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J. Biol. Chem., Vol. 279, Issue 20, 20866-20873, May 14, 2004

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The Establishment of Telomerase-immortalized Tangier Disease Cell Lines Indicates the Existence of an Apolipoprotein A-I-inducible but ABCA1-independent Cholesterol Efflux Pathway^*

Michael Walter, Nicholas R. Forsyth¶, Woodring E. Wright¶, Jerry W. Shay¶, and Michael G. Roth||

From the Department of Biochemistry and the ^¶Department of Cell Biology, the University of Texas, Southwestern Medical Center, Dallas, Texas 75235-9038

Tangier disease (TD) is a human genetic disorder associated with defective apolipoprotein-I-induced lipid efflux and increased atherosclerotic susceptibility. It has been linked to mutations in the ATP-binding cassette protein A1 (ABCA1). Here we describe the establishment of permanent Tangier cell lines using telomerase. Ectopic expression of the catalytic subunit of human telomerase extended the life span of control and TD skin fibroblasts, and (in contrast to immortalization procedures using viral oncogenes) did not impair apolipoprotein A-I-induced lipid efflux. The key characteristics of TD fibroblasts (reduced cholesterol and phospholipid efflux) were observed both in primary and telomerase-immortalized fibroblasts from two unrelated homozygous patients. Surprisingly, the apolipoprotein-inducible cholesterol efflux in TD cells was significantly improved after immortalization (up to 40% of normal values). In contrast to ABCA1-dependent cholesterol efflux, this efflux was not inhibited by brefeldin A, glybenclamide, or intracellular ATP depletion but was inhibited in the presence of cytochalasin D. Apolipoprotein A-I-dependent cholesterol efflux was inversely correlated with the population doubling number in cell culture and was inhibited up to 40% in near-senescent normal diploid fibroblasts. This inhibition was completely reversed by telomerase. Thus ectopic expression of telomerase is a way to circumvent the lack of critical experimental material and represents a major improvement for studying cholesterol efflux pathways in lipid disorders. Our findings indicate the existence of an ABCA1-independent but cytoskeleton-dependent cholesterol removal pathway that may help to prevent early atherosclerosis in Tangier disease but may also be sensitive to aging phenomena ex vivo and possibly in vivo.

Received for publication, February 17, 2004

Note Added in Proof—It has recently been shown that lipidation of apoA-I is not completely abolished in ABCA1-deficient hepatocytes (Kiss, R. S., McManus, D. C., Franklin, V., Tan, W. L., McKenzie, A., Chimini, G., and Marcel, Y. L. (2003) 278, 10110–10127; Sahoo, D., Trischuk, T. C., Chan, T., Drover, V. A., Ho, S., Chimini, G., Agellon, L. B., Agnihotri, R., Francis, G. A., and Lehner, R. (2004) J. Lipid. Res. doi:10.1194/jlr.M300529-JLR200).

^* This work was supported in part by grants from the National Institutes of Health and the Diane and Hal Brierley Chair in Biomedical Research (to M. G. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a research award from the Deutsche Forschungs-gemeinschaft.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9038. Tel.: 214-648-4542; Fax: 214-648-8856; E-mail: michael.roth{at}utsouthwestern.edu.

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