Haloperidol disrupts lipid rafts and impairs insulin signaling in SH-SY5Y cells.
Haloperidol exerts its therapeutic effects basically by acting on dopamine receptors. We previously reported that haloperidol inhibits cholesterol biosynthesis in cultured cells. In the present work we investigated its effects on lipid-raft composition and functionality. In both neuroblastoma SH-SY5Y and promyelocytic HL-60 human cell lines, haloperidol inhibited cholesterol biosynthesis resulting in a decrease of the cell cholesterol content and the accumulation of different sterol intermediates (7-dehydrocholesterol, zymostenol and cholesta-8,14-dien-3beta-ol) depending on the dose of the drug. As a consequence, the cholesterol content in lipid rafts was greatly reduced, and several pre-cholesterol sterols, particularly cholesta-8,14-dien-3beta-ol, were incorporated into the cell membrane. This was accompanied by the disruption of lipid rafts, with redistribution of flotillin-1 and Fyn and the impairment of insulin-Akt signaling. Supplementing the medium with free cholesterol abrogated the effects of haloperidol on lipid-raft composition and functionality. LDL (low-density lipoprotein), a physiological vehicle of cholesterol in plasma, was much less effective in preventing the effects of haloperidol, which is attributed to the drug's inhibition of intracellular vesicular trafficking. These effects on cellular cholesterol homeostasis that ultimately result in the alteration of lipid-raft-dependent insulin signaling action may underlie some of the metabolic effects of this widely used antipsychotic.
Sánchez-Wandelmer
J
J
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Madrid, Spain.
Dávalos
A
A
de la Peña
G
G
Cano
S
S
Giera
M
M
Canfrán-Duque
A
A
Bracher
F
F
Martín-Hidalgo
A
A
Fernández-Hernando
C
C
Lasunción
M A
MA
Busto
R
R
D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects* / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013261:Sterols / Q000096:biosynthesis / Q000378:metabolism
D008078:Cholesterol, LDL; D018492:Dopamine Antagonists; D007328:Insulin; D008565:Membrane Proteins; D013261:Sterols; C106354:flotillins; D002784:Cholesterol; D011972:Receptor, Insulin; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D051057:Proto-Oncogene Proteins c-akt; D006220:Haloperidol