Cholesteryl Ester Transfer Protein Mediates Selective Uptake of High Density Lipoprotein Cholesteryl Esters by Human Adipose Tissue

Abstract

We have determined the role of cholesteryl ester transfer protein (CETP) in selective uptake of high density lipoprotein (HDL)-derived cholesteryl esters (CE) by human adipose tissue, using organ culture or collagenase-digested adipocytes. Incubation of the fresh tissue fragments with HDL containing [ H]CE or125 I-apoprotein (apo) A-I resulted in significant uptake of HDL-CE-derived label. Addition of recombinant CETP (rCETP) increased CE uptake in a dose-response fashion. In contrast, little association of 125 I-apoA-I with adipose tissue was noted, and addition of rCETP did not alter apoA-I uptake or degradation. Incubation of adipose tissue with TP2, an anti-CETP monoclonal antibody, which inhibits neutral lipid transfer, markedly reduced selective uptake of HDL-CE. Studies using human adipocytes isolated by collagenase digestion also demonstrated selective uptake of HDL-CE and enhancement of this process by rCETP. To confirm that the association of HDL-CE-derived radioactivity with adipose tissue was not due to neutral lipid exchange between adipocytes and HDL, we measured changes in HDL composition following incubation of HDL and rCETP with isolated adipocytes. A decrease in HDL-CE concentration in the medium was observed, an effect which was markedly attenuated when incubations were carried out in the presence of monoclonal antibody TP2. Furthermore, the decrease in HDL-CE was accompanied by an increase in HDL free cholesterol, likely representing efflux of adipocyte cholesterol to HDL. There were no significant changes in phospholipid, apoA-I, or apoA-II in the medium following incubation with adipocytes. These data demonstrate a novel and important role for CETP in selective uptake of HDL-cholesteryl esters by human adipocytes and suggest that this pathway may be of quantitative physiological significance in HDL remodeling and adipocyte cholesterol accumulation.Uptake of HDL 1 -derived CE by adipocytes has been well documented and, in the obese state, plasma HDL-CE may be reduced as a consequence (1-3). The uptake of CE by adipose tissue is disproportionately greater than the uptake of HDL apolipoprotein (1, 4, 5). Thus, CE are transferred from HDL to adipocytes by a nonendocytotic process, known as selective cholesterol uptake (6 -9). The selective uptake of CE by adipose cells resembles in many ways the processes described in vivo for rat liver, ovary, and adrenal (6) and in vitro for adrenal cells (7, 10) and rat luteal cells (11). While many similarities in selective cholesteryl ester uptake have been noted in several tissues, the physiological consequences vary with cellular processing. It is likely that HDL can deliver cholesterol in the esterified form to adipocytes, where it is hydrolyzed to free cholesterol, which can then be stored in the oil droplet, equilibrate with the membrane, or efflux from the cell over time (12, 13). The role of CETP in reverse cholesterol transport has been well characterized (14). CETP is highly expressed in mammalian adipose tissue (15). There is also evidence of CET...

Adipocyte and erythrocyte plasma membrane phospholipid composition and hyperinsulinemia: a study in nondiabetic and diabetic obese women

“…40 Changes in lipoprotein composition 41 can modify the exchange of cholesterol and phospholipids between lipoproteins, or between lipoproteins and cells and in¯uence the composition of plasma membranes. These changes could be mediated by cholesteryl Hyperinsulinemia, adipocyte and erythrocyte phospholipids N Zeghari et al ester transfer protein (CETP), which has a role in the selective uptake of HDL cholesteryl esters by human adipocytes, 42 or by phospholipid transfer protein (PLTP). 43 CETP and PLTP activities are elevated in obesity 44 and in insulin resistance 45 as well as the HDL binding to adipocytes.…”

Cholesteryl Ester Transfer Protein Biosynthesis and Cellular Cholesterol Homeostasis Are Tightly Interconnected

“…Indeed, it has been shown that CETP enhances sperm capacitation (15) and facilitates the efflux of CE from cells (16). Additionally, CETP associates with cell plasma membranes where it appears to facilitate CE selective uptake (17).…”

Trophoblast‐like human choriocarcinoma cells serve as a suitable in vitro model for selective cholesteryl ester uptake from high density lipoproteins

“…In a parallel set of experiments, the selective CE-uptake from HDL 3 was calculated from double-labeled HDL 3 as the difference between [ 3 H]cholesteryl oleate-and 125 Ilabeled lipoprotein [35]. The sum of specific degradation (measured as described above) and specific cell association of 125 I-labeled HDL 3 reflects HDL 3 -holoparticle association.…”

“…The HDL 3 -band was aspirated and dialyzed against 10 mM NaCl/P i , pH 7.4. [35]. Following separation from the vesicles by ultracentrifugation, the labeled lipoproteins were subsequently labeled with 125 I-Na as described above using N-Br-succinimide.…”