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

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.