Potential safety implications of fatty acid-binding protein inhibition

Fatty acid-binding proteins (FABPs) are small intracellular proteins that regulate fatty acid metabolism, transport, and signalling. There are ten known human isoforms, many of which are upregulated and involved in clinical pathologies. As such, FABP inhibition may be beneficial in disease states su...

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Veröffentlicht in:Toxicology and applied pharmacology 2024-10, Vol.491, p.117079, Article 117079
Hauptverfasser: Warren, William G., Osborn, Myles, Duffy, Paul, Yates, Andrew, O'Sullivan, Saoirse E.
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Sprache:eng
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Zusammenfassung:Fatty acid-binding proteins (FABPs) are small intracellular proteins that regulate fatty acid metabolism, transport, and signalling. There are ten known human isoforms, many of which are upregulated and involved in clinical pathologies. As such, FABP inhibition may be beneficial in disease states such as cancer, and those involving the cardiovascular system, metabolism, immunity, and cognition. Recently, a potent, selective FABP5 inhibitor (ART26.12), with 90-fold selectivity to FABP3 and 20-fold selectivity to FABP7, was found to be remarkably benign, with a no-observed-adverse-effect level of 1000 mg/kg in rats and dogs, showing no genotoxicity, cardiovascular, central, or respiratory toxicity. To understand the potential implication of FABP inhibition more fully, this review systematically assessed literature investigating genetic knockout, knockdown, and pharmacological inhibition of FABP3, FABP4, FABP5, or FABP7. Analysis of the literature revealed that animals bred not to express FABPs showed the most biological effects, suggesting key roles of these proteins during development. FABP ablation sometimes exacerbated symptoms of disease models, particularly those linked to metabolism, inflammatory and immune responses, cardiac contractility, neurogenesis, and cognition. However, FABP inhibition (genetic silencing or pharmacological) had a positive effect in many more disease conditions. Several polymorphisms of each FABP gene have also been linked to pathological conditions, but it was unclear how several polymorphisms affected protein function. Overall, analysis of the literature to date suggests that pharmacological inhibition of FABPs in adults is of low risk. •This review assessed preclinical and polymorphism studies using fatty acid-binding 3, 5, and 7 inhibition.•Potential safety implications were mostly associated with fatty acid-binding protein knockout or knockdown.•Several polymorphisms of each fatty acid-binding protein gene were linked to pathological conditions.•There were very few adverse effects related to in vivo pharmacological inhibition of fatty acid-binding proteins.•Fatty acid-binding protein inhibition appears to be a promising target for many clinical indications.
ISSN:0041-008X
1096-0333
1096-0333
DOI:10.1016/j.taap.2024.117079