Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients

Abstract

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 HDL 3 -mediated lipid efflux and G i -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 4.4Ϯ0.3% S-phase and 19.1Ϯ0.5% G 2 /M-phase cells compared with 9.7Ϯ0.6% and 7.8Ϯ0.5%, respectively, in controls. Monensin, but not brefeldin A, induced an S-and G 2 /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 G i protein function by pertussis toxin nor PLD by butanol resulted in a G 2 /M-phase arrest. Propranolol, known to increase phosphatidic acid levels, was ineffective in reversing the G 2 /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 ␣ i 1, ␣ i 2, and ␣ i 3; phosphatidylinositol transfer proteins-␣ and -␤; 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 HDL 3 -mediated lipid efflux in control but not TD fibroblasts, similar pathways seem to be involved in the disturbances of lipid transport and growth retardation.

Molecular and Functional Interaction of the ATP-binding Cassette Transporter A1 with Fas-associated Death Domain Protein

“…Growth and cell cycle abnormalities of fibroblasts from Tangier disease patients have been described suggesting that similar pathways seem to be involved in the disturbances of lipid transport and growth retardation (22). An inverse relation between proliferation and apoA-I-mediated choline phospholipid efflux was described recently (23).…”

“…Besides being a signal transducer in apoptosis, the dominant negative form of FADD reduces the proliferation of T-cells and fibroblasts (13) and is involved in the regulation of the cell cycle (22). Growth and cell cycle abnormalities of fibroblasts from Tangier disease patients have been described suggesting that similar pathways seem to be involved in the disturbances of lipid transport and growth retardation (22).…”

Mammalian ABC Transporters in Health and Disease

“…Additional evidence for this putative function came from the observation that ABCA1 drives 571 MAMMALIAN ABC TRANSPORTERS phosphatidylserine (PS) translocation across the plasma membrane (335), since it is known that exposure of PS on the outer leaflet of the membrane is necessary for the recognition of apoptotic cells. However, it was recently found that ABCA1 has an essential role in cellular lipid efflux, as mutations in the ABCA1 gene cause Tangier disease (337)(338)(339)(340), a rare inherited disorder characterized by the virtual absence of high-density lipoprotein (HDL). These patients are not known to suffer from any defect in the clearance of apoptotic bodies.…”

Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

“…Tangier disease and FHD are both caused by mutations in the gene encoding ABCA1, a member of the large superfamily of ATP binding cassette transporters (13)(14)(15). Fibroblasts derived from patients with Tangier disease or FHD are defective in the efflux of cholesterol and phospholipid towards apoA-I, and partially defective in efflux towards HDL (16)(17)(18)(19)(20)(21).…”