Apolipoprotein CI binds free fatty acids and reduces their intracellular esterification

Marit Westerterp, Jimmy F.P. Berbee, Dianne J.M. Delsing, Miek C. Jong, Marion J.J. Gijbels, Vivian E.H. Dahlmans, Erik H. Offerman, Johannes A. Romijn, Louis M. Havekes, and Patrick C.N. Rensen

Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden 2333 ZA

Corresponding Author: M.Westerterp{at}lumc.nl

Mice that overexpress human apolipoprotein CI (apoCI) homozygously (APOC1+/+ mice) are protected against obesity and show cutaneous abnormalities. Although these effects can result from our previous observation that apoCI inhibits free fatty acid (FFA) generation by lipoprotein lipase (LPL), thereby reducing their availability for subsequent uptake by adipose tissue and skin, we have also found that plasma FFA levels are elevated in APOC1+/+ mice and that apoCI impairs the uptake of a FFA analogue in adipose tissue. In the present study we tested the hypothesis that apoCI interferes with cellular FFA uptake independent of LPL activity. The cutaneous abnormalities of APOC1+/+ mice were not affected after transplantation to wild-type mice, indicating that locally produced apoCI prevents lipid entry into the skin. Subsequent in vitro studies with apoc1-/- versus wild-type macrophages revealed that apoCI reduced the cell association and subsequent esterification of [3H]oleic acid by ~35% (P<0.05), and exogenous apoCI reduced the association of [3H]oleic acid to wild-type macrophages by 30% (P<0.05). We thus speculated that apoCI binds FFA extracellularly, thereby preventing cell association of FFA. We showed that elevated levels of FFA as observed in APOC1+/+ mice were present in VLDL, and that apoCI was indeed able to mediate the binding of oleic acid to otherwise protein-free VLDL-like emulsion particles involving electrostatic interaction. We conclude that apoCI binds FFA in the circulation, thereby reducing the availability of FFA for uptake by cells. This mechanism can serve as an additional mechanism to explain the resistance to obesity and the cutaneous abnormalities of APOC1+/+ mice.

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