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dc.contributor.authorBozić Stanojević, Milica
dc.contributor.authorGuzmán, Carla
dc.contributor.authorBenet, Marta
dc.contributor.authorSánchez-Campos, Sonia
dc.contributor.authorGarcía-Monzón, Carmelo
dc.contributor.authorGarí Marsol, Eloi
dc.contributor.authorGatius Calderó, Sònia
dc.contributor.authorValdivielso Revilla, José Manuel
dc.contributor.authorJover, Ramiro
dc.date.accessioned2017-01-31T08:01:11Z
dc.date.issued2016
dc.identifier.issn0168-8278
dc.identifier.urihttp://hdl.handle.net/10459.1/59168
dc.description.abstractBackground & Aims The pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD) is still incompletely understood. Several nuclear receptors play a role in liver lipid metabolism and can promote hepatosteatosis, but the possible role of vitamin D receptor (VDR) in NAFLD has not been investigated. Methods The expression of liver VDR was investigated in apolipoprotein E knockout (apoE−/−) mice on a high fat diet, in wild-type mice on methionine and choline deficient diet and in NAFLD patients with hepatosteatosis and non-alcoholic steatohepatitis. The relevance of VDR was assessed in apoE−/− mice by deletion of VDR or paricalcitol treatment and in human HepG2 cells by VDR transfection or silencing. The role of VDR in fibrosis was also determined in VDR knockout mice (VDR−/−) treated with thioacetamide. Results Expression of liver VDR was markedly induced in two mouse models of NAFLD, as well as in patients with hepatosteatosis, but decreased in non-alcoholic steatohepatitis. VDR deletion in high fat diet-fed apoE−/− mice protected against fatty liver, dyslipidemia and insulin resistance, and caused a decrease in taurine-conjugated bile acids, but did not influence fibrosis by thioacetamide. apoE−/−VDR−/− mouse livers showed decreased gene expression of CD36, DGAT2, C/EBPα and FGF21, and increased expression of PNPLA2, LIPIN1 and PGC1α. Treatment of apoE−/− mice on high fat diet with paricalcitol had modest opposite effects on steatosis and gene expression. Finally, this set of genes showed concordant responses when VDR was overexpressed or silenced in HepG2 cells. Conclusions Induced hepatocyte VDR in NAFLD regulates key hepatic lipid metabolism genes and promotes high fat diet-associated liver steatosis. Therapeutic inhibition of liver VDR may reverse steatosis in early NAFLD. Lay summary The amount of vitamin D receptor is induced early in the livers of mice and humans when they develop non-alcoholic fatty liver disease. If the gene for the vitamin D receptor is deleted, hepatic lipid metabolism changes and mice do not accumulate fat in the liver. We conclude that the vitamin D receptor can contribute to the fatty liver disease promoted by a high fat diet.ca_ES
dc.description.sponsorshipThis work was supported by grants PS12/01770, PI13/01470, PI13/01299 and REDinREN RD12/0021/0026 from the Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Economy and Competitiveness), and FEDER (European Union) funds. MB was supported by the REDinREN (RD12/0021/0026).ca_ES
dc.language.isoengca_ES
dc.publisherElsevierca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1016/j.jhep.2016.05.031ca_ES
dc.relation.ispartofJournal of Hepatology, 2016, vol. 65, núm. 4, p. 748–757ca_ES
dc.rights(c) Elsevier B.V., 2016ca_ES
dc.subjectVitamin D receptorca_ES
dc.subjectNon-alcoholic fatty liver diseaseca_ES
dc.subjectHigh fat dietca_ES
dc.subjectSteatosisca_ES
dc.subjectHepatocytesca_ES
dc.titleHepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosisca_ES
dc.typearticleca_ES
dc.identifier.idgrec024628
dc.type.versionpublishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_ES
dc.identifier.doihttps://doi.org/10.1016/j.jhep.2016.05.031
dc.date.embargoEndDate10000-01-01


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