 (TGF-β activated kinase 1) is activated by TLRs, IL-1, TNF, and TGF-β, and in turn, regulates two main transcription factors, IKK/NF- κB and JNK, which control a plethora of essential cellular functions such as cell proliferation, survival, growth, inflammation, tumorigenesis, insulin sensitivity and lipid metabolism.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> While sustained JNK signaling has been known to exert pathophysiological effects on the liver by causing inflammation, cell death, reactive oxygen species (ROS) generation, lipid accumulation and hepatocellular carcinoma (HCC),<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> IKK/NF- κB signaling has been shown to prevent TNF- and ROSmediated cell death, steatosis and HCC.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Since TAK1 regulates both IKK/NF- κB and JNK pathways with seemingly contrasting effects,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> its role in liver has been difficult to envisage. These authors previously showed that hepatocyte-specific ablation of TAK1 led to spontaneous liver inflammation, apoptosis, fibrosis and HCC development, mediated through TNF- and TGF-β signaling.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">In addition to regulating IKK/NF- κB and JNK, TAK1 signaling is also believed to enhance AMPK-mediated autophagy.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Since AMPK is a metabolic sensor, it is activated upon nutrient deprivation, and in turn suppresses mTORC1 complex, a regulator of lipid metabolism and autophagy.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Under of nutrient excess, conditions, when ATP levels are high, AMPK activity is suppressed leading to activation of mTORC1, and thereby increased lipid biosynthesis via upregulation of ppar γ and SREBP1c.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In addition, mTORC1 is also known to inhibit ppar alpha, which regulates hepatic fatty acid oxidation (FAO).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> AMPK activation and mTORC1 inhibition regulate autophagy, to remove and recycle cellular components, during a phase with limited nutrients. Autophagy promotes lipid breakdown and inhibits lipid storage.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">In this elegant work, the authors have expanded our understanding of this enigmatic and important regulator by clarifying the metabolic function of TAK1, and the pathophysiological relevance o f TAK1 regulating autophagy and lipid metabolism through AMPK/mTORC1, and therefore, its effect on liver metabolism and liver tumorigenesis.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">To address the physiological role of TAK1 in the liver, the authors first assessed the effect of acute fasting on 1 month old WT (wild type) mice, and mice carrying a hepatocyte-specific deletion of TAK1. After 12 hours of fasting, they found that the livers of Δhep TAK1 mice showed hepatic steatosis and had significantly elevated hepatic triglycerides. Hepatocytes isolated from such mice showed lipid accumulation, relative to their WT counterparts. Furthermore, liver lysates from fasted Δhep TAK1 mice showed overactivation of S6, a marker of mTORC1 activity, whereas WT livers showed an inhibition of mTORC1 activation, consistent with nutrient deficiency. Thus, lipid deposition in the liver is TAK1 dependent, and absence of TAK1 causes excessive mTORC1 activation.</p><p id="p0030" class="elsevierStylePara elsevierViewall">Next, the authors assessed AMPK activation and autophagy under fasting conditions in WT and Δhep TAK1 livers. They observed that AMPK activation was reduced in the livers of Δhep TAK1 mice, relative to WT livers. Furthermore, autophagy was reduced in the livers of Δhep TAK1 mice, assessed by the increased expression of p62, relative to fasted WT livers, which showed reduced p62 expression (a marker of autophagy induction). In addition, an AMPK activator such as metformin increased TAK1 kinase activity and overexpression of AMPK could stimulate autophagy in livers of Δhep TAK1 mice, indicating that AMPK is a downstream effector of TAK1, which mediates its effect on autophagy.</p><p id="p0035" class="elsevierStylePara elsevierViewall">The authors next wanted to address the cause of steatosis in the livers of Δhep TAK1 mice. On examining the expression of hepatic fatty acid oxidation (FAO) genes, they found that ppar alpha target genes and FAO genes (Cpt1a, Acox) were downregulated in the livers of Δhep TAK 1 mice relative to WT livers, indicating that TAK1 deficiency suppresses ppar alpha activity and the induction of its target genes, thus enhancing lipid accumulation in their livers.</p><p id="p0040" class="elsevierStylePara elsevierViewall">Since TAK1 deficiency causes overstimulation of mTORC1, the authors next asked if rapamycin (an established inhibitor of mTORC1) could restore autophagy in the livers of Δhep TAK mice, and ppar alpha function, reducing lipid accumulation in Δhep TAK1 livers. They found that autophagy was restored, and so was ppar alpha-induced FAO. This salutary effect of mTORC1 inhibition was due to restoration of autophagy, indicating that a defect in autophagy was responsible for the hepatic steatosis in the Δhep TAK1 livers. Furthermore, this rescue establishes that TAK1 acts upstream of mTORC1.</p><p id="p0045" class="elsevierStylePara elsevierViewall">Since TAK1 expression levels are lower in experimental fatty liver disease and in obese mice,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> the authors wished to test the response of liver-specific TAK1 ablation to a High Fat Diet (HFD) challenge. After 12 weeks on a HFD, relative to WT mice, TAK1 deficient livers showed increased steatosis, increased hepatic TG, FFA, serum ALT and impaired autophagy (increased p62 accumulation). They showed elevated expression of lipid synthesis genes (SREBP1C, DGAT1), inflammatory genes (TNF-α, IL-6), fibrogenic markers (collagen1a1,TGF-β) and also showed significantly enhanced expression of Afp, a HCC marker. Thus, TAK1 deficiency exacerbates a HFD- induced steatohepatitis, as a result of impaired lipid metabolism and autophagy, and also accelerates liver tumorigenesis. Notably, there was no difference in blood glucose levels and body weighs between HFD-fed WT and Δhep TAK1 mice, despite liver pathophysiology.</p><p id="p0050" class="elsevierStylePara elsevierViewall">Finally, the authors wanted to test if rapamycin would protect livers of Δhep TAK1 mice from hepatocellular-carcinoma (HCC), since these mice spontaneously develop HCC with expression of typical HCC markers such as alpha fetoprotein, glypican3 and others, relative to WT mice. The authors tested if restoration of autophagy and inactivation of mTORC1 could block HCC development. They found that rapamycin is effective in reducing the number of tumors in an early treatment regimen (2 -10 weeks from birth) and a late therapy with rapamycin (7-9 months of age) reduced the number and size of tumors and fibrosis.</p><p id="p0055" class="elsevierStylePara elsevierViewall">In summary, in this work the authors have shed light on yet another critical role of TAK1: as a regulator of AMPK, an inhibitor of mTORC1 and as a mediator of autophagy; serving as a master regulator of lipid metabolism in the liver. While there is still no evidence showing TAK1 deficiency in human HCC; TAK1 deletion is observed in human prostate cancers.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Based on the important findings in this study, it is conceivable that inhibition of mTORC1 activity could become a useful therapy for HCC.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "s0005" "titulo" => "Article commented:" ] 1 => array:2 [ "identificador" => "s0010" "titulo" => "Comment:" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-09-30" "fechaAceptado" => "2014-09-30" "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Targeting of TAK1 in inflammatory disorders and cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Sakurai H." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.tips.2012.06.007" "Revista" => array:7 [ "tituloSerie" => "Trends Pharmacol Sci" "fecha" => "2012" "volumen" => "33" "paginaInicial" => "522" "paginaFinal" => "530" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22795313" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1878875017316418" "estado" => "S300" "issn" => "18788750" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Seki E." 1 => "Brenner D.A." 2 => "Karin M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2012.06.004" "Revista" => array:7 [ "tituloSerie" => "Gastroenterology" "fecha" => "2012" "volumen" => "143" "paginaInicial" => "307" "paginaFinal" => "320" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22705006" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S187887501830514X" "estado" => "S300" "issn" => "18788750" ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nuclear factor-kappaB in cancer development and progression" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Karin M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature04870" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2006" "volumen" => "441" "paginaInicial" => "431" "paginaFinal" => "436" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16724054" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Inokuchi S." 1 => "Aoyama T." 2 => "Miura K." 3 => "Osterreicher C.H." 4 => "Kodama Y." 5 => "Miyai K." 6 => "Akira S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.0909781107" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci U S A" "fecha" => "2010" "volumen" => "107" "paginaInicial" => "844" "paginaFinal" => "849" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20080763" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Herrero-Martín G.I." 1 => "Høyer-Hansen M." 2 => "García-García C." 3 => "Fumarola C." 4 => "Farkas T." 5 => "López-Rivas A." 6 => "Jäättelä M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/emboj.2009.8" "Revista" => array:6 [ "tituloSerie" => "EMBO J" "fecha" => "2009" "volumen" => "28" "paginaInicial" => "677" "paginaFinal" => "685" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19197243" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "AMP-activated protein kinase: a target for old drugs against diabetes and cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Russo G.L." 1 => "Russo M." 2 => "Ungaro P." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bcp.2013.05.023" "Revista" => array:6 [ "tituloSerie" => "Biochem Pharmacol" "fecha" => "2013" "volumen" => "86" "paginaInicial" => "339" "paginaFinal" => "350" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23747347" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "mTOR: from growth signal integration to cancer, diabetes and ageing" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Zoncu R." 1 => "Efeyan A." 2 => "Sabatini D.M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrm3025" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Mol Cell Biol" "fecha" => "2011" "volumen" => "12" "paginaInicial" => "21" "paginaFinal" => "35" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21157483" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "mTORC1 controls fasting-induced ketogenesis and its modulation by ageing" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Sengupta S." 1 => "Peterson T.R." 2 => "Laplante M." 3 => "Oh S." 4 => "Sabatini D.M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature09584" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2010" "volumen" => "468" "paginaInicial" => "1100" "paginaFinal" => "1104" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21179166" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Inokuchi-Shimizu S." 1 => "Park E.J." 2 => "Roh Y.S." 3 => "Yang L." 4 => "Zhang B." 5 => "Song J." 6 => "Liang S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI74068" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "2014" "volumen" => "124" "paginaInicial" => "3566" "paginaFinal" => "3578" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24983318" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/16652681/0000001300000006/v1_201906150917/S1665268119309925/v1_201906150917/en/main.assets" "Apartado" => array:4 [ "identificador" => "77939" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Liver News Elsewhere" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/16652681/0000001300000006/v1_201906150917/S1665268119309925/v1_201906150917/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119309925?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 0 | 2 |
| 2024 October | 7 | 5 | 12 |
| 2024 September | 9 | 2 | 11 |
| 2024 August | 6 | 3 | 9 |
| 2024 July | 9 | 2 | 11 |
| 2024 June | 5 | 3 | 8 |
| 2024 May | 5 | 2 | 7 |
| 2024 April | 12 | 4 | 16 |
| 2024 March | 10 | 4 | 14 |
| 2024 February | 5 | 3 | 8 |
| 2024 January | 7 | 5 | 12 |
| 2023 December | 3 | 4 | 7 |
| 2023 November | 5 | 3 | 8 |
| 2023 October | 13 | 3 | 16 |
| 2023 September | 4 | 2 | 6 |
| 2023 August | 3 | 3 | 6 |
| 2023 July | 4 | 1 | 5 |
| 2023 June | 4 | 1 | 5 |
| 2023 May | 4 | 4 | 8 |
| 2023 April | 5 | 2 | 7 |
| 2023 March | 5 | 1 | 6 |
| 2023 February | 5 | 2 | 7 |
| 2023 January | 9 | 4 | 13 |
| 2022 December | 2 | 6 | 8 |
| 2022 November | 15 | 3 | 18 |
| 2022 October | 5 | 7 | 12 |
| 2022 September | 7 | 4 | 11 |
| 2022 August | 6 | 5 | 11 |
| 2022 July | 6 | 8 | 14 |
| 2022 June | 7 | 3 | 10 |
| 2022 May | 3 | 4 | 7 |
| 2022 April | 11 | 8 | 19 |
| 2022 March | 13 | 14 | 27 |
| 2022 February | 7 | 7 | 14 |
| 2022 January | 12 | 9 | 21 |
| 2021 December | 9 | 14 | 23 |
| 2021 November | 3 | 5 | 8 |
| 2021 October | 9 | 7 | 16 |
| 2021 September | 8 | 15 | 23 |
| 2021 August | 8 | 5 | 13 |
| 2021 July | 5 | 13 | 18 |
| 2021 June | 7 | 4 | 11 |
| 2021 May | 5 | 7 | 12 |
| 2021 April | 33 | 12 | 45 |
| 2021 March | 13 | 7 | 20 |
| 2021 February | 5 | 7 | 12 |
| 2021 January | 3 | 7 | 10 |
| 2020 December | 7 | 5 | 12 |
| 2020 November | 5 | 8 | 13 |
| 2020 October | 9 | 1 | 10 |
| 2020 September | 12 | 8 | 20 |
| 2020 August | 7 | 8 | 15 |
| 2020 July | 2 | 4 | 6 |
| 2020 June | 2 | 1 | 3 |
| 2020 May | 5 | 5 | 10 |
| 2020 April | 1 | 3 | 4 |
| 2020 March | 6 | 5 | 11 |
| 2020 February | 4 | 3 | 7 |
| 2020 January | 5 | 2 | 7 |
| 2019 December | 4 | 19 | 23 |
| 2019 November | 4 | 2 | 6 |
| 2019 October | 1 | 1 | 2 |
| 2019 September | 3 | 9 | 12 |
| 2019 August | 3 | 2 | 5 |
| 2019 July | 1 | 12 | 13 |
| 2019 June | 1 | 6 | 7 |
Show all
