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Shi, Y.; Wang, C.; Wu, L.; Zhang, Y.; Xu, A.; Wang, Y. Fatty Acid-Binding Orotein-4 on Pregnancy Health. Encyclopedia. Available online: https://encyclopedia.pub/entry/48375 (accessed on 26 June 2024).
Shi Y, Wang C, Wu L, Zhang Y, Xu A, Wang Y. Fatty Acid-Binding Orotein-4 on Pregnancy Health. Encyclopedia. Available at: https://encyclopedia.pub/entry/48375. Accessed June 26, 2024.
Shi, Yue, Chi-Chiu Wang, Liqun Wu, Yunqing Zhang, Aimin Xu, Yao Wang. "Fatty Acid-Binding Orotein-4 on Pregnancy Health" Encyclopedia, https://encyclopedia.pub/entry/48375 (accessed June 26, 2024).
Shi, Y., Wang, C., Wu, L., Zhang, Y., Xu, A., & Wang, Y. (2023, August 23). Fatty Acid-Binding Orotein-4 on Pregnancy Health. In Encyclopedia. https://encyclopedia.pub/entry/48375
Shi, Yue, et al. "Fatty Acid-Binding Orotein-4 on Pregnancy Health." Encyclopedia. Web. 23 August, 2023.
Fatty Acid-Binding Orotein-4 on Pregnancy Health
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This entry is adapted from the peer-reviewed paper 10.3390/ijms241612655

Fatty acid-binding protein-4 (FABP4), commonly known as adipocyte-fatty acid-binding protein (A-FABP), is a pleiotropic adipokine that broadly affects immunity and metabolism. Throughout pregnancy, FABP4 affects maternal–fetal interface homeostasis by affecting both glycolipid metabolism and immune tolerance, leading to adverse pregnancy outcomes, including miscarriage, gestational obesity, gestational diabetes, and preeclampsia. Moreover, maternal FABP4 levels exhibit a substantial linkage with the metabolic health of offspring. 

FABP4 metabolism placenta offspring

1. Introduction

Pregnancy constitutes a complex physiological process that engages robust immunological and metabolic adaptations [1]. These changes are precisely regulated by a myriad of hormones and cytokines, which are critical for ensuring a successful pregnancy [1]. The physiological dynamics include the establishment of the immune tolerance status for foreign alloantigen maintenance and endocrine alternation typified by insulin resistance [2]. Metabolic and immune maladaptation during pregnancy results in numerous complications, such as miscarriage, gestational diabetes mellitus (GDM), preeclampsia (PE), and preterm birth, which subsequently affect maternal long-term morbidity and mortality [3]. Moreover, these complications carry substantial intergenerational consequences, predisposing offspring to metabolic diseases later in life [4][5][6]. Consequently, a comprehensive understanding of the mechanisms and factors that orchestrate physiological adaptions during pregnancy is important for the prevention of reproductive and gestational complications and the improvement of maternal and child health.
Fatty acid-binding protein 4 (FABP4), a 14–15 kDa protein belonging to the lipocalin family, is also known as adipocyte fatty acid-binding protein (A-FABP) or adipocyte protein 2 (aP2) [7]. As an adipose-derived hormone, FABP4 is primarily expressed in adipocytes as a cellular marker of adipocyte maturation [8] and is mainly involved in immunometabolism implications and obesity-associated tumors [9]. Though FABP4 is predominantly enriched in adipose tissue [10], recent studies have revealed its expression in other cell types, including macrophages [11], dendritic cells [12], endothelial cells [13], and placental trophoblast cells [14]. FABP4 is a master regulator of lipid homeostasis [15]. It binds to and transports intracellular fatty acids (FA) and other lipophilic molecules to influence lipid metabolism [16]. FABP4 serves as an upstream activator that augments the activities of peroxisome proliferator-activated receptor gamma (PPARγ) [17], which regulates adipogenesis and adipocyte differentiation [18], as well as hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), which are all key factors promoting lipolysis and FA oxidation [19]. In immune cells, FABP4 expression is induced by inflammatory stimuli, such as lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-α) [20]. The LPS-activated c-Jun N-terminal kinase (JNK) pathway increases the phosphorylation of c-Jun in macrophages [21], which in turn binds to the activator protein 1 (AP-1) cis-element within the FABP4 gene promoter to enhance its transcription [21]. Increased FABP4 further potentiates LPS-elicited downstream activation, thereby creating a positive feedback loop to promote inflammation [21]. Collectively, FABP4 is a pleiotropic protein that regulates lipid storage, lipogenesis, and lipolysis [22][23] and plays a crucial role in the pathogenesis of metabolic inflammation.

2. The Role of FABP4 on Pregnancy Health

2.1. The Molecular Mechanism of FABP4 Regulating Placental Function

The placenta is an integral organ in the maintenance and development of pregnancy, whereas placental dysfunction results in serious complications for both mother and fetus [24]. Within the placenta, FABP4 expression was first identified in the placental labyrinth, especially in endothelial cells [13], and has also been detected in human epithelial cells of the uterine endometrium [25]. It profoundly modulates immune hemostasis, lipid metabolism, and fetal development by targeting the placenta throughout gestation.
The establishment and maintenance of pregnancy depend on the interaction between the embryo and the maternal uterine endometrium [26]. In the uterine endometrium, the expression of FABP4 is site-specific and time-dependent during gestation. Previous animal studies found that FABP4 is primarily expressed in the labyrinthine layer, and its expression reaches the maximum level at 14.5–16.5 gestational days [13]. In humans, FABP4 presents in the trophoblast layer and villous endothelial cells of the placenta [14]. Further study also showed FABP4 is notably expressed in endometrial epithelial cells during proliferative and secretory phases and in stromal cells in the secretory phase, where it regulates the proliferation, migration, and invasion of epithelial cells in the endometrium [25].
Of note, FABP4 expression has also been detected in various immune cells resident in the placenta, including macrophages [27], dendritic cells [12][28], and natural killer (NK) cells [12], which are instrumental in shaping the immune environment at the maternal–fetal interface. In macrophages, increased FABP4 has been shown to modulate macrophage polarization by promoting the M1 pro-inflammatory phenotype, and decreased FABP4 levels favors the M2 anti-inflammatory phenotype [11][29]. It triggers macrophage inflammation through activation of the Janus kinase 2/signal transducer and activator of the transcription 2 (JAK2/STAT2) pathway [30] and may promote macrophage inflammation via a reduced reactive oxygen species (ROS)-dependent mechanism [31]. In contrast, the absence of FABP4 in macrophages enhances the expression of sirtuin 3 (SIRT3) [32] and ROS production [33] for anti-inflammatory effects. Moreover, FABP4 influences NK cell activity and cytotoxicity by mediating lipid metabolism [34]. NK cells collected from an obese condition with a lipotoxic environment exhibited increased FABP4 expression levels aligned with lipid accumulation [34]. Further study showed that upregulation of FABP4 expression impaired NK cell function in the release of interferon-γ (IFN-γ) [35], which is a vital cytokine for pregnancy success [36]. Overall, given the importance of placenta–resident immune cells in pregnancy, these regulatory effects of FABP4 on immune cells have significant implications for immune surveillance and tolerance at the maternal–fetal interface, thereby potentially affecting placental functionality and development.
Furthermore, FABPs are essential for active FA transport, metabolism, and gene expression in the placenta for substantial intergenerational consequences [37]. A human study found FABP4 has a synergistic effect on placental lipid transport and accumulation at the maternal–placenta interface and endothelial layer to maintain high FA uptake rates into the placenta [38]. An in vitro study using human trophoblasts demonstrated FABP4 is expressed in both the trophoblast layer and fetal capillaries of placental villi [14], which is in charge of transplacental transport of lipids from the maternal blood into the fetal circulation through the syncytiotrophoblast and capillary endothelial cells [39]. Primary human trophoblasts (PHT) exposed to selective FABP4 inhibitor BMS309403 displayed decreased FA-induced FABP4 protein expression, reduced accumulation of lipid droplets, and abolished FA-induced triglycerides in trophoblasts [14]. Similarly, FABP4 knockdown by siRNA also attenuated lipid droplet buildup in PHT cells [14]. These results indicate that FABP4 plays a pivotal role in the uptake and accumulation of lipids in human trophoblasts. Moreover, the overexpression of FABP4 in pregnant rats and trophoblast cells increased transplacental transport of docosahexaenoic acid (22:6 n-3, DHA) without significant placental DHA accumulation [40], indicating FABP4 may play a more crucial role in FA transport than accumulation in placental lipid metabolism. However, current evidence proposes FABP4 might be dispensable for fetoplacental lipid transport. Minimal changes in weight and morphology were observed between FABP4−/− fetuses and wild type littermates, and similarities were noted in both maternal serum and fetal hepatic total cholesterol (TC) levels among the different genotypes [13], indicating that FABP4 deficiency did not impact the supply of TC to the developing fetus and predisposing offspring to metabolic diseases later in life. Further studies are still warranted to determine the impact of FABP4 in fetal lipid supply.
Taken together, FABP4 plays a crucial role in pregnancy establishment and maintenance, acting in different aspects, such as lipid metabolism, immune modulation, and fetal development. However, despite our understanding of its involvement, further research is necessary to elucidate the detailed mechanisms of FABP4 in maternal–fetal interface regulation and its potential as a therapeutic target for reproductive and pregnancy-related disorders as shown below.

2.2. Implantation Failure and Pregnancy Loss

Maternal inflammation constitutes a significant risk factor for pregnancy loss [41]. During embryo implantation, immune cells, such as macrophages and NK cells, aggregate and activate at the maternal–fetal interface to initiate immune responses [42][43]. Intriguingly, FABP4 has been identified in multiple studies as a crucial regulator of immune cells. It is highly expressed in activated NK cells to support mitochondrial metabolism [35]. In macrophages, increased FABP4 expression leads to the macrophage polarization from an anti-inflammatory status (M2) to a pro-inflammatory phenotype (M1), which consequently disrupts the immune homeostasis at the maternal–fetal interface and leads to failures in embryo implantation and decidualization [44]. Consistently, a recent study by Yang et al. determined serum FAPB4 levels was significantly higher in patients experiencing miscarriage at 8–12 weeks of gestation compared to age- and BMI-matched healthy pregnant women, positing that serum FABP4 levels may be a marker in predicting miscarriage [45].
FABP4 plays a vital role in embryo implantation, which has been confirmed by cell and mouse experiments. FABP4 silencing in the endometrial cell line significantly reduced the number of trophoblast spheroids adhered onto endometrial cells compared with scramble [41]. Moreover, FABP4 inhibitor treatment significantly impaired tube formation mediated by VEGF, DHA, and leptin, indicating the differential role of FABP4 in FA and angiogenic growth factors-mediated tube formation in the first-trimester trophoblast cells [46]. Mice administrated with FABP4 siRNA on the first day of pregnancy showed a decrease in the number of implanted embryos [41]. All these findings underscore that FABP4 is essential in the establishment and maintenance of pregnancy, and subsequently may be involved in the pathogenesis of implantation failure.
FABP4 may also be important for successful gestation during the post-implantation period, which provides essential nutrients to facilitate proper placental development [47]. Inhibiting nutrient sensors, including mechanistic targets of mechanistic target of rapamycin (mTOR) and PPARs, cause embryo loss, growth delay, and placental growth impairments in pregnant mice models [48]. An in vivo study demonstrated that inhibition of mTOR signaling results in embryo resorption and diminished FAPB4 expression in the decidual [48]. Likewise, blocking PPARγ or PPARδ pathway by chemical inhibitors also triggers fetoplacental growth dysfunction aligned with FABP4 downregulation [48], suggesting that FABP4 may play an important role in sustaining post-implantation growth.
Therefore, FABP4 may contribute to early pregnancy loss by affecting immunological and metabolic adaption. However, the question remains whether FABP4 represents a detrimental factor or a protective mechanism for miscarriage since the results of in vivo and in vitro studies were not consistent with the clinical finding. Additional investigations with FABP4 deficient mice model and clinical observations are necessary to definitively establish its specific roles in pregnancy maintenance.

2.3. Maternal Obesity

Obesity, a well-known risk factor for poor metabolic health, exhibits particularly detrimental effects during pregnancy. In pregnancy, maternal obesity is defined as being overweight (25.0–29.9 kg/m2) and obese (≥30 kg/m2) [49]. It is closely associated with the occurrence of gestational disorders, including PE and GDM [50]. Importantly, maternal obesity poses deleterious impacts on the offspring’s metabolic health later in life [51]. Extensive studies have proven that fetuses exposed to maternal obesity have a significantly elevated risk to develop obesity, hypertension, hyperglycemia, insulin resistance, hyperlipidemia, and non-alcoholic fatty-liver disease in their progeny including [52][53].
Circulating FABP4 levels are widely associated with obesity risk factors such as triglyceride, cholesterol, and leptin levels in humans and rodents [54]. Consistently, lines of evidence also revealed that serum FABP4 levels are positively associated with maternal BMI [55], especially in the subgroup with BMI surpassing 25 [56]. Moreover, maternal circulating FABP4 levels are also negatively associated with serum adiponectin levels, which is a metabolically beneficial hormone [56]. These findings underscore that elevated FABP4 levels are intricately linked to adiposity gain during pregnancy, thus suggesting that FABP4 levels could serve as a predictive indicator of the degree of maternal obesity.

2.4. Gestational Diabetes Mellitus (GDM)

GDM, characterized by the onset or first-recognized glucose intolerance in pregnancy, is diagnosed based on International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria: fasting glucose level of ≥5.1, and/or 2-h ≥ 8.5 mmol/L after a standardized oral glucose tolerance test (OGTT) [57]. It is the most common pregnancy complication affecting 14.0% of pregnant women worldwide [57], which increases the risk of multiple adverse outcomes in mothers and their offspring [58]. The positive association between elevated serum FABP4 level and glycemic dysfunction has been well recorded in a general population [59][60]. Similarly, the elevation in serum FABP4 level may indicate an increased risk in GDM. Accumulating clinical evidence also identified that FABP4 levels are positively associated with tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels in the serum of GDM patients [61][62]. In line with this clinical observation, suppression of FABP4 using a chemical inhibitor (BMS309403) led to decreased TNF-α and IL-6 levels, ameliorating glucose metabolism, and insulin tolerance in the GDM mouse model [63]. Glucose stimulates FABP4 expression in trophoblast cells [64], which enhances lipolysis and exacerbates pregnant insulin resistance (IR) [65][66], especially in the first and second trimesters [67]. These findings indicate FABP4 may aggravate the symptoms of GDM and the activation of inflammatory pathways [56].
Interestingly, serum FABP4 levels are strongly associated with the severity of GDM and postpartum consequences. A majority of clinical studies have reported higher serum FABP4 levels in women with GDM than in euglycemia pregnancies and positive correlations with biochemical parameters abnormality [63][65][66][67][68][69][70][71]. Only three studies reported no significant difference in serum FABP4 levels between groups with and without GDM [56][72][73]. A nested case-control study revealed that women in the upper tertial of FABP4 levels in the first and second trimesters had 5.3% and 44.7% higher risk of developing GDM respectively, compared to those in the lowest tertial [67]. A prospective cohort study found FABP4 levels increased remarkably in GDM groups from the second to the third trimester and were associated with a higher risk of GDM onset compared to other adipokines, such as leptin and retinol-binding protein 4 (RBP4) [74]. However, one study reported that the differences in maternal serum between GDM and euglycemic pregnancies appear to recede one week prior to delivery [72], which may be attributed to the increased accumulation of maternal adipose depot and natural progression in increased insulin resistance status during late pregnancy [50][75]. Therefore, FABP4 may serve as a valuable biomarker in the discrimination of at-risk GDM subjects, especially in the in mid-late pregnancy.

2.5. Preeclampsia (PE)

PE is a severe pregnancy-induced hypertensive condition diagnosed as systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg after 20 weeks of gestation concomitant with proteinuria and edema [76]. It is associated with multisystem disorders in the later stage of gestation, thereby leading to maternal and neonatal morbidity and mortality [77]. A nested case-control study detected markedly increased maternal serum FABP4 levels at 8 to 13 weeks of gestation in subjects who were eventually diagnosed with preeclampsia, suggesting that FAPB4 is a potential predictive biomarker for PE [78]. In accordance, among pregnant women with type 1 diabetes, those who developed PE exhibited increased FAPB4 levels during the first and second trimesters [79]. Another prospective longitudinal cohort in women with type 1 diabetes also demonstrated a significantly higher serum FABP4 level throughout the gestational period in those who later developed PE [80]. Animal study further corroborated this by showing that placental FAPB4 expression level was augmented in a preeclamptic rat model [81]. Importantly, overexpression of FAPB4 in trophoblast cells induced pro-inflammatory cytokines (e.g., IL-6 and TNF-α) secretion and triggered intracellular lipid accumulation [81], which are considered putative pathogeneses of preeclampsia [82][83]. Overall, these findings indicate that FAPB4 is a potential biomarker for the early detection of PE, and it may implicate the onset of PE by inducing placental inflammation. However, since PE is aligned with GDM and maternal obesity as aforementioned, which also contribute to the elevated serum FABP4 level. Therefore, whether circulating FABP4 level is an independent risk factor for PE should be further investigated by adjusting cofounding factors, e.g., BMI.

2.6. Preterm Birth

Premature birth occurs before the 37th week of pregnancy [84], accounting for 11% of all perinatal mortality and morbidity births worldwide [85]. Notably, preterm birth ranks as the leading cause of mortality among children under five years old [86] and predispose newborns to numerous early-age diseases as well as sensory impairment, learning disabilities, and respiratory illness in their later life [87].
FABP4 may be involved in premature delivery via immunologically generated processes in pregnant tissues, which mirrors the mechanism of pregnancy loss [12]. Higher serum FABP4 levels were measured in premature delivery in a clinical study [88], especially in very and extremely preterm infants. Lines of evidence have demonstrated that FABP4 in cord blood [88] and serum of one-month infants [89] tends to be higher in preterm neonates than in neonates delivered at term, and this difference increases with a lower gestational age [88]. A cross-sectional study detected higher FABP4 levels in infants with gestational age less than 30 weeks compared to full-term infants [88]. Likewise, A prospective cohort study observed that preterm neonates with a mean gestational age of 32.8 weeks had slightly higher FABP4 levels compared with the full-term infants [89]. Therefore, there could be a positive correlation between serum FABP4 levels and the onset of preterm labor.

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Subjects: Reproductive Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Yue Shi
,
Chi-Chiu Wang
,
Liqun Wu
,
Yunqing Zhang
,
Aimin Xu
,
Yao Wang
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Update Date: 24 Aug 2023
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