Identification of a Potential Biomarker for FABP4Inhibition: The Power of Lipidomics in Preclinical Drug Testing

Authors:
Karsten Suhre, Werner Römisch-Margl, Martin Hrabé de Angelis,Jerzy Adamski, Gerd Luippold, and Robert Augustin
In:
Source: J Biomol Screen
Publication Date: (2011)
Issue: 16: 5
Research Area:
Drug Discovery
Cells used in publication:
THP-1
Species: human
Tissue Origin: blood
Culture Media:
Experiment

They report the identification of a potential biomarker for acute in vivo FABP4 inhibition that is applicable for further investigations and can be implemented
in simple and fast-flow injection mass spectrometry assays.

Abstract

The fatty acid binding protein 4 (FABP4) belongs to the family of lipid chaperones that control intracellular fluxes and compartmentalization
of their respective ligands (e.g., fatty acids). FABP4, which is almost exclusively expressed in adipocytes
and macrophages, contributes to the development of insulin resistance and atherosclerosis in mice. Lack of FABP4 protects
against the development of insulin resistance associated with genetic or diet-induced obesity in mice. Furthermore, total or
macrophage-specific FABP4 deficiency is protective against atherosclerosis in apolipoprotein E–deficient mice. The FABP4
small-molecule inhibitor BMS309403 has demonstrated efficacy in mouse models for type 2 diabetes mellitus and atherosclerosis,
resembling phenotypes of mice with FABP4 deficiency. However, despite the therapeutically attractive long-term
effects of FABP4 inhibition, an acute biomarker for drug action is lacking. The authors applied mass spectrometry lipidomics
analysis to in vitro and in vivo (plasma and adipose tissue) samples upon inhibitor treatment. They report the identification
of a potential biomarker for acute in vivo FABP4 inhibition that is applicable for further investigations and can be implemented
in simple and fast-flow injection mass spectrometry assays. In addition, this approach can be considered a proof-ofprinciple
study that can be applied to other lipid-pathway targeting mechanisms.