Functional Characterization of the Novel and Specific Thyroid Hormone Transporter SLC17A4.

Background: A recent genome-wide association study identified the SLC17A4 locus associated with circulating free thyroxine (T4) concentrations. Human SLC17A4, being widely expressed in the gastrointestinal tract, was characterized as a novel triiodothyronine (T3) and T4 transporter. However, apart from the cellular uptake of T3 and T4, transporter characteristics are currently unknown. In this study, we delineated basic transporter characteristics of this novel thyroid hormone (TH) transporter. Methods: We performed a broad range of well-established TH transport studies in COS-1 cells transiently overexpressing SLC17A4. We studied cellular TH uptake in various incubation buffers, TH efflux, and the inhibitory effects of different TH metabolites and known inhibitors of other TH transporters on SLC17A4-mediated TH transport. Finally, we determined the effect of tunicamycin, a pharmacological inhibitor of N-linked glycosylation, and targeted mutations in Asn residues on SLC17A4 function. Results: SLC17A4 induced the cellular uptake of T3 and T4 by ∼4 times, and of reverse (r)T3 by 1.5 times over control cells. The uptake of T4 by SLC17A4 was Na+ and Cl- independent, stimulated by low extracellular pH, and reduced by various iodothyronines and metabolites thereof, particularly those that contain at least three iodine moieties irrespective of the presence of modification at the alanine side chain. None of the classical TH transporter inhibitors studied attenuated SLC17A4-mediated TH transport. SLC17A4 also facilitates the efflux of T3 and T4, and to a lesser extent of 3,3'-diiodothyronine (T2). Immunoblot studies on lysates of transfected cells cultured in absence or presence of tunicamycin indicated that SLC17A4 is subject to N-linked glycosylation. Complementary mutational studies identified Asn66, Asn75, and Asn90, which are located in extracellular loop 1, as primary targets. Conclusions: Our studies show that SLC17A4 facilitates the transport of T3 and T4, and less efficiently rT3 and 3,3'-T2. Further studies should reveal the physiological role of SLC17A4 in TH regulation.

GDF-15 Suppresses Atherosclerosis by Inhibiting oxLDL-Induced Lipid Accumulation and Inflammation in Macrophages.

The growth differentiation factor-15 (GDF-15) may be involved in atherosclerosis. However, the role of GDF-15 in atherosclerosis remains unclear. The main goal of this study was to verify the role and mechanism of GDF-15 in atherogenesis. We first compared the serum GDF-15 level between patients with coronary atherosclerosis and healthy people. And then one ApoE-/- mouse model of atherosclerosis was used to explore the effects of GDF-15 on oxidized low-density lipoprotein (oxLDL) accumulation, atherosclerosis-related gene expression, and lipid accumulation-related protein expression in mouse macrophages. As a result, the level of serum GDF-15 in patients with coronary atherosclerosis was significantly higher than that in healthy people. In the mouse model, GDF-15 expression was elevated in the core of plaque, and it was secreted mainly by the macrophages. In addition, GDF-15 decreased oxLDL-induced lipid accumulation and inflammation activation in macrophages. GDF-15 decreased the mRNA expressions of CD36, LOX1, and TLR4 that are associated with lipoprotein accumulation in macrophages. Further study showed that GDF-15 might suppress oxLDL-induced lipoprotein accumulation via inhibiting CD36 and LOX1 and decrease inflammation in macrophages by inhibiting TLR4. Thus, GDF-15 may suppress atherosclerosis and plaque formation by inhibiting lipoprotein accumulation and inflammation activation.

The biotransformation of soil phosphorus in the water level fluctuation zone could increase eutrophication in reservoirs.

The massive amounts of phosphorus (P) entering into rivers and reservoirs may induce eutrophication. However, the link between the transport and transformation of soil P and the dynamics of P availability in reservoir regions are not well demonstrated. The present study selected the Pengxi River suffering the anti-seasonal water level fluctuation of the Three Gorgers Reservoir as the study area. Soil nutrients along the longitudinal and lateral gradients of the Pengxi River were investigated to illustrate the spatial distribution patterns, analyzed by the Hedley extraction schemes. The effects of biotic and abiotic factors on soil P transformation and the dynamics of bioavailable P were evaluated via determinations of enzymatic hydrolysis phosphorus (EHP) with and without ultraviolet (UV) irradiation. The results indicated that soil nutrients varied significantly between the water level fluctuation zone (WLFZ) and upland along the river longitudinal gradients, where the trends of the extracted OP were the same in H2O, NaHCO3 and NaOH extractions. The EHP accounted for 33.67 ± 15.87% of the total extracted OP, of which Monoester P, Phytate-like P and NHOP were determined at all extracts but Diester P was mainly found at H2O and NaOH extracts. UV irradiation significantly increased P bioavailability up to 24.44%. These results could demonstrate the mechanism of soil P transformation via UV irradiation and enzymatic hydrolysis. Therefore, the bioavailable P enters the water body during the submergence period may lead to eutrophication in the Pengxi River, which could pose a risk to the reservoir ecosystem.

Response of dominant plant species to periodic flooding in the riparian zone of the Three Gorges Reservoir (TGR), China.

Human-induced disturbances such as dam construction and regulation often change the duration and frequency of flooding and thus notably influence plant dominance in riparian zones. Even though numerous studies have indicated that the oxidative stress and antioxidative stress systems are essential for plant defenses against adverse flooding stress, the mechanism of vegetation distribution due to hydrological regimes is still unclear. In the current study, the riparian zone of the Three Gorges Reservoir (TGR), which experiences seasonal and anti-seasonal water-level fluctuations, was used to investigate the dominant species. To our knowledge, this is the first study that links molecular-physiological-morphological mechanisms to explore the development of flooding tolerance of dominant riparian species. Physiological traits (e.g., chlorophyll and protein contents), morphological traits (e.g., leaf length), and molecular traits (e.g., enzymatic antioxidant activity and the malondialdehyde content) were analyzed at different water-level gradient zones of the dominant species to evaluate the influence of flooding. To explore the regulation mechanisms of submergence for the vegetation distribution, correlation analysis, PCA (principal component analysis) and laboratory flooding experiments were conducted. The results showed that Cynodon dactylon, which has a rapid antioxidative system, was the dominant species in the riparian zone of the TGR. The leaf length varied significantly along with water level gradients (p < 0.05) with the minimum values appearing in the lowest part of the riparian zone and the maximum values observed in the highest areas. The chlorophyll and protein contents fluctuated in different water level gradient zones, but significant differences were not observed. Within the antioxidative system, catalase was found to be essential for riparian plants in their response to flooding. The current study could provide insight to explore the specific mechanism of resistance for dominant plants to periodic flooding, and the reason why dominant species can survive adverse stress.