© 1999 American Heart Association, Inc.
Original Contributions |
Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients
From the Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Regensburg, Regensburg, Federal Republic of Germany.
Correspondence to Prof Dr G. Schmitz, Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Regensburg, Franz-Josef-Strauß-Allee 11, D-93042 Regensburg, Germany. E-mail gerd.schmitz{at}klinik.uni-regensburg.de
Abstract—We have investigated
the abnormal proliferation and morphology of fibroblasts from patients
with Tangier disease (TD), a high density lipoprotein (HDL) deficiency
syndrome that is characterized by impairment of
HDL3-mediated lipid efflux and
Gi-protein–mediated signaling via
phosphatidylinositol-specific phospholipase C (PI-PLC) and
phospholipase D (PLD). TD fibroblasts displayed a 30% to 50% reduced
in vitro growth rate and a 1.6-fold increased cell surface area. The
response to different mitogens was diminished, and asynchronously
growing TD fibroblasts showed 4.4±0.3% S-phase and 19.1±0.5%
G2/M-phase cells compared with 9.7±0.6% and
7.8±0.5%, respectively, in controls. Monensin, but not brefeldin A,
induced an S- and G2/M-phase distribution in control cells
similar to that found in TD fibroblasts. This effect of monensin was
accompanied by an increase of ceramide levels in controls, whereas TD
fibroblasts already had a 2.5-fold increased basal ceramide
concentration. Incubation of control cells with C2 ceramide and
threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol
(PDMP) mimicked the effect of monensin on the cell cycle. The
inhibition of neither Gi protein function by pertussis
toxin nor PLD by butanol resulted in a G2/M-phase arrest.
Propranolol, known to increase phosphatidic acid levels,
was ineffective in reversing the G2/M-phase arrest in TD
fibroblasts. In addition, cDNA sequences and mRNA expression of the
participants of PI-PLC or PLD signaling, ie, G-protein subunits
i1, i2, and i3;
phosphatidylinositol transfer proteins- and -ß; and ADP
ribosylation factors 1 and 3 were found to be normal. Thus, growth and
cell cycle abnormalities in TD fibroblasts are likely to be related to
impaired Golgi function and sphingolipid signaling rather than
inoperative G-protein signal transduction. Because PDMP was also found
to decrease HDL3-mediated lipid efflux in control but not
TD fibroblasts, similar pathways seem to be involved in the
disturbances of lipid transport and growth retardation.
Key Words: Tangier disease • ceramide • Golgi apparatus • cell cycle • cholesterol efflux
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