Characterization of apoA-I-dependent lipid efflux from adipocytes and role of ABCA1

Abstract

Adipose tissue is a major reservoir of cholesterol and, as such, it may play a significant role in cholesterol homeostasis. The aims of this study were to obtain a quantitative characterization of apolipoprotein A-I (apoA-I)-dependent lipid efflux from adipocytes and examine the role of ATPbinding cassette transporter A1 (ABCA1) in this process. The rates of apoA-I-induced cholesterol and phospholipid efflux were determined and normalized by cellular protein or ABCA1 levels. In order to allow a comparative analysis, parallel experiments were also performed in macrophages. These studies showed that apoA-I induces cholesterol efflux from adipocytes at similar rates as from macrophages. Enhancement of the expression of ABCA1 increased the rates of cholesterol efflux from both adipocytes and macrophages. The results also suggested that a non-ABCA1-dependent mechanism could make significant contributions to the rate of apoA-I-dependent cholesterol efflux when the expression levels of ABCA1 are low. Furthermore, the study of the effect of inhibitors of lipid efflux showed that glyburide and brefeldin A, which affect ABCA1 function, exerted strong and similar inhibitory effects on lipid efflux from both adipocytes and macrophages, whereas BLT1, an SRB-I inhibitor, only exerted a moderate inhibition. Overall these studies suggest that ABCA1 plays a major role in apoA-I-dependent lipid efflux from adipocytes and showed high similarities between the abilities of adipocytes and macrophages to release cholesterol in an apoA-I-dependent fashion.

ABCA1 in adipocytes regulates adipose tissue lipid content, glucose tolerance, and insulin sensitivity

“…ABCA1 has been shown to regulate adipocyte cholesterol levels ( 7,8 ). However, the role of ABCA1 in adipocyte function with regard to body weight and glucose metabolism is unknown.…”

“…This hypothesis is also supported by our data because we observed that ABCA1-defi cient adipose tissue accumulates TGs and cholesterol in response to an HFHC diet. It has been shown in vitro that increased ABCA1-mediated cholesterol effl ux from adipocytes occurs following the stimulation of TG lipolysis ( 7,8 Decreased insulin sensitivity in peripheral tissues results in increased insulin secretion by the pancreas to compensate for this insulin resistance ( 30,31 ). Increased production of insulin may eventually lead to beta-cell failure and reduced insulin secretion ( 30,31 ).…”

“…Cholesterol and TGs are taken up by adipocytes from plasma lipoproteins via lipoprotein receptors including the LDL receptor (LDLR), scavenger receptor B1 (SR-B1), and CD36 (3)(4)(5). TGs leave adipose tissue as NEFAs after TG lipolysis ( 6 ), while cholesterol is removed from adipocytes via transporters such as ABCA1 and ABCG1 ( 7,8 ).…”

“…For example, lack of ABCA1 in the brain leads to changes in motor activity and sensorimotor function ( 12 ), whereas ABCA1 deficiency in beta cells reduces insulin release ( 14 ). ABCA1 has been shown to be expressed and functional in adipocytes ( 7,8 ). Gonadal adipose tissue (GAT) lacking ABCA1 has reduced cholesterol effl ux concomitant with increased cholesterol stores ( 9,15 ), indicating that ABCA1-mediated cholesterol effl ux is important in adipocyte cholesterol metabolism.…”

Regulation of ABCA1 and ABCG1 gene expression in the intraabdominal adipose tissue

“…АТР-связывающие трансмембранные транспортеры семейства АВС -ABCA1 и ABCG1, координирующие элиминацию холестерина из клеток, исключительно важны для регуляции содержания холестерина в адипоцитах [6,7]. ABCA1 участвует в биогенезе ЛПВП на этапе формирования незрелых частиц пре-b-ЛПВП, в то время как ABCG1 осуществляет насыщение холестерином зрелых ЛПВП [8].…”