FABPs are small secreted proteins that are widely found in most mammalian cells (Chmurzynska, 2006). Previous studies have reported that the whole FABPs family has nine isoforms including L-FABP/FABP1 (liver), I-FABP/FABP2 (intestinal), H-FABP/FABP3 (heart), A-FABP/FABP4/aP2 (adipocyte), E-FABP/FABP5/mal1 (epidermal), IL-FABP/FABP6 (ileal), B-FABP/FABP7 (brain), M-FABP/FABP8 (myelin), and T-FABP/FABP9 (testis) ( Table 1). The isoforms are grouped according to the organs or tissues in which they were initially identified, isolated, and where they are most predominant. In other words, most tissues express multiple FABP isoforms and the expression of FABPs has no tissue specificity, which resulted in confusion and misunderstanding (Furuhashi and Hotamisligil, 2008).

The structure of the FABP family also contains vitamin A derivative-specific binding proteins including cytosolic retinol-binding protein (CRBPI/CRBPII/CRBPIII/CRBPIV) and cytosolic retinoic acid-binding protein (CRABPI/CRABPII) (Noy, 2000). The entire FABP family members share a highly conserved set of gene structures consisting of four exons separated by three introns. There is a similar position of exons and introns while the length of the introns between different subtypes is varied (Zimmerman and Veerkamp, 2002). Several studies have reported that the tertiary structures of FABP proteins are virtually superimposable despite the members exhibiting 22–73% amino acid sequence similarity (Banaszak et al., 1994; Storch and Thumser, 2010) (Figure 2A). The tertiary structure of FABPs comprises two α-helices as well as ten anti-parallel β-strands (Figure 2B). The available studies hypothesize the portal for fatty acids (FA) access and egress as a dynamic region made of α-helix II and the turns between βC-βD and βE-βF loops. The helix-turn-helix/portal region of FABP is considered a critical region that determines numerous functions of this protein family (Storch and Mcdermott, 2009).

Dictated by the characteristic structure, the main function of the FABPs is to bind fatty acids, as well as the intake, transportation and consumption, despite their different selectivity, affinity, and binding mechanism (Storch and Thumser, 2000; Smathers and Petersen, 2011; Zhao et al., 2017). Structure-function studies of AFABP and KFABP reveal these specific ligands binding to FABP result in subtle conformational changes on its portal surface, promoting specific interactions and ultimately determining the functions of each FABP (Gillilan et al., 2007; Storch and Mcdermott, 2009). Consequently, the FABPs, including FABP3 (Zhuang et al., 2019), FABP4 (Furuhashi, 2019), FABP5 (Sharifi et al., 2013), FABP6 (Duggavathi et al., 2015), FABP7 (Sharifi et al., 2013; Ebrahimi et al., 2016; Xie et al., 2020), FABP9 (Moradi et al., 2019), play a systemic effect on the body’s lipid and energy metabolism by regulating FA transport in the nuclear and extra-nuclear compartments of the cell (Atshaves et al., 2010; Li et al., 2020) (Figure 3).

FABP5 is also known as epidermal FABP (E-FABP), cutaneous fatty acid-binding protein (C-FABP), psoriasis-associated FABP (PA-FABP), keratinocyte FABP (K-FABP), intracellular lipid-binding protein (iLBP), and mal-1. FABP5 was first discovered in the keratinocytes of psoriatic lesions, followed by characterization in the epidermis (Madsen et al., 1992). It is located at chromosome (Chr) 8q21. Immunohistochemistry results obtained from previous studies have indicated that FABP5 is expressed in a plethora of tissues or organs including the skin, eyes, lungs, spleens, kidneys, brain, liver, bone, tongue, adipose tissue, breast, retina tissue, cardiac, and intestinal tissue (Masouyé et al., 1997; Smathers and Petersen, 2011).

The major function of FABP5 is to regulate the intracellular levels of fatty acids and specific metabolic pathways. However, FABP5 has several extra features. One remarkable difference is that the electrophoretic mobility of recombinant human FABP5 is different from that of FABPs and CRBPs within the scope of pI = 6.2–6.4 (Hohoff et al., 1999). In addition, there are six cysteines and one disulphide bridge between cysteines 120 and 127 in FABP5, which promote protein stability (Figure 4). Several studies have reported that the disulphide bridge may be associated with physiological and pathophysiological functions such as relieving oxidative damage to the epidermis and other tissues through the thiol-disulphide exchange reaction (Hohoff et al., 1999; Odani et al., 2000). Human FABP5 is highly polymorphic. With the exception of the general binding and trafficking functions, FABP5 is also diverse and hyperspecific in modulating the metabolism and function of its binding ligands. However, the existence of extra FABPs in several tissues makes it hard to define the exact function of FABP5, as well as its physiological ligand and underlying mechanism, which requires further research.

Metabolic syndromes such as obesity, high uric acid, high blood fat, hypertension, type II diabetes, and atherosclerosis, have received increasing attention due to the great changes that have occurred in eating habits and the general lifestyle (Figure 5). Accumulating evidence shows that the level of FABP5 may be closely associated with the pathogenesis of chronic metabolic diseases through its expression in adipocytes and macrophages (Hotamisligil et al., 1996; Maeda et al., 2005; Cao et al., 2006).

Yeung et al., (2008) reported that the serum FABP5 level is positively associated with the parameters of body fat contents (BMI, hip, and waist circumference), poor blood lipid status (high triglycerides and low HDL-C), and hyperinsulinemia. The same correlation was reported in other previous studies (Yeung et al., 2008; Zhang et al., 2020). Notably, a statistical analysis of 225 men reported that FABP5 is an important independent risk factor for carotid intima-media thickness, which indicates that FABP5 is relevant to cardiovascular metabolic risks. In addition, atherosclerotic low-density lipoprotein (LDL) receptor-deficient mice treated with a Western-style high-cholesterol diet enhanced the expression of FABP5, as well as plasma levels of atherogenic lipoproteins, very low-density lipoprotein (VLDL), and LDL (Hoekstra et al., 2006). Similarly, when fed on a Western-style diet, survival of FABP4^–/–FABP5^–/–ApoE^–/–mice (FABP4 and FABP5 co-deficient mice crossed into ApoE^−/− model) were found to significantly increase, which may be due to increased plaque stability (Boord et al., 2004; Ibarretxe et al., 2016). Furthermore, the low-density action of circulating FABP5 led to a decreased cholesterol efflux capacity (CEC) from macrophages, which is the first step in the reverse cholesterol transport pathway and carotid atherosclerosis. This suggests that the serum FABP5 concentration is a regulatory factor of CEC and a potential biomarker for residual risk of atherosclerosis (Furuhashi et al., 2017). These results suggest a particular role of FABP5 in atherogenesis. Bagheri et al. (2010) reported, for the first time, the link between FABP5 and metabolic and inflammatory cardiovascular disease (CVD) risk factors in humans. The study pointed out that FABP4 and FABP5 synergistically promote inflammatory, metabolic, and atherogenic processes, suggesting their roles in representing mediators and biomarkers of metabolic and CVD disease in T2DM (Bagheri et al., 2010). Further studies reported that a combined deficiency of FABP4 and FABP5 does not reduce weight gain or adiposity but it improves glucose tolerance and insulin sensitivity, and may prevent the onset of fatty liver. Therefore, although limited under some conditions, FABP5 shows potential importance in controlling systematic metabolism (Cao et al., 2006; Hotamisligil and Bernlohr, 2015).

Analysis of FABP5^−/−mice indicated the necessity of FABP5 for enteroendocrine cell development due to the finding which indicated that genetic depletion of FABP5 is linked with a significant reduction in plasma glucose-dependent insulinotropic polypeptide (GIP) concentration, which probably stems from impaired neural regulation of GIP secretion (Yamane et al., 2016). GIP, also known as a gastric inhibitory polypeptide, is produced by a subset of enteroendocrine cells known as K cells. GIP is a hormone that induces the postprandial insulin response and affects nutrient intake, especially fat (Shibue et al., 2015). This remarkable observation reconfirmed the contribution of FABP5 in the lipid metabolism and development of obesity. The finding also provided strong support for FABP5’s function in the prevention and treatment of metabolic diseases.

Interestingly, Hertzel et al. (2002) reported contradictory results. There were no significant differences in overall morphology, weight, and serum-free fatty acid concentrations between wild-type mice and FABP5 transgenic mice. In addition, both basal and hormone-stimulated lipolysis were increased in adipocytes of FABP5 transgenic mice (Hertzel et al., 2002). These results were consistent with the results obtained in another study done by Hertzel et al. (2006) which reported that overexpression of FABP5 in adipose tissues causes an increase in lipolysis and a decrease in cellular free fatty acid levels (Hertzel et al., 2006). Triglycerides must be mobilized by lipolysis before re-esterification until they can be reassembled on the endoplasmic reticulum and thus incorporated into lipoprotein particles (Gilham et al., 2005). Therefore, the presence of FABP5 may cause an increment in the efficacy of fatty acid release and promote the re-esterification of liberated fatty acids in the endoplasmic reticulum. This may be a key step explaining why the overexpression of FABP5 results in increased lipolysis. Furthermore, it might also reasonably explain why FFAs and triglycerides are increased in ARPE-19 cells by 18% and 67%, respectively, after siRNA treatment (Wu et al., 2010).

The mechanism underlying the close correlation between insulin resistance and lipid metabolism is getting clearer (Rachek, 2014; Athyros et al., 2018). Fatty acids can stimulate insulin secretion when transiently elevated, and can lead to pancreatic islet failure, lipotoxicity, and apoptosis when chronically elevated (Poitout et al., 2006; Acosta-Montaño et al., 2019). Studies conducted on FABP4 null mice with induced obesity suggested that the metabolism of adipocyte fatty acids is a crucial component of the mechanisms leading to systemic insulin resistance in obesity (Hotamisligil et al., 1996; Shaughnessy et al., 2000). Both FABP3 and FABP5 are thought to be associated with the stimulus-secretion coupling mechanisms and insulin secretion process (Hyder et al., 2010). The adipocytes of FABP5-deficient mice exhibited an enhanced capacity for the transport of insulin-dependent glucose and a modest increase in systemic insulin sensitivity while overexpressing FABP5 aggravated insulin resistance and hyperglycaemia (Maeda et al., 2003). Further profiling of the lipids indicated an increase in the number of shorter-chain (C14) fatty acids and a decrease in the number of longer-chain (C18 or C20) fatty acids in the adipose and muscle tissues of FABP4^–/–FABP5^–/– mice, which favors the enhancement of insulin receptor signaling and insulin-stimulated glucose uptake (Maeda et al., 2005). Experiments conducted on the structure-binding relationship have also found that FABP5 has a high affinity for stearic acid, which decreases when the number of carbon atoms decreases or when double bonds are introduced into the fatty acid chain (Siegenthaler et al., 1994). These observations probably suggest that the distribution and availability of intracellular fatty acids and their derivatives may be more critical than the absolute amounts of fatty acids.

In addition to the vital role of FABP5 in binding FFAs and moderating lipid metabolism and transport, it is also closely associated with adipogenesis. Specifically, FABP5 maintains the viability of pre-adipocytes by activating the Akt cascade, and reduced FABP5 expression induces apoptosis of differentiated pre-adipocytes through caspase-3 activation (Ma X. et al., 2010) (Figure 5).

Vascular endothelial growth factor (VEGF) is one of the most effective stimulating factors for angiogenesis and is thus involved in the progression of angiogenesis-related diseases, such as facilitating the malignant dissemination of the primary tumor cells (Neufeld et al., 1999). VEGF regulates most of the endothelial responses, especially endothelial cell proliferation and migration (Matsumoto and Ema, 2014) (Figure 5).

The regulation of endothelial cell homeostasis and vascular integrity is necessary for normal organ functions such as tissue repair and regeneration (Huang et al., 2019). A study demonstrated the presence of enriched FABP5 expression in aging human dermal microvascular endothelial cells obtained from elderly skin tissues (Ha et al., 2004). It also revealed the expression of FABP5 in the endothelial cells of some larger vessels, involving arteries and veins. This finding could be a valuable supplement to earlier findings that endothelial cell-FABP5 expression is confined to the microvasculature of some tissues in the kidney, heart, and placenta (Masouyé et al., 1997). A large amount of FABP5 expression has also been observed in endothelial cells within cutaneous hemangiomas (the most frequent endothelial cell-derived tumors). FABP5 also promotes the chemotactic migration and angiogenic sprouting of endothelial cells both in vitro and ex vivo (Yu et al., 2016). However, the FABP5 level shows no response to VEGF, despite studies proving that the FABP5 expressed in endothelial cells and VEGF significantly enhances endothelial cell proliferation. This indicates that FABP5 is not a downstream target of VEGF, instead, it is probably regulated by the extracellular lipids in endothelial cells. In addition, FABP5 may promote apoptosis resulting in vascular regression when meeting the conditions of nutrient deprivation, such as tissue ischemia or starvation, or induced by other stressors (Figure 5). A recent study suggested that autophagic response may be a potential explanation, however, the hypothesis needs to be addressed in future studies (Yu et al., 2016) (Figure 5). Interestingly, opposite results were obtained in other studies demonstrating that FABP5 induces metastasis of rat mammary epithelial cells (Rama 37 cells) through the up-regulation of VEGF expression (Jing et al., 2001) (Figure 5). In line with this observation, another study confirmed that the expression of FABP5 is involved in airway remodeling and inflammation in asthma by inducing VEGF production, and a positive correlation between FABP5 and VEGF levels was also observed in those circumstances (Suojalehto et al., 2015) (Figure 5).

Considering the role of FABP5 in neurite outgrowth, Liu et al. (2015) found that cells lacking FABP5 are less responsive to nerve growth factor (NGF) treatment than control cells as manifested by a significant reduction of neurite expression. The study also reported that FABP5 is up-regulated by NGF and is vital for NGF-induced and polyunsaturated fatty acid-potentiated neurite outgrowth (Liu et al., 2015). A further study reported that FABP5 is expressed in retinal ganglion cells (RGCs) since these cells reached the ganglion cell layer, thereby unraveling the functional role of FABP5 in the elaboration of RGC axons in both development and regeneration (Allen et al., 2001).

In contrast to FABP3, the expression of FABP5 is dominant in the glia of the pre-natal and peri-natal brain (Owada et al., 1996). The differential temporal expression of FABP5 during the development can be attributed to its proposed role in transporting long chain-free fatty acids and/or other hydrophobic ligands during neuronal differentiation and axon growth (Liu et al., 2000). The differentiation of progenitor cells into mature neurons, the late stage of the RA-induced neuronal differentiation process, is mediated through PPARβ/δ (Yu et al., 2012) (Figure 5). Accumulating evidence has shown that FABP5 is also implicated in the neurogenesis, development of astrocytes, neuronal migration, and terminal differentiation of neurons, indicating that FABP5 is required for neuronal development in nervous tissues (Liu et al., 2000).

FABP5 has an inseparable relationship with immune cell biology since lipid metabolism plays a key role in innate and adaptive immune responses and the profound effects of FABP5 on the pathways related to the signaling of lipid metabolism (Zhang and Li, 2014). Accumulating correlative evidence has stressed the important contribution of FABP5 in the regulation of immune function, which hassled to the underlying mechanisms becoming increasingly well understood (Westerbacka et al., 2007). A recent study investigated the response of lung epithelial cells to infection by the influenza virus, thereby adding more evidence on the link between FABP5 and the immune system. In the study, FABP5^−/− mice exhibited sustained tissue inflammation characterized by increased cell infiltration of macrophages and neutrophils when compared with wild-type mice, both infected with the influenza A virus. The adaptive immune response characterized by the accumulation of T and B cells in lung tissue and increased levels of H1N1-specific IgG antibodies was also increased in FABP5^−/− mice. These results support the speculation that FABP5, as a transporter of fatty acids, plays a crucial protective role against the oxidative damage to lipids during infection. Interestingly, the expression of FABP5 in wild-type lung tissue was decreased after infection with the influenza A virus, which is in conjunction with a decrease in the anti-inflammatory molecule PPAR-γ activity. A possible explanation for the biphasic expression of FABP5 is that the initial down-regulation is regarded as part of the immune response initiation, while the subsequent recovery of FABP5 expression levels is to aid attenuation of the inflammatory response (Gally et al., 2013b).

A recent study conducted on alveolar macrophages during acute rejection of rat lungs has for the first time provided evidence on the up-regulation of FABP5 expression in alveolar macrophages (AM) during severe inflammation (Holler et al., 2010). Monocytes, which accumulate in the graft vessels lumina of renal allografts, also express elevated FABP5 levels during rejection (Grau et al., 2003). All the evidence supports the idea that FABP5 is implicated in the immunological rejection response after allograft organ transplantation and thus it can be exploited to improve the outcome of transplantation.

However, another study reported that FABP5^−/− mice infected with Listeria monocytogenes showed no defect in clonal expansion, contraction, and formation of memory CD8⁺ T cells and CD4⁺ T cells when compared with wild-type mice. This indicates that FABP5 is not necessary for antigen-specific T cell responses after a bacterial infection (Li and Schmidt, 2016). Moreover, there is also a model in which cigarette smoking-induced FABP5 inhibition contributed to increased inflammation in COPD exacerbations, which is speculated to be as a result of decreasing PPARγ activity (Gally et al., 2013a; Rao et al., 2019).

Recent studies have reported that FABP5 limits the anti-inflammatory response, and the pharmacological inhibition of FABP5 reduce inflammation and pain (Abplanalp et al., 2020). An innovative study focusing on infected mice suffering acute inflammation reported a remarkable phenomenon where the inhibition of FABP5 reduced pain, edema, cytokine, and PGE2 levels, which is a major eicosanoid that increases pain in inflammatory settings (Bogdan et al., 2018) Endocannabinoid anandamide (AEA), also known as the endogenous lipid arachidonoyl ethanolamide, exerts neurobehavioral, cardiovascular, and immune-regulatory effects via cannabinoid receptors (CB) (Pacher et al., 2005). Elevated endocannabinoids levels can have beneficial pharmacological effects on stress, pain, and inflammation, as well as ameliorate the effects of drug withdrawal. Recent studies conducted in the last decade have elucidated the link between FABP5 and endocannabinoid anandamide (AEA) where FABP5 has been identified as an intracellular transporter of AEA (Sanson et al., 2014). Another study reported that FABP5 hydrolyzes AEA into arachidonic acid (AA) and ethanolamine, which is catalyzed by fatty acid amide hydrolase (FAAH), an enzyme localized in the endoplasmic reticulum (Kaczocha et al., 2009). The presence and overexpression of FABP5 significantly enhance pain and inflammation since AEA becomes inactivated after cellular uptake and subsequent catabolism, thereby losing the antinociceptive function. Therefore, the role of FABP5 in pain and inflammation positions FABP5 inhibitors as potential anti-inflammatory and analgesic drugs (Kaczocha et al., 2015).

Blowout studies conducted in the past decade have shed light on the molecular function of immune factors and inflammatory cytokines (Gu et al., 2019; Sun et al., 2020). The studies have revealed that the pro-inflammatory response (M1) is to a large extent activated by interferon-γ (IFN-γ) and/or lipopolysaccharide (LPS), characterized by increased pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 12 (IL-12), and IL-6, and decreased transforming growth factor β (TGF-β) (Ambarus et al., 2012). Alternatively, the non-classical anti-inflammatory (M2) response is originally triggered by IL-4, IL-13, and IL-10. Accumulating evidence suggests that FABP5 may be involved in the production of cytokines in macrophages and dendritic cells by controlling cellular lipid metabolism and signaling (Kitanaka et al., 2003). A previous study reported that FABP5 null macrophages display suppression of inflammatory genes, such as COX2 and IL-6 (Babaev et al., 2011). In addition, FABP5 null mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM1, and Fizz-1 in the liver when compared with wild-type mice. All these findings suggest that FABP5 functions as a major regulator of the pro-inflammatory response inextricably linked with its interactions with various distinct cytokines. It is also worth noting that the homeostasis of macrophage phenotypes (M1 and M2) is a key component in the inflammation process. Some researchers have hypothesized that deletion of FABP5 can produce higher levels of M2-related cytokines and genes, and the subsequent effect should be addressed in future studies (Moore et al., 2015).

Recent studies have reported that obesity is positively associated with a bacterial skin infection and inflammatory skin disorders including pruritus and seborrheic dermatitis. However, the underlying mechanisms have not yet been elucidated. FABP5 as a specific factor that is correlated with lipid metabolism and inflammation, presents a novel and viable idea for understanding obesity-associated inflammatory skin diseases in humans. FABP5 is up-regulated in macrophages and keratinocytes in skin tissues during a high-fat diet, thereby significantly instigating inflammatory skin lesions in the obesity mouse model. This suggests that FABP5 might represent a molecular sensor for triggering high fat diet-induced skin inflammation (Zhang et al., 2015). Furthermore, FABP5 deficiency abrogated high-saturated-fat diet-induced skin lesions in obese mouse models in vivo (Zeng et al., 2018). On the other hand, the deletion of FABP5 in macrophages resulted in increased insulin signaling and glucose uptake in adipocytes. These observations indicate that the interactions between FABP5 and adipocyte/macrophage are critical for the inflammatory basis of metabolic deterioration (Furuhashi et al., 2008).

The skin is thought to have numerous lipid-rich microenvironments because the epidermis and sebaceous glands are active sites for fatty acids synthesis. Therefore, it is doubtless that FABP5 plays a crucial role in skin homeostasis and pathology (Figure 7). FABP5 is found localized in the suprabasal layers of healthy epidermis, with elevated expression in the spinous, granular layers, and actively proliferating tissue (Ogawa et al., 2011). FABP5 was initially detected and cloned in psoriasis, a hyperproliferative skin disease characterized by abnormal differentiation and disordered lipid metabolism (Madsen et al., 1992). The expression level of FABP5 is markedly elevated in this pathological situation, and it mainly resides in the stratum spinosum (Watanabe et al., 1997). In addition, silencing or overexpressing FABP5 significantly influences keratinocyte differentiation in normal and psoriatic cells, suggesting a link between FABP5 and keratinocyte differentiation (Dallaglio et al., 2013). The lipid composition of epidermal layers is also altered during keratinocyte differentiation, suggesting that FABP5 induces normal human keratinocyte proliferation and differentiation by altering lipid metabolism. Moreover, the up-regulation of FABP5 may be partially involved in the alteration of the differentiation mechanism in psoriasis. In addition to psoriasis, FABP5 is also involved in atopic dermatitis (AD) (Yamane et al., 2009), radiation-induced skin fibrosis (Song et al., 2018), and skin tumor development (Zhang et al., 2018), as a biochemical marker in the skin’s horny layer.

Recent studies have unraveled the function of FABP5 as a prominent marker of sebaceous glands and anagen follicle bulbs (Collins and Watt, 2008). High expression of FABP5 has been consistently found in differentiated sebocytes, while the size of sebaceous glands is significantly reduced in FABP5-deficient mice. Furthermore, the sebum volume was increased as the lipid composition changed, suggesting that FABP5 may regulate the activity of the sebaceous gland through the modulation of cellular lipid signaling and metabolism in the sebocytes (Sugawara et al., 2012). Another study has also reported that FABP5 acts as an antioxidant in the skin by covalently modifying cysteine residues to scavenge peroxidized lipids (Bennaars-Eiden et al., 2002). Additionally, Kusakari et al. (2006) reported an increased expression of FABP5 in regenerative keratinocytes of healing wounds, suggesting that the FABP5 elevation may be warranted in the activation of regenerative epidermal cells motility during wound healing (Kusakari et al., 2006).

Although the function of FABP5 in skin homeostasis and pathology has not been elucidated, it is clear that FABP5 is responsible for the water permeability barrier of the skin. Interestingly, only a minor decrease in the trans-epidermal water loss was observed in the FABP5-deficient mice, and the loss was lower in the knock-out mice than in the wild-type mice (Owada et al., 2002a). However, the skin analyses indicated that there were no differences in the contents of major fatty acids between the knock-out and wild-type mice (Owada et al., 2002b). Considering the robust correlation between FABP5 and FABP3 (H-FABP), a possible explanation might be associated with the compensatory roles that H-FABP plays in the tissues (Owada et al., 2002b). In view of the important role of FABP5 in the skin, further elucidation of the underlying molecular mechanism should be done.

Recently, inspired by the essential roles of fatty acids, especially long-chain PUFAs in the normal development of the central nervous system (Liu et al., 2010), the cellular distribution, transcriptional regulation, and function of FABP5 in the normal and diseased brain of humans have been further studied. Studies have reported that FABP5 contributes to neurogenesis and is widely expressed in various cell types (Gerstner et al., 2008), especially mature neurons, in most regions of the brain (Matsumata et al., 2012). The hippocampi of FABP5-null mice had an excessive accumulation of neuronal progenitor cells and a deficit in mature neurons when compared with wild-type animals (Yu et al., 2012). Yu et al. (2014) reported that FABP5 regulates hippocampal function by promoting the hydrolysis of the endocannabinoid anandamide into a form acting as a PPARβ/δ ligand. In addition, FABP5 promotes the hydrolysis of AEA into AA and directly shuttles AA to the nucleus and delivers it to PPARβ/δ, which enables its activation. Mice with FABP5 ablation displayed excess accumulation of AEA and abolishment of PPARβ/δ activation in the brain, thereby significantly impairing hippocampus-based learning and memory. This indicated that FABP5 plays an important role in regulating hippocampal cognitive function by controlling the distribution and activity of anandamide (Yu et al., 2014).

Docosahexaenoic acid (DHA) is an omega-3 PUFA, which serves as a beneficial factor in cognitive function and memory. DHA is sufficiently essential in brain function and its levels are reduced in neurodegenerative diseases such as Alzheimer’s disease (Low et al., 2020). An intracellular carrier protein is required to facilitate the cytosolic trafficking of DHA across the brain endothelial cell to maintain the brain levels of DHA since DHA is not produced by the brain. FABP5 is the key contributor to the uptake of DHA and subsequent trafficking across the blood-brain barrier (BBB) (Pan et al., 2016). In addition, FABP5 is an important player in the promotion of cellular uptake, transport, and metabolism of DHA after spinal cord injury, and thus it has been considered as a significant contributor to basic repair mechanisms in the injured spinal cord (Figueroa et al., 2016). Similarly, a previous study reported that the FABP5 expressed in primary human brain endothelial cells is involved in the transport of palmitic, oleic, and linoleic acids across the primary brain endothelial cells. This finding is consistent with the role of FABP5 in transporting DHA (Mitchell et al., 2011). All the studies conducted on DHA highlight the importance of FABP5 in availing DHA to the brain as an intracellular protein, thereby guaranteeing the growth and functional development of the brain.

As for the role of FABP5 in the pathogenesis of schizophrenia and autism spectrum disorder (ASD), further studies have proved that disturbances in brain-expressed FABP5 could result in a proportion of psychiatric illnesses (Shimamoto et al., 2014). FABP5 is involved in acoustic startle response and performance of prepulse inhibition (PPI), a deficit of which is a biological marker for psychiatric illnesses such as schizophrenia and bipolar disorder (Iwayama et al., 2010). However, mice deficient for FABP5 exhibits no difference in other behavior performances, such as spatial memory, anxiety-like behavior, and diurnal changes of general activity (Matsumata et al., 2016). Moreover, FABP5 expression is up-regulated (or altered) under pathological conditions, such as peripheral nerve injury, ischemic brain damage, and stroke, as well as a neurodegenerative disorder, such as Creutzfeldt-Jakob disease (Lescuyer et al., 2004; Ma D. et al., 2010).

FABP5 is found up-regulated in the tumor-associated epithelial cell, and it affects tumor growth and progression by binding transported fatty acids and their derivatives, hormones, steroids, carcinogens, and other ligands (Zimmerman et al., 2001). In addition, there are several previous studies on the correlation between fatty acids and tumors. It is common knowledge that various types of cancers display increased biosynthesis of endogenous fatty acids, whereas the de novo synthesis of fatty acids is inhibited in most normal cells except for adipocytes and hepatocytes (Mashima et al., 2009). For example, prostate cancer utilizes fatty acid oxidation as the main bioenergy pathway for supporting proliferation (Zadra et al., 2013). The rationale behind this phenomenon is that the survival of cancer cells depends on the uptake and consumption of fatty acids to maintain their rapid proliferation and metastatic behavior, which further leads to cancer initiation, progression, and metastasis (Daniëls et al., 2014). Silencing or down-regulating FABP5 in human cancer cells inhibits cell proliferation and decreases the expression of the genes which are involved in altered lipid metabolism, lipolysis, and de novo synthesis of fatty acids in various tumors. Therefore, it is possible for FABP5 to act as a potential biomarker for tumors based on the key role of FABP5 in lipid metabolism, especially fatty acids metabolism.

Neoplastic transformation and tumor growth, two fundamental processes in early tumorigenesis, are characterized by acquiring the traits of sustained proliferation and cell death resistance (Hanahan and Weinberg, 2011). A comparison of normal cells with benign hyperplasia indicates that FABP5 is ubiquitously overexpressed in most the cancers including breast cancer, cervical cancer (CCa), endometrial cancer (EC), head and neck squamous cell carcinoma (HNSC), prostate cancer (PCa), hepatocellular carcinoma (HCC), tongue carcinoma, esophageal cancer (ESCA), clear cell renal cell carcinoma (ccRCC), stomach adenocarcinoma (STAD), and lung squamous cell carcinoma (LUSC) ( Table 2). Mechanism studies have revealed that FABP5 regulates tumorigenesis and cancer progression by regulating different pathways including MMP-2/MMP-9, PI3K/AKT, and PPARs pathways (Rauch et al., 2004; Shi et al., 2012; Forootan et al., 2014; Ohyama et al., 2014; Nitschke et al., 2020) (Figure 7 and Table 2). Ki67, a notable cell proliferation marker in the tumor, could independently predict cancer progression (Yang et al., 2018). It was reported that the number of Ki67-stained cells was significantly decreased in the FABP5 knockdown group and significantly increased in the FABP5 overexpression group (Zhang et al., 2020) (Table 2). In addition, silencing FABP5 may reduce the invasiveness of cancer cells, inhibit cell proliferation, and increase cell apoptosis (Powell et al., 2015; Zhao et al., 2017; Lv et al., 2019) (Table 2). All these strong pieces of evidence prove that FABP5 is an important regulator of tumor cell proliferation.

Epithelial-mesenchymal transitions (EMT) is a multistep morphogenetic process in which epithelial cells lose their epithelial properties while fully acquiring their mesenchymal properties. It is thought to be a critical process in the migration, invasion, and metastatic spread of cancer cells (Thiery and Sleeman, 2006). It was reported that FABP5 may regulate the development and progression of cancer cells by mediating signaling pathways that are involved in EMT (Wu et al., 2019) (Table 2). Another study reported that the overexpression of FABP5 in oral cancer cells enhances cell proliferation and invasiveness by increasing the expression of MMP-9, while the knockdown of FABP5 using shRNA significantly inhibits the activity of MMP-9 (Fang et al., 2010). These findings suggest an undeniable correlation between FABP5 and MMP-9 (Table 2). Similarly, the down-regulation of FABP5 in cervical cancer inhibits the in vivo and in vitro expression of MMP-2 and MMP-9 (Wang et al., 2016) (Table 2). In the mechanism, the extracellular matrix is degraded and the basal membrane expression of cervical cancer cells is destroyed by up-regulating the expression of MMP-2 and MMP-9, thereby resulting in carcinogenesis and metastasis (Zhan et al., 2019) (Table 2). Furthermore, FABP5 (as an epithelial marker) can be inhibited by autophagy and thus induce the expression of mesenchymal markers as well as MMP-9, thereby stimulating cell invasion (Li et al., 2013). Collectively, great progress has been made in revealing the interactions among FABP5, MMP-9, and EMT. However, definitive evidence on the underlying molecular mechanism and signaling pathway have not been provided.

Interestingly, some studies have exact opposite results. FABP5 has been shown to suppress chemically-induced skin tumorigenesis through regulation of the IFN/p53/SOX2 pathway, where it down-regulates the expression of SOX2 mediated by p53 in keratinocytes (Figure 7). Herein, FABP5 represents a previously unknown molecular mechanism where the host maintains skin homeostasis thereby preventing the skin tumorigenesis induced by environmental insults (Zhang et al., 2018) (Table 2). Hammamieh, et al. (2004) reported that FABP5 was down-regulated in prostate cancer cell lines (DU145) and breast cancer cell lines (MCF-7) when compared with that of normal cells in tissue cultures and biopsy samples (Hammamieh et al., 2004; Hammamieh et al., 2005). And it was also found that the expression of FABP5 in different types of human breast cancer tissues was significantly lower than that of normal breast tissues (Zhang et al., 2014). Recent studies have helped us to further unravel the underlying mechanisms. One possible explanation is that the regulation of FABP5 in intracellular immune responses enhances tumor immune surveillance and induces tumoricidal activity. However, the peculiarities of cancer metabolism might counteract the immune killing effect of FABP5 on a tumor, which may partially explain why FABP5 is down-regulated in PCa and breast cancer. Specifically, PCa and breast cancer presents unique metabolic features as they use lipids as the dominant energy source while general cancers are characterized by an accelerated glucose utilization. (Slebe et al., 2016). This can probably be attributed to the metabolic adaptation to lipid-rich and/or glucose-poor cellular microenvironments. Future studies should aim at further exploring the exact roles of FABP5 in anti-tumor immunological surveillance or in promoting tumor progression through lipid metabolism, and the balance between them.

FABP5/PPARβ/δ pathway is critical in tumorigenesis and cancer growth (Figure 7), which is similar to its role in enhancing the proliferation of keratinocytes (Schug et al., 2007; Morgan et al., 2010) (Table 2). FABP5 regulates metabolic gene expression through a PPARβ/δ independent pathway in colorectal cancer cells (Kawaguchi et al., 2016b) (Figure 7). However, there is a discrepancy where some literature has reported that PPARβ/δ signaling does not enhance the growth of human cancer cell lines and it attenuates colon carcinogenesis (Marin et al., 2006; Hollingshead et al., 2007; Palkar et al., 2010). Similarly, another study reported that PPARβ/δ is not a potential biomarker for assessing the degree of malignancy or a prognosis predictor of PCa because there was no correlation found between the expression of PPARβ/δ and patient survival (Forootan et al., 2014) (Table 2).

In addition to its important role in tumorigenesis, FABP5 is also closely correlated with tumor grade and metastasis (Liu et al., 2013). The alteration of lipid metabolism plays a crucial role in cancer development and metastasis. For instance, the dysregulation of lipid metabolism and signaling pathway has been recognized as a major driver of PCa metastasis (Ahmad et al., 2016; Zadra et al., 2019). Moreover, high levels of lipid droplets and stored cholesteryl ester contents are the hallmarks of cancer aggressiveness (Bozza and Viola, 2010). Therefore, FABP5 might be implicated in cancer metastasis through the reprogramming of lipid metabolism. FABP5 is involved in the malignant dissemination of some human cancers (Jing et al., 2000) (Table 2). For instance, Jing et al. (2001) transfected a benign, non-metastatic rat mammary epithelial cell line (Rama 37 cells) with FABP5 and then inoculated it in syngeneic rats. Almost one-third of FABP5-transfected animals developed metastases, while the animals treated with non-FABP5-transfected remained free of metastases. This indicates that an elevated expression of FABP5 may induce metastasis of cancer cells (Jing et al., 2001). In addition, FABP5 has been identified as an independent predictor of lymph node metastasis (LNM) (Jeong et al., 2012; Wang et al., 2014). The mRNA and protein expression levels of FABP5 in cervical cancer (CCa) cells derived from lymph node metastatic sites (MS751) were significantly higher than those in CCa cells derived from primary sites (HeLa and SiHa) (Zhang et al., 2020). FABP5 was also highly expressed in invasive cancer cell lines (LI-7 and HLE) than in the noninvasive cell lines (Hep3B and HepG2) of HCC (Ohata et al., 2017) (Table 2). This finding confirmed the role of FABP5 as a promoter of tumor metastasis. Nevertheless, there was no notable difference in the expression of FABP5 between cancer tissues with lower Gleason scores (scores of 1–5) and those with higher Gleason scores (scores of 5–10). This suggested that FABP5 does not increase with the increasing metastatic potential and that FABP5 may play a more important role in the initiation of early malignant transformation than in the promotion of metastasis (Adamson et al., 2003) (Table 2).

Overexpression of FABP5 interacts with PPARγ in a coordinated manner to promote malignant progression of tumor including tumor expansion and aggressiveness caused by reduced apoptosis and increased angiogenesis (Naeem et al., 2019) (Table 2). In addition to PPARγ, other receptors including the related PPARβ/δ and estrogen-related receptor α, and signaling involving VEGF are also known to increase the metastatic potential of cancer (Carbonetti et al., 2019) (Table 2). As mentioned before, FABP5 affects the survival pathways by activating RA through PPARβ/δ, and the ratio of FABP5 to CRABPII may lead to the results of natural apoptosis, or unrestricted cell growth (Schug et al., 2007; Zhou et al., 2016).

Despite the molecular cascades of metastasis involving polygenic and complex alterations, angiogenesis is still an important common mechanism for metastasis and the formation of solid tumors. As discussed above, VEGF has been identified as a key mediator of angiogenesis in cancer and FABP5 has been positively correlated with VEGF expression (Figure 7). Studies have revealed that the microvascular density of metastatic tumors and their primary tumors transfected with FABP5 is significantly higher than that of the primary tumors developed from the control vector transfectants (Jing et al., 2000). However, the effect of FABP5 on VEGF is limited since a further increase in FABP5 may have a little additional effect on the expression of VEGF once the threshold level is exceeded, which might explain why FABP5 and VEGF are not under a simple linear relationship. FABP5 was demonstrated to promote angiogenesis through activating the IL6/STAT3/VEGFA pathway in HCC (Pan et al., 2018) (Table 2), or transporting excessive levels of fatty acids into the nucleus of the cancer cells to activate PPARγ thereby up-regulating the expression of VEGF (Bao et al., 2013) (Figure 7 and Table 2). Moreover, FABP5 can induce the production of reactive oxygen species (ROS) and activate nuclear factor-kappa B (NF-κB) signaling, which leads to the up-regulation of its target genes (Senga et al., 2018) (Figure 7). In addition, NF-κB in turn induces the expression of FABP5, by activation of epidermal growth factor receptors (EGFR) ligand heregulin-β1 signals through the ERK and the phophatidylinositol-3-kinase cascades (Kannan-Thulasiraman et al., 2010) (Figure 7). Mechanistic studies have also revealed that FABP5 stabilizes EGFR protein expression by preventing EGFR ubiquitination and degradation, thereby promoting metastasis. This indicates its special effect on EGF-induced metastatic signaling (Powell et al., 2015) (Table 2). FABP5 was also found as a direct target of c-Myc, a proto-oncogene, leading to the up-regulation of FABP5 transcription through the hypo-methylation of the FABP5 promoter (Uma et al., 2007; Kawaguchi et al., 2016a) (Table 2). And it was confirmed in squamous cell carcinoma (SCC) lines and primary head and neck carcinomas (Münz et al., 2005).