Low-dose expression of a human apolipoprotein E transgene in macrophages restores cholesterol efflux capacity of apolipoprotein E-deficient mouse plasma

Yenhong Zhu, Stefano Bellosta, Claus Langer, Franco Bernini, Robert E. Pitas, Robert W. Mahley, Gerd Assmann, Arnold Von Eckardstein

Research output: Contribution to journalArticlepeer-review

Abstract

Apolipoprotein E- (apoE) deficient (E(-/-)) mice develop severe hyperlipidemia and diffuse atherosclerosis. Low-dose expression of a human apoE3 transgene in macrophages of apoE-deficient mice (E(-/-)hTgE(+/0)), which results in about 5% of wild-type apoE plasma levels, did not correct hyperlipidemia but significantly reduced the extent of atherosclerotic lesions. To investigate the contribution of apoE to reverse cholesterol transport, we compared plasmas of wild-type (E(+/+)), E(-/-), and E(-/- )hTgE(+/0) mice for the appearance of apoE-containing lipoproteins by electrophoresis and their capacity to take up and esterify 3H-labeled cholesterol from radiolabeled fibroblasts or J774 macrophages. Wild-type plasma displayed lipoproteins containing apoE that were the size of high density lipoprotein and that had either electrophoretic α or γ mobilities. Similar particles were also present in E(-/-)hTgE(+/0) plasma. Depending on incubation time, E(-/-) plasma released 48-74% less 3H-labeled cholesterol from fibroblasts than E(+/+) plasma, whereas cholesterol efflux into E(-/- )hTgE(+/0) plasma was only 11-25% lower than into E(+/+) plasma. E(-/- )hTgE(+/0) plasma also released 10% more 3H-labeled cholesterol from radiolabeled J774 macrophages than E(-/-) plasma. E(+/+) and E(-/) -hTgE(+/0) plasma each esterified significantly more cell-derived 3H-labeled cholesterol than E(-/-) plasma. Moreover, E(-/-) plasma accumulated much smaller proportions of fibroblast-derived 3H-labeled cholesterol in fractions with electrophoretic γ and α mobility than E(+/+) and E(-/- )hTgE(+/0) plasma. Thus, low-dose expression of apoE in macrophages nearly restored the cholesterol efflux capacity of apoE-deficient plasma through the formation of apoE-containing particles, which efficiently take up cell- derived cholesterol, and through the increase of cholesterol esterification activity. Thus, macrophage-derived apoE may protect against atherosclerosis by increasing cholesterol efflux from arterial wall cells.

Original languageEnglish
Pages (from-to)7585-7590
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number13
DOIs
Publication statusPublished - Jun 23 1998

Keywords

  • Atherosclerosis
  • High density lipoprotein
  • Lecithin:cholesterol acyltransferase
  • Reverse cholesterol transport
  • Subclasses

ASJC Scopus subject areas

  • Genetics
  • General

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