title: Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Experimental Nephrology Laboratory, IRBLLEIDA, Lleida, Spain.
authors.forename: Milica
authors.initials: M
authors.lastname: Bozic
authors.affiliation: Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Guzmán
authors.affiliation: Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Benet
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, Spain; CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sánchez-Campos
authors.affiliation: Liver Research Unit, Hospital Santa Cristina, IIS Princesa, Madrid, Spain; CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: García-Monzón
authors.affiliation: Dep. Ciències Mèdiques Bàsiques, Universitat de Lleida, Spain.
authors.forename: Eloi
authors.initials: E
authors.lastname: Gari
authors.affiliation: Department of Pathology and Molecular Genetics, HUAV, IRBLLEIDA, Lleida, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Gatius
authors.affiliation: Experimental Nephrology Laboratory, IRBLLEIDA, Lleida, Spain. Electronic address: valdivielso@medicina.udl.es.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Valdivielso
authors.affiliation: 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. Electronic address: ramiro.jover@uv.es.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Jover
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D022781:Hepatocytes; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D018167:Receptors, Calcitriol
chemical_list: D018167:Receptors, Calcitriol
keywords: Hepatocytes; High fat diet; Non-alcoholic fatty liver disease; Steatosis; Vitamin D receptor