Serum adipocyte fatty acid-binding protein in the critically ill

Sepsis due to unabated inflammation is common. Increased production of pro-inflammatory cytokines, free radicals, and eicosanoids has been detected in sepsis and other critical illnesses but could also be due to decreased synthesis and release of anti-inflammatory molecules. Increased serum adipose-fatty acid-binding protein (A-FABP) levels can cause insulin resistance and have been reported in the critically ill, serve as a marker of prognosis, and thus link metabolic homeostasis and inflammation. A-FABP can be linked to the expression of Toll-like receptors, macrophage activation, synthesis and release of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, activation of cyclooxygenase 2 (COX-2) expression, and eicosanoid synthesis, events that can cause insulin resistance and initiation and progression of inflammation and sepsis. Unsaturated fatty acids and their anti-inflammatory products, such as lipoxins, resolvins, and protectins, may suppress A-FABP expression, inhibit macrophage and COX-2 activation, and decrease production of pro-inflammatory cytokines and ultimately could lead to a decrease in insulin resistance and resolution of inflammation and recovery from sepsis. Serial measurement of these pro- and anti-inflammatory molecules and correlation of their levels to the progression to or recovery from (or both) sepsis and other inflammatory processes may form a new approach to predict prognosis in inflammatory conditions and eventually could lead to the development of new therapeutic strategies.


Introduction
In a study in the previous issue of Critical Care, Huang and colleagues [1] observed that, in the critically ill, adipose-fatty acid-binding protein (A-FABP) concentrations were elevated and that the serum A-FABP con centrations were independently related to serum creatinine, fasting plasma glucose, total cholesterol, tumor necrosis factor-alpha (TNF-α), albumin, and the Acute Physiology and Chronic Health Evaluation II scores, suggesting that higher A-FABP levels (>40 ng/mL) were associated with an unfavorable outcome in patients with sepsis. Th ese results not only are interesting but also suggest that perhaps A-FABP could be used a biomarker of prognosis in the critically ill. But it is not clear why A-FABP levels should be increased in the critically ill or what this increase signifi es.
Adipocyte fatty acid-binding protein (A-FABP or FABP4), also known as aP2 (adipocyte protein 2), is a carrier protein for fatty acids and is expressed primarily in adipocytes and macrophages. A-FABP belongs to the fatty acid-binding protein super-family whose members have relative molecular masses of approximately 15,000. A-FABP is a predominant cytosolic protein of mature adipo cytes, accounts for approximately 6% of total cellular proteins, and is an important regulator of sys temic insulin sensitivity and lipid and glucose meta bolism [2]. Mice defi cient in A-FABP are protected from development of hyperinsulinemia, hyperglycemia, and insulin resistance [3]. Adipocytes obtained from A-FABP-null mice had markedly reduced effi ciency of lipolysis in vivo and in vitro [4] and showed a two-to three-fold decrease in fatty acid release, suggesting that A-FABP regulates effl ux of fatty acids under normal physiological conditions. Acute insulin secretory response to β-adrenergic stimulation was profoundly suppressed in A-FABP −/− mice compared with their wild-type littermates [4], indicat ing that A-FABP could regulate systemic insulin sensitivity through its actions on other distal target tissues.

Adipose-fatty acid-binding protein and infl ammation
A-FABP is also present in macrophages, and its expression in macrophages can be induced by oxidized lowdensity lipoprotein (LDL) [5] and Toll-like receptor (TLR) agonists [6] and suppressed by statins [7]. A-FABP modulates infl ammatory cytokine production and Abstract Sepsis due to unabated infl ammation is common. Increased production of pro-infl ammatory cytokines, free radicals, and eicosanoids has been detected in sepsis and other critical illnesses but could also be due to decreased synthesis and release of antiinfl ammatory molecules. Increased serum adipose-fatty acid-binding protein (A-FABP) levels can cause insulin resistance and have been reported in the critically ill, serve as a marker of prognosis, and thus link metabolic homeostasis and infl ammation. A-FABP can be linked to the expression of Toll-like receptors, macrophage activation, synthesis and release of pro-infl ammatory cytokines interleukin-6 and tumor necrosis factoralpha, activation of cyclooxygenase 2 (COX-2) expression, and eicosanoid synthesis, events that can cause insulin resistance and initiation and progression of infl ammation and sepsis. Unsaturated fatty acids and their anti-infl ammatory products, such as lipoxins, resolvins, and protectins, may suppress A-FABP expression, inhibit macrophage and COX-2 activation, and decrease production of pro-infl ammatory cytokines and ultimately could lead to a decrease in insulin resistance and resolution of infl ammation and recovery from sepsis. Serial measurement of these pro-and anti-infl ammatory molecules and correlation of their levels to the progression to or recovery from (or both) sepsis and other infl ammatory processes may form a new approach to predict prognosis in infl ammatory conditions and eventually could lead to the development of new therapeutic strategies.
choles terol ester accumulation [8]. Ablation of the A-FABP gene protected against atherosclerosis [9]. Th is evidence suggests that A-FABP, by integrating metabolic and infl ammatory pathways, provides a key link between components of metabolic syndrome, implying that blocking A-FABP protein could be considered in the treatment of heart disease, diabetes mellitus, asthma, obesity, and fatty liver disease, which are all infl ammatory conditions.
In this context, it is interesting to note that A-FABP −/− mice are protected from experimental autoimmune encephalo myelitis and showed reduced levels of proinfl ammatory cytokine mRNA expression in central nervous system tissue as compared with wild-type mice.

IL-6, TNF -, HMGB1
A-FABP A-FABPs plays a signifi cant role in adaptive immune responses and infl ammation [10]. Th ese results -coupled with the observations that unsaturated fatty acids, such as palmitoleic acid, oleic acid, linoleic acid, linolenic acid, and eicosapentaenoic acid, signifi cantly repressed the basal as well as lipopolysaccharide-induced A-FABP expres sion in macrophages and depletion of A-FABP ex pression by RNA interference (RNAi) decreased cyclooxygenase 2 (COX-2) mRNA expression and potentiated the repression by linoleic acid [11] -give interesting insights into the relationship among A-FABP, cytokines, and unsaturated fatty acids and their involvement in sepsis and other critical illnesses.

Adipose-fatty acid-binding protein, Toll-like receptors, unsaturated fatty acids, and infl ammation
Recent studies [12,13] revived the controversy of whether unsaturated fatty acids are benefi cial in the management of sepsis. Th e fact that A-FABP is increased in sepsis, induced by oxidized LDL and TLR agonists, and suppressed by statins and enhances the production of IL-6 and TNF-α and COX-2 expression whereas unsaturated fatty acids suppress A-FABP expression and IL-6 and TNF-α production [14] indicates the complexity of the involvement of TLRs, A-FABP, cytokines, unsaturated fatty acids, and their products in sepsis.
Th e unsaturated fatty acid arachidonic acid (AA) is the precursor of two series of prostaglandins (PGs), two series of thromboxanes (TXs), and four series of leukotrienes (LTs); eicosa pentaenoic acid (EPA) is the precursor of three series of PGs, three series of TXs, and fi ve series of LTs. PGs, TXs, and LTs formed from EPA are less pro-infl ammatory in nature compared with PGs, TXs, and LTs formed from AA but still are proinfl ammatory in nature [15]. Interestingly, AA, EPA, and docosahexaenoic acid (DHA) suppress the production of pro-infl ammatory cytokines IL-6 and TNF-α both in vitro and in vivo. In addition, free radicals act on unsaturated fatty acids to give rise to F2-isoprostanes, a group of pro-infl ammatory substances, whereas nitric oxide and unsaturated fatty acids interact to form nitrolipids that have anti-infl ammatory action [15].
Furthermore, AA is the precursor of lipoxin A 4 (LXA 4 ), and EPA and DHA give rise to resolvins and DHA gives rise to protectins; resolvins and protectins have potent anti-infl ammatory actions, resolve infl ammation, and enhance wound healing by suppressing the production of free radicals, myeloperoxidase, IL-6, TNF-α, and HMGB1 (high-mobility box 1) and antagonize the pro-infl ammatory actions of leukotrienes [15]. Resolvins and protectins block TLR-mediated activation of macrophages [15] and enhance the anti-bacterial action of antibiotics and augment the clearance of bacteria [16]. Th is implies that the optimal production of lipoxins, resolvins, and protectins from unsaturated fatty acids is essential for clearing the invading pathogens, resolving infl ammation, and preventing tissue damage.

Balance between pro-and anti-infl ammatory events and molecules determines prognosis
Under normal physiological conditions, a balance between pro-and anti-infl ammatory molecules is maintained. A tilting of this balance in favor of the former would lead to initiation and progression of infl ammation, insulin resistance, and consequent tissue damage [17]. Such an infl am matory process could be due not only to increased expression of A-FABP and augmented production of proinfl ammatory molecules but also to defi ciency of antiinfl ammatory molecules such as IL-4, IL-10, lipoxins, resolvins, and protectins ( Figure 1). In this context, it is noteworthy that A-FABP suppresses cardiomyocyte contrac tion [18] whereas unsaturated fatty acids seem to prevent cardiac failure [19], reinforcing close inter action(s) among various pro-and anti-infl ammatory molecules and their role in sepsis. Hence, a better understanding of the interaction(s) among these molecules in infl ammatory conditions is essential in order to develop meaning ful and novel therapeutic strategies especially for sepsis.

Competing interests
The author declares that he has no competing interests.