in a study in the previous issue of critical care , huang and colleagues   observed that , in the critically ill , adipose - fatty acid - binding protein ( a - fabp ) concentrations were elevated and that the serum a - fabp concentrations were independently related to serum creatinine , fasting plasma glucose , total cholesterol , tumor necrosis factor - alpha ( tnf- ) , 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 .
these 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 signifies .
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 adipocytes , accounts for approximately 6% of total cellular proteins , and is an important regulator of systemic insulin sensitivity and lipid and glucose metabolism .
mice deficient in a - fabp are protected from development of hyperinsulinemia , hyperglycemia , and insulin resistance .
adipocytes obtained from a - fabp - null mice had markedly reduced efficiency of lipolysis in vivo and in vitro   and showed a two- to three - fold decrease in fatty acid release , suggesting that a - fabp regulates efflux of fatty acids under normal physiological conditions .
acute insulin secretory response to -adrenergic stimulation was profoundly suppressed in a - fabpmice compared with their wild - type littermates , indicating that a - fabp could regulate systemic insulin sensitivity through its actions on other distal target tissues .
a - fabp is also present in macrophages , and its expression in macrophages can be induced by oxidized low - density lipoprotein ( ldl )   and toll - like receptor ( tlr ) agonists   and suppressed by statins .
this evidence suggests that a - fabp , by integrating metabolic and inflammatory 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 inflammatory conditions . in this context , it is interesting to note that a - fabpmice are protected from experimental autoimmune encephalomyelitis and showed reduced levels of pro - inflammatory cytokine mrna expression in central nervous system tissue as compared with wild - type mice . in vitro ,
antigen recall responses of myelin oligodendrocyte glycoprotein 35 - 55-immunized a - fabpmice showed reduced proliferation and impaired interferon - gamma production .
dendritic cells deficient in fabps were poor producers of pro - inflammatory cytokines - interleukin-6 ( il-6 ) and tnf-- and did not promote pro - inflammatory t - cell responses , suggesting that metabolic - inflammatory pathway cross - regulation by a - fabps plays a significant role in adaptive immune responses and inflammation .
these results - coupled with the observations that unsaturated fatty acids , such as palmitoleic acid , oleic acid , linoleic acid , linolenic acid , and eicosapentaenoic acid , significantly repressed the basal as well as lipopolysaccharide - induced a - fabp expression in macrophages and depletion of a - fabp expression by rna interference ( rnai ) decreased cyclooxygenase 2 ( cox-2 ) mrna expression and potentiated the repression by linoleic acid   -give interesting insights into the relationship among a - fabp , cytokines , and unsaturated fatty acids and their involvement in sepsis and other critical illnesses .
recent studies   revived the controversy of whether unsaturated fatty acids are beneficial in the management of sepsis .
the 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- and cox-2 expression whereas unsaturated fatty acids suppress a - fabp expression and il-6 and tnf- production   indicates the complexity of the involvement of tlrs , a - fabp , cytokines , unsaturated fatty acids , and their products in sepsis .
the 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 ) ; eicosapentaenoic acid ( epa ) is the precursor of three series of pgs , three series of txs , and five series of lts .
pgs , txs , and lts formed from epa are less pro - inflammatory in nature compared with pgs , txs , and lts formed from aa but still are pro - inflammatory in nature .
interestingly , aa , epa , and docosahexaenoic acid ( dha ) suppress the production of pro - inflammatory cytokines il-6 and tnf- 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 - inflammatory substances , whereas nitric oxide and unsaturated fatty acids interact to form nitrolipids that have anti - inflammatory action .
furthermore , aa is the precursor of lipoxin a4 ( lxa4 ) , and epa and dha give rise to resolvins and dha gives rise to protectins ; resolvins and protectins have potent anti - inflammatory actions , resolve inflammation , and enhance wound healing by suppressing the production of free radicals , myeloperoxidase , il-6 , tnf- , and hmgb1 ( high - mobility box 1 ) and antagonize the pro - inflammatory actions of leukotrienes .
resolvins and protectins block tlr - mediated activation of macrophages   and enhance the anti - bacterial action of antibiotics and augment the clearance of bacteria .
this implies that the optimal production of lipoxins , resolvins , and protectins from unsaturated fatty acids is essential for clearing the invading pathogens , resolving inflammation , and preventing tissue damage .
under normal physiological conditions , a balance between pro- and anti - inflammatory molecules is maintained .
a tilting of this balance in favor of the former would lead to initiation and progression of inflammation , insulin resistance , and consequent tissue damage .
such an inflammatory process could be due not only to increased expression of a - fabp and augmented production of pro - inflammatory molecules but also to deficiency of anti - inflammatory molecules such as il-4 , il-10 , lipoxins , resolvins , and protectins ( figure 1 ) . in this context , it is noteworthy that a - fabp suppresses cardiomyocyte contraction   whereas unsaturated fatty acids seem to prevent cardiac failure , reinforcing close interaction(s ) among various pro- and anti - inflammatory molecules and their role in sepsis .
hence , a better understanding of the interaction(s ) among these molecules in inflammatory conditions is essential in order to develop meaningful and novel therapeutic strategies especially for sepsis .
interaction(s ) among adipose - fatty acid - binding protein ( a - fabp ) , toll - like receptor ( tlr ) , cytokines , free radicals , unsaturated fatty acids , and their products and inflammation and resolution of inflammation . infections , injuries ( including surgery ) , and high - fat diet activate macrophages and tlrs , leading to secretion of increased amounts of pro - inflammatory cytokines that , in turn , produce an excess of free radicals .
pro - inflammatory cytokines , tlrs , and free radicals activate a - fabp and cyclooxygenase 2 ( cox-2 ) , leading to increased production of pro - inflammatory prostaglandins ( pgs ) , leukotrienes ( lts ) , and thromboxanes ( txs ) from unsaturated fatty acids and decreases in the synthesis and release of anti - inflammatory lipoxins ( lxs ) , resolvins ( rsvs ) , and protectins ( prts ) .
unsaturated fatty acids and lxs , rsvs , and prts are expected to suppress macrophage activation and expression of a - fabp and tlrs and inhibit inflammation .
increased expression of a - fabp also occurs in obesity , type 2 diabetes mellitus ( dm ) , and coronary heart disease ( chd ) .
interleukin-6 ( il-6 ) , tumor necrosis factor - alpha ( tnf- ) , macrophage activation , increased expression of a - fabp , and increased production of pgs , lts , txs , and free radicals enhance insulin resistance in infections and sepsis .
aa , arachidonic acid ; dha , docosahexaenoic acid ; epa , eicosapentaenoic acid ; hmgb1 , high - mobility group box 1 ; lps , lipopolysaccharide ; nl , nitrolipid ; no , nitric oxide ; ros , reactive oxygen species .
aa : arachidonic acid ; a - fabp : adipose - fatty acid - binding protein ; cox-2 : cyclooxygenase 2 ; dha : docosahexaenoic acid ; epa : eicosapentaenoic acid ; il : interleukin ; ldl : low - density lipoprotein ; lt : leukotriene ; pg : prostaglandin ; tlr : toll - like receptor ; tnf- : tumor necrosis factor - alpha ; tx : thromboxane .
und is the recipient of a ramalingaswami fellowship from the department of biotechnology , new delhi , india .
this work was supported by grants from the department of biotechnology ( bt / pr11627/med/30/157/2010 ) , the department of science and technology ( ir / so / lu/03/2008/1 ) under intensification of research in high priority areas ( irpha ) , and the defence research and development organisation , new delhi ( tc/2519/inm-03/2011/cars ) under r&d project inm-311 .
 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
Adipose-fatty acid-binding protein and inflammation
Adipose-fatty acid-binding protein, Toll-like receptors, unsaturated fatty acids, and inflammation
Balance between pro- and anti-inflammatory events and molecules determines prognosis
Abbreviations
Competing interests
Acknowledgements