Fig. 2.

Possible intracellular and extracellular functions of FABP4

FABP4 is abundant in the cytosolic fraction of adipocytes and can bind one long-chain fatty acid (FA), including palmitic acid (PA), stearic acid (SA), oleic acid (OA), linoleic acid (LA) or α-linolenic acid (ALA). FABP4 facilitates the transport of FAs to specific organelles in the cell such as the mitochondrion, peroxisome, endoplasmic reticulum (ER) and nucleus, regulates enzyme activity, and stores excess FA as lipid droplets in adipocytes. LA-bound, but not SA- or OA-bound, FABP4 can be moved into the nucleus by unmasking of the nuclear localization signal (NLS). The protein-protein interactions of FABP4 with hormone-sensitive lipase (HSL) and comparative gene identification-58 (CGI-58), a potent co-activator of adipose triglyceride lipase (ATGL), regulate intracellular triglyceride hydrolysis, and FABP4 is secreted from adipocytes in a non-classical pathway associated with lipolysis. FABP4 in macrophages inhibits the peroxisome proliferator-activated receptor γ (PPARγ)-liver X receptor α (LXRα)-ATP-binding cassette A1 (ABCA1) pathway and induces inflammatory responses through activation of the inhibitor of nuclear kappa B kinase (IKK)-nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) pathways. FABP4 is ectopically induced in injured arterial endothelial cells (ECs). Macrophages and ECs can also secrete FABP4. Secreted FABP4 may act as a carrier of LA and ALA, essential polyunsaturated FAs, to organs because of high affinities for FABP4 under normal conditions. Circulating FABP4 may affect several responses in target cells, including macrophages, ECs, smooth muscle cells (SMCs), adipocytes and other cells, through unidentified receptor-mediated effects in bound FA-dependent and -independent manners and/or possible internalization of FABP4 into the cell. Obesity and increased visceral fat promote oxidative stress. An oxidative stress condition can induce conformation change of the FABP4 structure and decrease affinity of most of the FAs, except for PA, for FABP4. Under a specific condition such as obesity-induced oxidative stress, PA would have relatively high affinity for FABP4, leading to PA-dependent inflammatory responses through unidentified receptors of PA-bound FABP4 and/or delivery of PA to toll-like receptor 4 (TLR4).

Receptor*, an unidentified receptor of non-specific FA-bound FABP4. Receptor^†, an unidentified receptor of specific PA-bound FABP4.