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Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis

  • Milica Bozic
    Affiliations
    Experimental Nephrology Laboratory, IRBLLEIDA, Lleida, Spain
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  • Carla Guzmán
    Affiliations
    Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain
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  • Marta Benet
    Affiliations
    Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain
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  • Sonia Sánchez-Campos
    Affiliations
    Institute of Biomedicine (IBIOMED), University of León, Spain

    CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain
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  • Carmelo García-Monzón
    Affiliations
    Liver Research Unit, Hospital Santa Cristina, IIS Princesa, Madrid, Spain

    CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain
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  • Eloi Gari
    Affiliations
    Dep. Ciències Mèdiques Bàsiques, Universitat de Lleida, Spain
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  • Sonia Gatius
    Affiliations
    Department of Pathology and Molecular Genetics, HUAV, IRBLLEIDA, Lleida, Spain
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  • Author Footnotes
    † These authors share senior authorship.
    José Manuel Valdivielso
    Correspondence
    Corresponding authors. Addresses: Experimental Nephrology Laboratory, Lab. b1.10, IRBLLEIDA, Edificio Biomedicina 1, Rovira Roure 80, E-25198 Lleida, Spain. Tel.: +34973003650 (J.M. Valdivielso), or Experimental Hepatology Unit, IIS Hospital La Fe. Torre A, Planta 6ª, Lab. 6.13, Avenida Fernando Abril Martorell, 106, E-46026 Valencia. Spain. Tel.: +3496 1246653 (R. Jover).
    Footnotes
    † These authors share senior authorship.
    Affiliations
    Experimental Nephrology Laboratory, IRBLLEIDA, Lleida, Spain
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  • Author Footnotes
    † These authors share senior authorship.
    Ramiro Jover
    Correspondence
    Corresponding authors. Addresses: Experimental Nephrology Laboratory, Lab. b1.10, IRBLLEIDA, Edificio Biomedicina 1, Rovira Roure 80, E-25198 Lleida, Spain. Tel.: +34973003650 (J.M. Valdivielso), or Experimental Hepatology Unit, IIS Hospital La Fe. Torre A, Planta 6ª, Lab. 6.13, Avenida Fernando Abril Martorell, 106, E-46026 Valencia. Spain. Tel.: +3496 1246653 (R. Jover).
    Footnotes
    † These authors share senior authorship.
    Affiliations
    Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain

    CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain

    Dep. Biochemistry and Molecular Biology, University of Valencia, Spain
    Search for articles by this author
  • Author Footnotes
    † These authors share senior authorship.

      Background & 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.

      Graphical abstract

      Abbreviations:

      apoE (apolipoprotein E), BA (bile acids), CAR (constitutive androstane receptor), CD36 (cluster of differentiation 36 or fatty acid translocase (FAT)), CEBPα (transcription factor CCAAT/enhancer binding protein α), DGAT2 (diacylglycerol O-acyltransferase 2), eWAT (epididymal white adipose tissue), FA (fatty acid), FGF21 (fibroblast growth factor 21), FXR (farnesoid X receptor), GAPDH (glyceraldehyde 3-phosphate dehydrogenase), HDL (high density lipoprotein), HFD (high fat diet), IR (insulin resistance), LC-MS (liquid chromatography – mass spectrometry), LDL (low density lipoprotein), MCD (methionine-choline-deficient), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), PNPLA2 (patatin-like phospholipase domain containing 2), RXR (retinoid X receptor), TAA (thioacetamide), TBP (TATA-binding protein), TG (triglycerides), VDR (vitamin D receptor), VLDL (very low density lipoprotein)

      Keywords

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