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.
Rodríguez-Acebes
Sara
S
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.
Cueva
Paloma de la
P
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.
Ferruelo
Antonio J
AJ
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.
Fernández-Hernando
Carlos
C
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.
Lasunción
Miguel A
MA
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.
Martínez-Botas
Javier
J
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.
Gómez-Coronado
Diego
D
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.
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