title: Curcumin Mitigates the Intracellular Lipid Deposit Induced by Antipsychotics In Vitro.
abstract: METHODS
  First- and second-generation antipsychotics (FGAs and SGAs, respectively), both inhibit cholesterol biosynthesis and impair the intracellular cholesterol trafficking, leading to lipid accumulation in the late endosome/lysosome compartment. In this study we examined if curcumin, a plant polyphenol that stimulates exosome release, can alleviate antipsychotic-induced intracellular lipid accumulation.
  
  
  METHODS
  HepG2 hepatocarcinoma cells were treated with antipsychotics or placebo and DiI-labelled LDL for 18 h and then exposed to curcumin for the last 2 h. Cells and media were collected separately and used for biochemical analyses, electron microscopy and immunocytochemistry. Exosomes were isolated from the incubation medium by ultracentrifugation.
  
  
  RESULTS
  Curcumin treatment reduced the number of heterolysosomes and shifted their subcellular localization to the periphery, as revealed by electron microscopy, and stimulated the release of lysosomal β-hexosaminidase and exosome markers flotillin-2 and CD63 into the media. The presence of DiI in exosomes released by cells preloaded with DiI-LDL demonstrated the endolysosomal origin of the microvesicles. Furthermore, curcumin increased the secretion of cholesterol as well as LDL-derived DiI and [3H]-cholesterol, in association with a decrease of intracellular lipids. Thus, the disruption of lipid trafficking induced by FGAs or SGAs can be relieved by curcumin treatment. This polyphenol, however, did not mitigate the reduction of cholesterol esterification induced by antipsychotics.
  
  
  CONCLUSIONS
  Curcumin stimulates exosome release to remove cholesterol (and presumably other lipids) accumulated within the endolysosomal compartment, thereby normalizing intracellular lipid homeostasis. This action may help minimize the adverse metabolic effects of antipsychotic treatment, which should now be evaluated in clinical trials.
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Canfrán-Duque
authors.affiliation: Servicio de Bioquímica-Clínica, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Pastor
authors.affiliation: Celltec-UB, Department of Cell Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Reina
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Lerma
authors.affiliation: Unidad de Geriatría, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain.
authors.forename: Alfonso J
authors.initials: AJ
authors.lastname: Cruz-Jentoft
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lasunción
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Busto
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects*; D002784:Cholesterol / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D002784:Cholesterol; D003474:Curcumin