Date of this Version
Circulation. 2011 October 11; 124(15): 1663–1672.
Background—Adipose tissue (AT) is the body’s largest free cholesterol (FC) reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), a key cholesterol transporter for 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 ABCA1floxed mice with aP2 cre transgenic mice. AT from ABCA1−A/−A mice had <10% of wild type (WT) ABCA1 protein expression, but normal hepatic and intestinal expression. Deletion of adipocyte ABCA1 resulted in a significant decrease in plasma HDL cholesterol (~15%) and apoA-I (~13%) concentrations. AT from ABCA1−A/−A mice had a twofold increase in FC content, compared to WT mice, and failed to efflux cholesterol to apoA-I.
However, cholesterol efflux from AT to plasma HDL was similar for both genotypes of mice.
Incubation of WT AT explants with apoA-I resulted in formation of multiple discrete-sized
nascent HDL particles ranging in diameter from 7.1–12 nm; similar incubations with ABCA1−A/−A AT explants resulted in nascent HDL <8 nm. Plasma decay and tissue uptake of WT 125I-HDL tracer was 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.