Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo

Soonkyu Chung, Janet K. Sawyer, Abraham K. Gebre, Nobuyo Maeda, John S. Parks

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Background-: Adipose tissue (AT) is the body's largest free cholesterol reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), a key cholesterol transporter for high-density lipoprotein (HDL) biogenesis. However, the extent to which AT ABCA1 expression contributes to HDL biogenesis in vivo is unknown. Methods and Results-: Adipocyte-specific ABCA1 knockout mice (ABCA1 -A/-A) were generated by crossing ABCA1 floxed mice with aP2Cre transgenic mice. AT from ABCA1 -A/-A mice had <10% of wild-type ABCA1 protein expression but normal hepatic and intestinal expression. Deletion of adipocyte ABCA1 resulted in a significant decrease in plasma HDL cholesterol (≈15%) and apolipoprotein A-I (≈13%) concentrations. AT from ABCA1 mice had a 2-fold increase in free cholesterol content compared with wild-type mice and failed to efflux cholesterol to apolipoprotein A-I. However, cholesterol efflux from AT to plasma HDL was similar for both genotypes of mice. Incubation of wild-type AT explants with apolipoprotein A-I resulted in the formation of multiple discrete-sized nascent HDL particles ranging in diameter from 7.1 to 12 nm; similar incubations with ABCA1 -A/-A AT explants resulted in nascent HDL <8 nm. Plasma decay and tissue uptake of wild-type 125I-HDL tracer were similar in both genotypes of recipient mice, suggesting that adipocyte ABCA1 deficiency reduces plasma HDL concentrations solely by reducing nascent HDL particle formation. Conclusions-: We provide in vivo evidence that AT ABCA1-dependent cholesterol efflux and nascent HDL particle formation contribute to systemic HDL biogenesis and that AT ABCA1 expression plays an important role in adipocyte cholesterol homeostasis.

Original languageEnglish (US)
Pages (from-to)1663-1672
Number of pages10
JournalCirculation
Volume124
Issue number15
DOIs
StatePublished - Oct 11 2011

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ATP-Binding Cassette Transporters
HDL Lipoproteins
Adipose Tissue
Cholesterol
Adipocytes
Apolipoprotein A-I
HDL Cholesterol
Genotype
Knockout Mice
Transgenic Mice
Homeostasis

Keywords

  • adipocytes
  • adipose tissue
  • apolipoproteins
  • cholesterol
  • lipids
  • lipoproteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo. / Chung, Soonkyu; Sawyer, Janet K.; Gebre, Abraham K.; Maeda, Nobuyo; Parks, John S.

In: Circulation, Vol. 124, No. 15, 11.10.2011, p. 1663-1672.

Research output: Contribution to journalArticle

Chung, Soonkyu ; Sawyer, Janet K. ; Gebre, Abraham K. ; Maeda, Nobuyo ; Parks, John S. / Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo. In: Circulation. 2011 ; Vol. 124, No. 15. pp. 1663-1672.
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abstract = "Background-: Adipose tissue (AT) is the body's largest free cholesterol reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), a key cholesterol transporter for high-density lipoprotein (HDL) biogenesis. However, the extent to which AT ABCA1 expression contributes to HDL biogenesis in vivo is unknown. Methods and Results-: Adipocyte-specific ABCA1 knockout mice (ABCA1 -A/-A) were generated by crossing ABCA1 floxed mice with aP2Cre transgenic mice. AT from ABCA1 -A/-A mice had <10{\%} of wild-type ABCA1 protein expression but normal hepatic and intestinal expression. Deletion of adipocyte ABCA1 resulted in a significant decrease in plasma HDL cholesterol (≈15{\%}) and apolipoprotein A-I (≈13{\%}) concentrations. AT from ABCA1 mice had a 2-fold increase in free cholesterol content compared with wild-type mice and failed to efflux cholesterol to apolipoprotein A-I. However, cholesterol efflux from AT to plasma HDL was similar for both genotypes of mice. Incubation of wild-type AT explants with apolipoprotein A-I resulted in the formation of multiple discrete-sized nascent HDL particles ranging in diameter from 7.1 to 12 nm; similar incubations with ABCA1 -A/-A AT explants resulted in nascent HDL <8 nm. Plasma decay and tissue uptake of wild-type 125I-HDL tracer were similar in both genotypes of recipient mice, suggesting that adipocyte ABCA1 deficiency reduces plasma HDL concentrations solely by reducing nascent HDL particle formation. Conclusions-: We provide in vivo evidence that AT ABCA1-dependent cholesterol efflux and nascent HDL particle formation contribute to systemic HDL biogenesis and that AT ABCA1 expression plays an important role in adipocyte cholesterol homeostasis.",
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