Dose-dependent dual effects of cholesterol and desmosterol on J774 macrophage proliferation.
We addressed the ability of native, oxidized and acetylated low-density lipoproteins (nLDL, oxLDL and acLDL, respectively) and desmosterol to act as sources of sterol for the proliferation of J774A.1 macrophages. Treatment with 0.5 microM lovastatin and lipoprotein-deficient serum suppressed cell proliferation. This inhibition was effectively prevented by nLDL, but only to a lesser extent by oxLDL. AcLDL, despite its ability to deliver a higher amount of cholesterol to J774 macrophages than the other LDLs, was dependent on mevalonate supply to sustain cell proliferation. Similarly, exogenous desmosterol, which is not converted into cholesterol in J774 cells, required the simultaneous addition of mevalonate to support optimal cell growth. Expression of hydroxymethyl glutaryl coenzyme A reductase mRNA was potently down-regulated by acLDL and exogenous desmosterol, but the effect was weaker with other sterol sources. We conclude that nLDL is more efficient than modified LDL in sustaining macrophage proliferation. Despite the requirement of cholesterol or desmosterol for J774 cell proliferation, excessive provision of either sterol limits mevalonate availability, thus suppressing cell proliferation.
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
Sara
S
Rodríguez-Acebes
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.
Paloma de la
P
Cueva
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.
Antonio J
AJ
Ferruelo
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.
Carlos
C
Fernández-Hernando
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Spain.
Miguel A
MA
Lasunción
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
Javier
J
Martínez-Botas
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: diego.gomez@hrc.es.
Diego
D
Gómez-Coronado
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D008078:Cholesterol, LDL / Q000494:pharmacology*; D003897:Desmosterol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice
D008078:Cholesterol, LDL; D003897:Desmosterol