Reduction in apolipoprotein-mediated removal of cellular lipids by immortalization of human fibroblasts and its reversion by cAMP: Lack of effect with Tangier disease cells

John F. Oram, Armando J. Mendez, James Lymp, Terrance J. Kavanagh, Christine L. Halbert

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

High density lipoprotein (HDL) phospholipids and apolipoproteins remove cellular lipids by two distinct mechanisms, but their relative contribution to reverse cholesterol transport is unknown. Whereas phospholipid-mediated cholesterol efflux from cultured cells reflects the activity of the HDL receptor SR-BI, apolipoprotein-mediated lipid removal is regulated in response to changes in cellular cholesterol content (positive) and cell proliferation rates (negative). Here we show that immortalization of human skin fibroblast lines with the papillomavirus E6/E7 oncogenes increased their proliferation rates and selectively reduced the activity of the apolipoprotein-mediated lipid removal pathway. This reduction was accompanied by a decrease in cellular cAMP levels and was reversed by treatment with a cAMP analog. The stimulatory effect of cAMP was independent of changes in cellular phenotype or activities of cholesteryl ester cycle enzymes. The severely impaired apolipoprotein-mediated lipid removal pathway in Tangier disease fibroblasts, which persisted after immortalization, was not improved by treatment with a cAMP analog, implying that the cellular defect in Tangier disease is upstream from this cAMP-dependent signaling pathway. These results indicate that papillomavirus-induced immortalization of fibroblasts selectively reduces the activity of the apolipoprotein-mediated lipid removal pathway by a cAMP-dependent process, perhaps to prevent loss of cellular lipids needed for continual membrane synthesis.

Original languageEnglish (US)
Pages (from-to)1769-1781
Number of pages13
JournalJournal of Lipid Research
Volume40
Issue number10
StatePublished - Oct 1 1999

Keywords

  • Apolipoproteins
  • Cholesterol efflux
  • High density lipoprotein
  • Immortalized cells
  • Phospholipid efflux
  • Tangier disease

ASJC Scopus subject areas

  • Endocrinology

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