ReviewFatty acid-binding proteins as plasma markers of tissue injury
Introduction
The appearance in plasma of cellular proteins released after tissue injury, or produced by malignant cells, commonly referred to as biochemical markers, is gaining more and more interest as being important in the management of patients with tissue injury due to acute ischemia/reperfusion, neurological disorders, cancer, organ rejection or trauma.
One of the promising new biomarker proteins is the fatty acid-binding protein (FABP). This relatively small (15 kDa) cytoplasmic protein is abundantly expressed in tissues with an active fatty acid metabolism like heart and liver [1], [2]. Presently, nine distinct types have been identified, with each type showing a characteristic pattern of tissue distribution and a stable intracellular half-life of 2–3 days [1]. These FABP types are named after the tissue in which they were first identified and belong to a multigene family of intracellular lipid-binding proteins [1], [3], [4]. Their tertiary structure resembles a clam shell in which the ligand is bound between the two halves of the clam by interaction with specific amino acid residues within the binding pocket, the so-called β-barrel [3], [5]. The primary function of FABP is the facilitation of intracellular long-chain fatty acid transport [6], while other functions include regulation of gene expression by mediating fatty acid signal translocation to peroxisome proliferator activated receptors (PPARs) [7] and putative protection of cardiac myocytes against the detergent-like effects of locally high concentrations of long-chain fatty acids, especially during ischemia [1], [8]. The cellular expression of FABPs is regulated primarily at the transcriptional level and is responsive to changes in lipid metabolism as induced by (patho)physiological and pharmalogical stimuli like ischemia [9], endurance training [10], diabetes [11], [12], hypertrophy [13], [14] and hypolipidemic drugs [15].
When evaluating FABP as clinical tissue injury marker, we have to take into account that after cell damage small proteins diffuse more rapidly than large proteins through the interstitial space via endothelial clefts into vascular space. The size of these endothelial clefts is variable, from large clefts in the liver to smaller pores in the heart, the skeletal muscle and finally to almost complete impermeability in the brain (blood–brain barrier). As a result, the diffusion rate of the released proteins into the circulation also differs. Therefore, the time of appearance of these marker proteins in plasma is not only dependent on the time course of the disease, but also on the molecular size and distribution over extravascular compartments [16].
Heart-type FABP (H-FABP) was first shown to be released from injured myocardium in 1988 [17], after which several studies have investigated its application as a biochemical marker of myocardial injury. Following the finding that H-FABP is an early and sensitive marker for injured myocardium [18], [19], additional studies were set up to evaluate the application of this and other FABP types for the monitoring of tissue injury. In this paper we review the current status of FABP assays, and the clinical application of plasma FABP determination for monitoring cardiac, skeletal muscle, kidney, liver, intestinal and brain injury, in comparison with currently used markers of tissue injury.
Section snippets
Tissue content and distribution of FABP types
Cytoplasmic FABPs have been detected in virtually all rodent and human tissues. These proteins of the intracellular lipid-binding family contain 126–137 amino acid residues and show an amino acid sequence homology of 20–70%. Due to single amino acid mutations, different isoforms are reported, mainly differing in isoelectric point [1]. Initially, FABPs from human kidney [20] and mammary gland [21], as well as rat skeletal muscle [22] each were regarded as distinct FABP types, but later were
Assays for FABPs
Mono- and polyclonal antibodies were raised against different types of FABP and both immunohistochemical and immunological assays were developed to measure tissue contents and serum/plasma and urine concentrations of specific FABP types [30], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46].
For H-FABP, polyclonal antibodies were first used in ELISAs to study the role of FABP in fatty acid metabolism in the rat [22], [44], [47], pig [23], cattle [41], [48], birds [49], [50],
Reference limits
Proper interpretation of plasma concentrations of biochemical markers for clinical diagnosis is dependent on the establishment of reference limits. As already stated by Jaffe [77], the minimal detection limit and reproducibility of the assay, as well as biological variation and upper reference limit (URL) of the marker must be stated correctly to enable efficient comparison of clinical data. Many clinical investigators have used apparently healthy individuals to obtain reference values for
Detection of myocardial injury and re-infarction
The potential of H-FABP as sensitive and early marker for myocardial injury has been reported by several groups [18], [19], [39], [53], [55], [79], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94]. The characteristics of the release of H-FABP from injured myocardium closely resemble those of myoglobin. However, because the cardiac tissue content of H-FABP is much higher than that of myoglobin and the normal plasma value of H-FABP is much lower than that of myoglobin, H-FABP is a more
Conclusions and perspectives
FABPs are novel biochemical markers with relatively high tissue concentrations and low normal plasma concentrations, which result in sensitive release. Heart-type FABP (H-FABP) has proven not only to be an excellent marker for the early, within 6 h, detection of cardiac injury in acute coronary syndromes, but also showed to be sensitive enough for detecting minor myocardial injury in heart failure and displayed promising prognostic values for cardiac events in ACS and CHF. Importantly, each of
Acknowledgements
The authors gratefully acknowledge the following colleagues for stimulating discussions: F. Spener, T. Börchers, University of Münster, Germany; C. McNeil, M. Gok, University of Newcastle Upon Tyne, United Kingdom; J. Chapelle, University of Liège, Belgium; D. Davis, Astra Zeneca, United Kingdom; A. Trull, A. Morovat, Addenbrooke's Hospital, Cambridge, United Kingdom. R. Renneberg, University of Science and Technology, Hong Kong; J. Górski, Z. Namiot, Medical Academy of Bialystok, Poland; J.
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