Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition

Abstract

The family of intracellular lipid binding proteins (iLBPs) is comprised of sixteen members of structurally related binding proteins that have ubiquitous tissue expression in humans. iLBPs collectively bind diverse essential endogenous lipids and xenobiotics. iLBPs solubilize and traffic lipophilic ligands through the aqueous milieu of the cell. Their expression is correlated with increased rates of ligand uptake into tissues and altered ligand metabolism. The importance of iLBPs in maintaining lipid homeostasis is well established. Fatty acid binding proteins (FABPs) make up the majority of iLBPs and are expressed in major organs relevant to xenobiotic absorption, distribution and metabolism. FABPs also bind a variety of xenobiotics including non-steroidal anti-inflammatory drugs, psychoactive cannabinoids, benzodiazepines, antinociceptives and peroxisome proliferators. FABP function is also associated with metabolic disease making FABPs currently a target for drug development. Yet, the potential contribution of FABP binding to distribution of xenobiotics into tissues and the mechanistic impact iLBPs may have on xenobiotic metabolism is largely undefined. This review examines the tissue specific expression and functions of iLBPs, the ligand binding characteristics of iLBPs, their known endogenous and xenobiotic ligands, methods for measuring ligand binding and mechanisms of ligand delivery from iLBPs to membranes and enzymes. Current knowledge of the importance of iLBPs in affecting disposition of xenobiotics is collectively described. Significance StatementThe data reviewed here show that FABPs bind many drugs and suggest that binding of drugs to FABPs in various tissues will affect drug distribution into tissues. The extensive work and findings with endogenous ligands suggest that FABPs may also alter the metabolism and transport of drugs. This review illustrates the potential significance of this understudied area.

Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein (FABP1) and FABP1 Binding Alters Drug Metabolism

“…Fatty acid binding proteins (FABPs) are intracellular lipid binding proteins broadly expressed in tissues (Smathers and Petersen, 2011; Yabut and Isoherranen, 2023). They bind essential endogenous lipids such as fatty acids, bile acids, cholesterol and eicosanoids (Smathers and Petersen, 2011; Yabut and Isoherranen, 2023).…”

“…Fatty acid binding proteins (FABPs) are intracellular lipid binding proteins broadly expressed in tissues (Smathers and Petersen, 2011; Yabut and Isoherranen, 2023). They bind essential endogenous lipids such as fatty acids, bile acids, cholesterol and eicosanoids (Smathers and Petersen, 2011; Yabut and Isoherranen, 2023). FABPs are critical for lipid homeostasis and signaling in variety of tissues through regulation of the uptake, metabolism and cellular trafficking of their ligands (Smathers and Petersen, 2011; Yabut and Isoherranen, 2023).…”

“…They bind essential endogenous lipids such as fatty acids, bile acids, cholesterol and eicosanoids (Smathers and Petersen, 2011; Yabut and Isoherranen, 2023). FABPs are critical for lipid homeostasis and signaling in variety of tissues through regulation of the uptake, metabolism and cellular trafficking of their ligands (Smathers and Petersen, 2011; Yabut and Isoherranen, 2023). FABPs can also play a role in the pharmacological effects of drugs that bind FABPs.…”

“…Fluorescence displacement assays are widely used to identify FABP ligands and characterize ligand binding to FABPs (Thumser and Wilton, 1994; Velkov et al ., 2007; Chuang et al ., 2008; Zhou et al ., 2019; Yabut and Isoherranen, 2023). However, FABP1 has a large binding cavity and multiple endogenous ligands have been shown to bind FABP1 simultaneously (Santambrogio et al ., 2013; Favretto et al ., 2015).…”