FABP4

FABP4 Full Name

fatty acid binding protein 4, adipocyte

FABP4 Introduction

FABP4 encodes adipocyte fatty acid-binding protein 4, also known as aP2, a small cytoplasmic protein that chaperones hydrophobic fatty acids within adipocytes and macrophages. Fatty acid-binding proteins bind long-chain fatty acids with high affinity and deliver them to the organelles and enzymes where they are oxidized, esterified, or used for signaling, effectively acting as intracellular lipid transporters that buffer the low solubility of free fatty acids. FABP4 is one of the most abundant proteins in mature adipocytes, where it coordinates the uptake, storage, and release of fatty acids, and it is also expressed in macrophages, where it integrates lipid handling with inflammatory signaling. The physiological importance of FABP4 was revealed by genetic studies in mice: animals lacking FABP4 are protected from the insulin resistance, hyperglycemia, and atherosclerosis that normally accompany obesity, despite accumulating fat normally, a finding that identified FABP4 as a link between lipid metabolism and systemic inflammation. Remarkably, FABP4 is also secreted from adipocytes and circulates in the blood, where its levels correlate with obesity, the metabolic syndrome, and cardiovascular risk, making it a candidate biomarker and a potential therapeutic target. Small-molecule inhibitors of FABP4 have been developed and shown to improve metabolic parameters and to reduce atherosclerosis in animal models, positioning FABP4 at the interface between fundamental lipid biochemistry and the treatment of metabolic disease.

Figure 1. FABP4 as a key determinant of metastatic potential of ovarian cancer.

Intracellular Lipid Chaperone Structure and Ligand Binding
FABP4 is a member of the intracellular fatty acid-binding protein family, whose members share a conserved beta-barrel structure that encloses a large internal cavity for ligand binding.
The protein consists of ten antiparallel beta-strands arranged into a beta-barrel, capped by a helix-loop-helix 'lid' domain that controls access to the binding cavity.
Within the cavity, long-chain fatty acids are bound with their carboxylate group anchored by conserved arginine residues and their acyl chain accommodated in the hydrophobic interior.
The FABP4 gene is located on human chromosome 8, and its expression is controlled by transcription factors that drive adipocyte differentiation, including PPAR-gamma and C/EBP family members, as well as by insulin and fatty acid availability.
In adipocytes, FABP4 constitutes a major fraction of total cytosolic protein, reflecting its central role in the high-flux lipid metabolism of these cells.
The protein binds not only fatty acids but also other lipophilic molecules, including some synthetic ligands and lipid signaling mediators, which has enabled the development of pharmacological inhibitors.
Upon fatty acid binding, FABP4 undergoes conformational changes that promote its interaction with enzymes and with the nucleus, coupling lipid sensing to cellular responses.

Adipose Function, Insulin Resistance, Atherosclerosis, and Biomarker Utility
In adipocytes FABP4 channels fatty acids toward storage as triglyceride during feeding and toward release during fasting, and it buffers the intracellular concentration of free fatty acids that would otherwise be toxic.
In macrophages, FABP4 promotes the accumulation of cholesterol esters and amplifies inflammatory responses, contributing to the formation of the foam cells that populate atherosclerotic plaques.
Mice lacking FABP4 are strikingly protected from the metabolic consequences of obesity: they develop less insulin resistance, less hepatic steatosis, and less atherosclerosis even on high-fat diets, establishing FABP4 as a molecular link between obesity and its complications.
FABP4 is secreted from adipocytes through unconventional pathways and is present in the circulation; plasma FABP4 levels rise with obesity and are associated with type 2 diabetes, hypertension, and cardiovascular events in human populations.
Pharmacological inhibition of FABP4 with small molecules such as BMS309403 improves glucose handling and reduces atherosclerosis in mouse models, supporting the concept of FABP4 as a druggable target.
The combination of a well-defined binding pocket, a clear disease association, and validated animal models has made FABP4 one of the most intensively pursued targets in metabolic disease research.

Alternate Names for FABP4

FABP4; fatty acid binding protein 4, adipocyte; aP2; ALBP; AFABP; A-FABP; HEL-S-104; fatty acid-binding protein, adipocyte; fatty acid-binding protein 4; adipocyte lipid-binding protein; epididymis secretory protein Li 104; adipocyte-type fatty acid-binding protein;

• 1.Gharpure K M, Pradeep S, Sans M, et al. FABP4 as a key determinant of metastatic potential of ovarian cancer. Nature communications, 2018, 9(1): 2923.