Table 1.
Characteristics of studies included in the analysis.
| Author | Year | Number of patients | Pathological condition | Methodology | Amino-acid transporters | Results |
|---|---|---|---|---|---|---|
| Aiko et al. (27) | 2014 | n = 40 (FGR, n = 10; PE, n = 10, full-term control, n = 10; pre-term control, n = 10) | FGR | Protein expression: IHC of formalin-fixed, paraffin-embedded placental tissue + image analysis software | SLC7A5 (LAT1) | 1. LAT1 expression levels were significantly higher in the syncytiotrophoblast of FGR placentas compared to both full-term and pre-term controls (p < 0.05). |
| Castillo-Castrejon et al. (28) | 2021 | n = 18 (T2DM, n = 9; NGT, n = 9) | T2DM | Protein expression: WB in isolated MVM and BM fractions System A transporter activity: Na+-dependent 14C-MeAIB uptake in isolated MVM vesicles |
SLC38A1 (SNAT1), SLC38A2 (SNAT2), SLC38A4 (SNAT4), SLC7A5 (LAT1), SLC7A8 (LAT2) | 1. SNAT1 and SNAT2 expression in the MVM was significantly increased among T2DM women (+26%, p=0.05, +47%, p=0.01, respectively) when compared to NGT. 2. No differences in SNAT4 expression in the MVM between both groups were noted. 3. LAT1 and LAT2 expression in the MVM was significantly increased in T2DM women (+27%, p=0.01; +59%, p=0.01, respectively) when compared to NGT. No differences in transporters expression in BM were noted. 4. SNAT1 expression in the MVM of T2DM women was positively associated with FBW (r = 0.84, p = 0.004), but not with neonatal fat mass. 5. SNAT2 expression in the MVM was not correlated with FBW or fat mass in neonates born to T2DM women. 6. SNAT4 expression in the MVM was negatively correlated with FBW in NGT (r =− 0.72, p = 0.02) and T2DM women (r = − 0.71, p = 0.01), but not with neonatal adiposity. 7. LAT1 expression in the T2DM group correlated with FBW (r = 0.59, p = 0.04) and neonatal fat mass (r = 0.76, p = 0.06). 8. LAT2 expression was not correlated with FBW nor neonatal fat mass. |
| Chen et al. (29) | 2015 | n = 48 (SGA, n = 16; LGA, n = 14; AGA, n = 17) | SGA, LGA | Protein expression: WB in total placental tissue | SLC38A1 (SNAT1), SLC38A2 (SNAT2), SLC38A4 (SNAT4), SLC7A5 (LAT1), SLC7A8 (LAT2) | 1. Protein expression of LAT1 and LAT2 was significantly lower in the SGA group compared to the AGA and LGA groups (p < 0.01). 2. LAT 1 and LAT 2 expression was positively correlated with the FBW in total study population (p < 0.01). 3. The expression levels of System A transporters (SNAT1, SNAT2, and SNAT4) did not differ significantly between the groups. |
| Chen et al. (30) | 2015 | n = 44 (pre-term FGR, n = 14; term FGR, n = 11; preterm control, n = 12; term control, n = 7) | FGR | Protein expression: WB in total placental homogenates and isolated MVM fractions System A transporter activity: 14C-MeAIB uptake in isolated MVM vesicles using rapid filtration |
System A, SLC38A1 (SNAT1), SLC38A2 (SNAT2) | 1. Protein expression of SNAT-1 and SNAT-2 was significantly decreased in the MVM of FGR placentas (–42%, p < 0.05; –31%, p < 0.05, respectively). 2. No significant change could be observed in the expression of the SNAT-4 isoform. 3. MVM System A activity was significantly lower in the FGR cohort (76.5 ± 14.9 pmol/mg × 30 s) compared to the control group (271.1 ± 33.3 pmol/mg × 30 s), representing a 72% reduction (p < 0.0001). 4. The regression analysis indicated a strong positive correlation between gestational age and System A activity within the FGR group (r = 0.79, p < 0.001). |
| Glazier et al. (31) | 1997 | n = 26 (FGR, n = 16, AGA, n = 10) | FGR | System A transporter activity: radiolabeled substrate uptake assays in isolated MVM vesicles | System A (SLC38 family) | 1. In the FGR group System A activity in MVM vesicles was decreased compared to AGA controls (0.026 ± 0.004 vs. 0.053 ± 0.005 nmol/mg protein/30 s; p < 0.001). 2. System A activity showed severity-dependent impairment: levels were preserved in mild FGR but significantly reduced in severe phenotypes. |
| Harrington et al. (32) | 1999 | n = 49 (SGA, n = 25; AGA, n = 24) | SGA | System A transporter activity: radiolabeled substrate uptake assays in isolated MVM vesicles | System A (SLC38 family) | 1. System A activity was significantly lower in MVM vesicles from SGA placentas compared to AGA (p = 0.006). 2. In the SGA group System A activity correlated positively with FBW, neonatal subscapular and triceps skin-fold thickness (r = 0.48, p < 0.05; r = 0.42, p < 0.05, respectively), and PW (r = 0.42, p < 0.05). |
| Huang et al. (33) | 2018 | n = 43 (FGR, n = 8; PE, n = 5; PE + FGR, n = 10 and controls - term, n = 13; preterm, n = 7) | FGR | Protein expression: WB in total tissue lysates and isolated membrane fractions | SLC7A7 (y+LAT1), SLC38A5 (SNAT5) | 1. The expression of SNAT5 in FGR (+/- PE) placentas was unaltered. 2. y+LAT1 transporter was found to be significantly down-regulated in FGR placentas (p < 0.05). 3. y+LAT1 transporter was significantly up-regulated in PE+FGR and PE placentas (p < 0.05). |
| Jansson et al. (34) | 1998 | n = 14 (FGR, n = 8; control, n = 6) | FGR | System L transporter activity: radiolabeled substrate uptake assays in isolated MVM and BM vesicles | System L (SLC38 family) | 1. System L activity was significantly reduced in FGR, in both the syncytial MVM (-46%, p < 0.05) and BM (-38%, p < 0.05). |
| Jansson et al. (35) | 2002a | n = 84 (T1DM, n = 8; T1DM/LGA, n = 13; GDM, n = 10; GDM/LGA, n = 10; LGA, n = 8; NGT, n = 35) | T1DM, GDM, LGA | System A and System L transporter activity: radiolabeled substrates (14C-MeAIB and 3H-leucine) uptake in isolated MVM and BM fractions and rapid filtration techniques | System A (SLC38 family) and System L (SLC7 family) | 1. System A activity in MVM was significantly increased (65–80%, p < 0.05) in all groups with diabetes independent of fetal overgrowth. 2. MVM System A activity was unaffected in placentas of non-diabetic pregnancies with LGA fetuses and controls. 3. System L activity was increased in GDM women delivering LGA neonates (p < 0.05). 4. No differences in the activity of System A and System L in the syncytial BM were observed. |
| Jansson et al. (36) | 2002b | n = 36 (preterm FGR, n = 8; term FGR, n = 11; preterm controls, = 8; term controls, n = 9) | FGR | System A transporter activity: Na+-dependent uptake of 14C-MeAIB in isolated MVM and BM vesicles | System A (SLC38 family) | 1. System A activity in MVM was reduced by 50% in the preterm FGR cohort in comparison with the preterm controls (p < 0.05). 2. No significant change for MVM System A activity was reported in the term FGR group compared to gestational age-matched controls. 3. MVM System A activity was positively correlated with gestational age in both FGR cohorts (r = 0.74, p < 0.01). No such association was reported for the controls. 4. System A activity in BM was not altered in FGR cohorts. |
| Kadife et al. (37) | 2022 | n = 119 (early preterm <34 weeks of gestation: PE + FGR, n = 22; FGR, n = 13; preterm controls, n = 20 and late preterm 34–36 weeks: PE + FGR, n = 11; FGR, n = 29; preterm controls, n = 24) | FGR | Protein expression: WB in total placental tissue | SLC38A1 (SNAT1), SLC38A4 (SNAT4) | 1. Significantly lower SNAT4 expression was observed in early preterm FGR (+/- PE) as compared to controls (p < 0.01). 2. SNAT4 expression remained unaltered in late preterm cohorts. 3. SNAT1 levels showed no significant differences across early and late preterm cohorts. |
| Kuruvilla et al. (38) | 1994 | n = 43 (DM with AGA, n = 12; DM with fetal macrosomia, n = 13; controls without fetal macrosomia, n = 18) | T1DM, GDM, fetal macrosomia | System A and System L transporter activity: Na+-dependent 14C-MeAIB and 14C-leucine uptake in isolated MVM vesicles | System A (SLC38 family) and System L (SLC7 family) | 1. System A transporter activity was 49% lower in DM –associated fetal macrosomia compared to non-diabetic controls (p < 0.02). 2. No significant difference in System A activity between DM-AGA and control cohorts was noted. 3. No significant difference regarding the activity of system L between the subgroups was observed. |
| Li et al. (39) | 2011 | n = 52 (fetal macrosomia >4000g; n = 20; low birth weight <2500g, n = 22; normal birth weight 2500-4000g, n = 10) | fetal macrosomia | Protein expression: WB in total placental tissue System A transporter activity: isotope incorporation assay measuring 3H-proline uptake in placental villous fragments |
System A (SLC38 family), SLC38A4 (SNAT4) | 1. SNAT4 expression in the fetal macrosomia group was significantly higher compared to the normal birth weight cohort (p < 0.05). 2. System A activity in the macrosomia group was increased (1.2 ± 0.20 vs. 1.0 ± 0.18; p < 0.05), compared to the normal birth weight cohort. |
| Mahendran et al. (40) | 1993 | n = 32 (SGA, n = 14; AGA controls, n = 18) | SGA | System A transporter activity: Na+-dependent 14C-MeAIB uptake in isolated MVM vesicles | System A (SLC38 family) | 1. System A activity was significantly lower (63% reduction) in SGA vesicles (p < 0.001). 2. Vmax of the amino acid transfer was significantly reduced (p < 0.001), with no change in transporter affinity (Km). |
| Sakuragi et al. (41) | 2024 | n =101 (GI, n = 61; non-GI, n = 40) | T2DM, GDM, overt DM, LGA | Protein expression: IHC of formalin-fixed, paraffin-embedded placental tissue + image analysis software | SLC38A1 (SNAT1), SLC7A5 (LAT1) | 1. The per villus unit expression (density) level of SNAT1 was significantly lower in the GI group than in the non-GI group [0.59 (0.48-0.80) vs. 0.76 (0.62-0.81), p= 0.003. 2. No statistically significant difference for LAT1 was found [0.55 (0.51-0.61 vs. 0.58 (0.54-0.62), p = 0.20). 3. The per placental unit (total) expression levels of both SNAT1 and LAT1 were significantly higher in the GI group compared to the non-GI cohort (both p < 0.001). 4. SNAT1 and LAT1 expression was significantly increased in the GI/LGA group compared to the non-GI/non-LGA cohort (both p < 0.001). |
| Shang et al. (42) | 2018 | n = 50 (GDM, n = 50, including: fetal macrosomia, n = 23; normal weight infants, n = 27) | GDM, macrosomia | Protein expression: WB in total placental tissue | SLC38A1 (SNAT1), SLC38A2 (SNAT2), SLC38A4 (SNAT4) | 1. Placental expression of SNAT1 was significantly higher in fetal macrosomia compared to normal weight controls (0.29 ± 0.11, p < 0.05). No differences for SNAT2 (0.34 ± 0.15 vs. 0.30 ± 0.19) and SNAT4 expression (0.29 ± 0.09 vs. 0.31 + 0.16) were found. 2. The expression of SNAT1 was positively correlated with FBW (p < 0.05). |
| Shibata et al. (19) | 2008 | n = 29 (SGA, n = 5; PE + SGA, n = 5; PE, n = 10; controls, n = 9) | SGA | System A transporter activity: Na+-dependent 14C-MeAIB uptake in isolated placental villous tissue | System A (SLC38 family) | 1. System A activity was significantly reduced in SGA placentas without PE compared to normal controls (p < 0.001). 2. System A activity was unaltered in pregnancies with PE + SGA. |
AGA, appropriate for gestational age; BM, basal membrane; DM, diabetes mellitus; FBW, fetal birth weight; FGR, fetal growth restriction; GDM, gestational diabetes mellitus; GI, glucose intolerance; IHC, immunohistochemistry; LAT1, L-type amino acid transporter 1; LAT2, L-type amino acid transporter 2; LGA, large for gestational age; MeAIB - [11C] methyl alpha-aminoisobutyric acid; MVM, microvillous membrane; NGT, normoglycemic controls; PE, preeclampsia; PW, placental weight; SGA, small for gestational age; SLC, solute carrier; SNAT1, sodium-coupled neutral amino acid transporter 1; SNAT2, sodium-coupled neutral amino acid transporter 2; SNAT4, sodium-coupled neutral amino acid transporter 4; SNAT5, sodium-coupled neutral amino acid transporter 5; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; y+LAT1, y+ L-type amino acid transporter; WB, Western blot.