Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.

Regulation of glucose transporter translocation in health and diabetes.

To enhance glucose uptake into muscle and fat cells, insulin stimulates the translocation of GLUT4 glucose transporters from intracellular membranes to the cell surface. This response requires the intersection of insulin signaling and vesicle trafficking pathways, and it is compromised in the setting of overnutrition to cause insulin resistance. Insulin signals through AS160/Tbc1D4 and Tbc1D1 to modulate Rab GTPases and through the Rho GTPase TC10α to act on other targets. In unstimulated cells, GLUT4 is incorporated into specialized storage vesicles containing IRAP, LRP1, sortilin, and VAMP2, which are sequestered by TUG, Ubc9, and other proteins. Insulin mobilizes these vesicles directly to the plasma membrane, and it modulates the trafficking itinerary so that cargo recycles from endosomes during ongoing insulin exposure. Knowledge of how signaling and trafficking pathways are coordinated will be essential to understanding the pathogenesis of diabetes and the metabolic syndrome and may also inform a wide range of other physiologies.

Gut bacteria are essential for development of an invasive bark beetle by regulating glucose transport.

Insects and their gut bacteria form a tight and beneficial relationship, especially in utilization of host nutrients. The red turpentine beetle (RTB), a destructive and invasive pine pest, employs mutualistic microbes to facilitate its invasion success. However, the molecular mechanism underlying the utilization of nutrients remains unknown. In this study, we found that gut bacteria are crucial for the utilization of D-glucose, a main carbon source for RTB development. Downstream assays revealed that gut bacteria-induced gut hypoxia and the secretion of riboflavin are responsible for RTB development by regulating D-glucose transport via the activation of a hypoxia-induced transcription factor 1 (Hif-1α). Further functional investigations confirmed that Hif-1α mediates glucose transport by direct upregulation of two glucose transporters (ST10 and ST27), thereby promoting RTB development. Our findings reveal how gut bacteria regulate the development of RTB, and promote our understanding of the mutualistic relationship of animals and their gut bacteria.

The molecular basis for sugar import in malaria parasites.

Elucidating the mechanism of sugar import requires a molecular understanding of how transporters couple sugar binding and gating events. Whereas mammalian glucose transporters (GLUTs) are specialists1, the hexose transporter from the malaria parasite Plasmodium falciparum PfHT12,3 has acquired the ability to transport both glucose and fructose sugars as efficiently as the dedicated glucose (GLUT3) and fructose (GLUT5) transporters. Here, to establish the molecular basis of sugar promiscuity in malaria parasites, we determined the crystal structure of PfHT1 in complex with D-glucose at a resolution of 3.6 Å. We found that the sugar-binding site in PfHT1 is very similar to those of the distantly related GLUT3 and GLUT5 structures4,5. Nevertheless, engineered PfHT1 mutations made to match GLUT sugar-binding sites did not shift sugar preferences. The extracellular substrate-gating helix TM7b in PfHT1 was positioned in a fully occluded conformation, providing a unique glimpse into how sugar binding and gating are coupled. We determined that polar contacts between TM7b and TM1 (located about 15 Å from D-glucose) are just as critical for transport as the residues that directly coordinate D-glucose, which demonstrates a strong allosteric coupling between sugar binding and gating. We conclude that PfHT1 has achieved substrate promiscuity not by modifying its sugar-binding site, but instead by evolving substrate-gating dynamics.

2-deoxyglucose transiently inhibits yeast AMPK signaling and triggers glucose transporter endocytosis, potentiating the drug toxicity.

2-deoxyglucose is a glucose analog that impacts many aspects of cellular physiology. After its uptake and its phosphorylation into 2-deoxyglucose-6-phosphate (2DG6P), it interferes with several metabolic pathways including glycolysis and protein N-glycosylation. Despite this systemic effect, resistance can arise through strategies that are only partially understood. In yeast, 2DG resistance is often associated with mutations causing increased activity of the yeast 5'-AMP activated protein kinase (AMPK), Snf1. Here we focus on the contribution of a Snf1 substrate in 2DG resistance, namely the alpha-arrestin Rod1 involved in nutrient transporter endocytosis. We report that 2DG triggers the endocytosis of many plasma membrane proteins, mostly in a Rod1-dependent manner. Rod1 participates in 2DG-induced endocytosis because 2DG, following its phosphorylation by hexokinase Hxk2, triggers changes in Rod1 post-translational modifications and promotes its function in endocytosis. Mechanistically, this is explained by a transient, 2DG-induced inactivation of Snf1/AMPK by protein phosphatase 1 (PP1). We show that 2DG-induced endocytosis is detrimental to cells, and the lack of Rod1 counteracts this process by stabilizing glucose transporters at the plasma membrane. This facilitates glucose uptake, which may help override the metabolic blockade caused by 2DG, and 2DG export-thus terminating the process of 2DG detoxification. Altogether, these results shed a new light on the regulation of AMPK signaling in yeast and highlight a remarkable strategy to bypass 2DG toxicity involving glucose transporter regulation.

Drosophila transmembrane protein 214 (dTMEM214) regulates midgut glucose uptake and systemic glucose homeostasis.

The availability of glucose transporter in the small intestine critically determines the capacity for glucose uptake and consequently systemic glucose homeostasis. Hence a better understanding of the physiological regulation of intestinal glucose transporter is pertinent. However, the molecular mechanisms that regulate sodium-glucose linked transporter 1 (SGLT1), the primary glucose transporter in the small intestine, remain incompletely understood. Recently, the Drosophila SLC5A5 (dSLC5A5) has been found to exhibit properties consistent with a dietary glucose transporter in the Drosophila midgut, the equivalence of the mammalian small intestine. Hence, the fly midgut could serve as a suitable model system for the study of the in vivo molecular underpinnings of SGLT1 function. Here, we report the identification, through a genetic screen, of Drosophila transmembrane protein 214 (dTMEM214) that acts in the midgut enterocytes to regulate systemic glucose homeostasis and glucose uptake. We show that dTMEM214 resides in the apical membrane and cytoplasm of the midgut enterocytes, and that the proper subcellular distribution of dTMEM214 in the enterocytes is regulated by the Rab4 GTPase. As a corollary, Rab4 loss-of-function phenocopies dTMEM214 loss-of-function in the midgut as shown by a decrease in enterocyte glucose uptake and an alteration in systemic glucose homeostasis. We further show that dTMEM214 regulates the apical membrane localization of dSLC5A5 in the enterocytes, thereby revealing dTMEM214 as a molecular regulator of glucose transporter in the midgut.

The novel chloroplast glucose transporter pGlcT2 affects adaptation to extended light periods.

Intracellular sugar compartmentation is critical in plant development and acclimation to challenging environmental conditions. Sugar transport proteins are present in plasma membranes and in membranes of organelles such as vacuoles, the Golgi apparatus, and plastids. However, there may exist other transport proteins with uncharacterized roles in sugar compartmentation. Here we report one such novel transporter of the Monosaccharide Transporter Family, the closest phylogenetic homolog of which is the chloroplast-localized glucose transporter pGlcT and that we therefore term plastidic glucose transporter 2 (pGlcT2). We show, using gene-complemented glucose uptake deficiency of an Escherichia coli ptsG/manXYZ mutant strain and biochemical characterization, that this protein specifically facilitates glucose transport, whereas other sugars do not serve as substrates. In addition, we demonstrate pGlcT2-GFP localized to the chloroplast envelope and that pGlcT2 is mainly produced in seedlings and in the rosette center of mature Arabidopsis plants. Therefore, in conjunction with molecular and metabolic data, we propose pGlcT2 acts as a glucose importer that can limit cytosolic glucose availability in developing pGlcT2-overexpressing seedlings. Finally, we show both overexpression and deletion of pGlcT2 resulted in impaired growth efficiency under long day and continuous light conditions, suggesting pGlcT2 contributes to a release of glucose derived from starch mobilization late in the light phase. Together, these data indicate the facilitator pGlcT2 changes the direction in which it transports glucose during plant development and suggest the activity of pGlcT2 must be controlled spatially and temporarily in order to prevent developmental defects during adaptation to periods of extended light.

Glucose transporter GLUT1 expression is important for oriental river prawn (Macrobrachium nipponense) hemocyte adaptation to hypoxic conditions.

Crustaceans have an open vascular system in which hemocytes freely circulate in hemolymph. Hemocytes are rich in hemocyanin, a specific oxygen-transport protein in crustaceans; therefore, understanding the response of hemocytes to hypoxia is crucial. Although hemocytes take up glucose during hypoxia, the molecular mechanism of glucose uptake in crustaceans remains unclear. Herein, we identified two highly conserved glucose transporters (GLUT1 and GLUT2) in Macrobrachium nipponense (oriental river prawn) and analyzed their tissue-specific expression patterns. Our immunofluorescence assays showed that GLUT1 and GLUT2 are located on the cell membrane, with a strong GLUT1 signal in primary hemocytes under hypoxia. We found that during acute hypoxia, hypoxia-inducible factor-1α-related metabolic alterations result in decreased mitochondrial cytochrome c oxidase activity, implying a classic glycolytic mechanism. As a proof of concept, we replicated these findings in insect S2 cells. Acute hypoxia significantly induced hypoxia-inducible factor-1α, GLUT1, and pyruvate dehydrogenase kinase isozyme 1 expression in primary hemocytes, and hypoxia-induced increases in glucose uptake and lactate secretion were observed. GLUT1 knockdown induced intracellular reactive oxygen species generation and apoptosis in vitro and in vivo, resulting in increased prawn mortality and more apoptotic cells in their brains, implying a vital function of GLUT1 in hypoxia adaptation. Taken together, our results suggest a close relationship between hypoxia-mediated glycolysis and GLUT1 in hemocytes. These results demonstrated that in crustaceans, adaptation to hypoxia involves glucose metabolic plasticity.

Heparin and calreticulin interact on the surface of early G0/G1 dividing rat mesangial cells to regulate hyperglycemic glucose-induced responses.

Heparin can block pathological responses associated with diabetic nephropathy in animal models and human patients. Our previous studies showed that the interaction of heparin on the surface of rat mesangial cells (RMCs) entering G1 of cell division in hyperglycemic glucose: 1) blocked glucose uptake by glucose transporter 4; 2) inhibited cytosolic uridine diphosphate-glucose elevation that would occur within 6 h from G0/G1; and 3) prevented subsequent activation of hyaluronan synthesis in intracellular compartments and subsequent inflammatory responses. However, specific proteins that interact with heparin are unresolved. Here, we showed by live cell imaging that fluorescent heparin was rapidly internalized into the cytoplasm and then into the endoplasmic reticulum, Golgi, and nuclei compartments. Biotinylated-heparin was applied onto the surface of growth arrested G0/G1 RMCs in order to extract heparin-binding protein(s). SDS-PAGE gels showed two bands at ∼70 kDa in the extract that were absent when unlabeled heparin was used to compete. Trypsin digests of the bands were analyzed by MS and identified as calreticulin and prelamin A/C. Immunostaining with their antibodies identified the presence of calreticulin on the G0/G1 RMC cell surface. Previous studies have shown that calreticulin can be on the cell surface and can interact with the LDL receptor-related protein, which has been implicated in glucose transport by interaction with glucose transporter 4. Thus, cell surface calreticulin can act as a heparin receptor through a mechanism involving LRP1, which prevents the intracellular responses in high glucose and reprograms the cells to synthesize an extracellular hyaluronan matrix after division.

SGLT2 inhibitor dapagliflozin protects the kidney in a murine model of Balkan nephropathy.

Proximal tubular uptake of aristolochic acid (AA) forms aristolactam (AL)-DNA adducts, which cause a p53/p21-mediated DNA damage response and acute tubular injury. Recurrent AA exposure causes kidney function loss and fibrosis in humans (Balkan endemic nephropathy) and mice and is a model of (acute kidney injury) AKI to chronic kidney disease (CKD) transition. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. C57BL/6J mice (15-wk-old) were administered vehicle or AA every 3 days for 3 wk (10 and 3 mg/kg ip in females and males, respectively). Dapagliflozin (dapa, 0.01 g/kg diet) or vehicle was initiated 7 days prior to AA injections. All dapa effects were sex independent, including a robust glycosuria. Dapa lowered urinary kidney-injury molecule 1 (KIM-1) and albumin (both normalized to creatinine) after the last AA injection and kidney mRNA expression of early DNA damage response markers (p53 and p21) 3 wk later at the study end. Dapa also attenuated AA-induced increases in plasma creatinine as well as AA-induced up-regulation of renal pro-senescence, pro-inflammatory and pro-fibrotic genes, and kidney collagen staining. When assessed 1 day after a single AA injection, dapa pretreatment attenuated AL-DNA adduct formation by 10 and 20% in kidney and liver, respectively, associated with reduced p21 expression. Initiating dapa application after the last AA injection also improved kidney outcome but in a less robust manner. In conclusion, the first evidence is presented that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.NEW & NOTEWORTHY Recurrent exposure to aristolochic acid (AA) causes kidney function loss and fibrosis in mice and in humans, e.g., in the form of the endemic Balkan nephropathy. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. Here we provide the first evidence in a murine model that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.

Revisiting the roles of glucose transporters in skeletal muscle physiology: is GLUT10 a novel player?

Skeletal muscle is the largest metabolic tissue responsible for systemic glucose handling. Glucose uptake into skeletal tissue is highly dynamic and delicately regulated, in part through the controlled expression and subcellular trafficking of multiple types of glucose transporters. Although the roles of GLUT4 in skeletal muscle metabolism are well established, the physiological significance of other, seemingly redundant, glucose transporters remain incompletely understood. Nonetheless, recent studies have shed light on the roles of several glucose transporters, such as GLUT1 and GLUT10, in skeletal muscle. Mice experiments suggest that GLUT10 could be a novel player in skeletal muscle metabolism in the context of mechanical overload, which is in line with the meta-analytical results of gene expression changes after resistance exercise in humans. Herein we discuss the knowns, unknowns, and implications of these recent findings.

Predictors of efficacy of Sodium-GLucose Transporter-2 inhibitors and Glucagon-Like Peptide 1 receptor agonists: A retrospective cohort study.

AIMS: The aim of the present study was to verify predictors of HbA1c reduction with Sodium-GLucose Transporter-2 (SGLT2) inhibitors and Glucagon-Like Peptide 1 (GLP1) receptor agonists in routine clinical practice. MATERIALS AND METHODS: A retrospective cohort study was performed, enrolling patients with type 2 diabetes aged ≥18 years who received a prescription of an SGLT2 inhibitor or a long-acting GLP1 receptor agonist with at least 6 months of persistence in therapy. Therapeutic success was defined as HbA1c reduction >10 mmol/mol or attainment of the recommended HbA1c target. RESULTS: Out of 236 patients receiving SGLT2 inhibitors, 148 were categorised as successes: successes had a mean lower age and higher estimated Glomerular Filtration Rate than failures, but only age retained statistical significance at multivariate analysis (Odds Ratio with 95% confidence interval: 0.94 [0.91-0.98], p = 0.006). In the GLP1 receptor agonists cohort (N = 214) there were 146 successes, showing a significantly shorter duration of diabetes even after adjusting for age, and baseline HbA1c (HR 0.96 [0.91-0.99], p = 0.02). CONCLUSIONS: The present study is a preliminary exploration of factors associated with HbA1c response to SGLT2 inhibitors and GLP1 receptor agonists. Differences in predictors of HbA1c changes across different classes of drugs could be useful in identifying the most suitable drug in individual patients. SGLT2 inhibitors seem to be associated with a greater reduction of HbA1c in younger subjects, and GLP1 agonists in those with a shorter duration of diabetes.

Evolutionary balance between foldability and functionality of a glucose transporter.

Despite advances in resolving the structures of multi-pass membrane proteins, little is known about the native folding pathways of these complex structures. Using single-molecule magnetic tweezers, we here report a folding pathway of purified human glucose transporter 3 (GLUT3) reconstituted within synthetic lipid bilayers. The N-terminal major facilitator superfamily (MFS) fold strictly forms first, serving as a structural template for its C-terminal counterpart. We found polar residues comprising the conduit for glucose molecules present major folding challenges. The endoplasmic reticulum membrane protein complex facilitates insertion of these hydrophilic transmembrane helices, thrusting GLUT3's microstate sampling toward folded structures. Final assembly between the N- and C-terminal MFS folds depends on specific lipids that ease desolvation of the lipid shells surrounding the domain interfaces. Sequence analysis suggests that this asymmetric folding propensity across the N- and C-terminal MFS folds prevails for metazoan sugar porters, revealing evolutionary conflicts between foldability and functionality faced by many multi-pass membrane proteins.

Target Separation and Potential Anticancer Activity of Withanolide-Based Glucose Transporter Protein 1 Inhibitors from Physalis angulata var. villosa.

The glucose transporter 1 (GLUT1) protein is involved in the basal-level absorption of glucose in tumor cells. Inhibiting GLUT1 decreases tumor cell proliferation and induces tumor cell damage. Natural GLUT1 inhibitors have been studied only to a small extent, and the structures of known natural GLUT1 inhibitors are limited to a few classes of natural products. Therefore, discovering and researching other natural GLUT1 inhibitors with novel scaffolds are essential. Physalis angulata L. var. villosa is a plant known as Mao-Ku-Zhi (MKZ). Withanolides are the main phytochemical components of MKZ. MKZ extracts and the components of MKZ exhibited antitumor activity in recent pharmacological studies. However, the antitumor-active components of MKZ and their molecular mechanisms remain unknown. A cell membrane-biomimetic nanoplatform (CM@Fe3O4/MIL-101) was used for target separation of potential GLUT1 inhibitors from MKZ. A new withanolide, physagulide Y (2), together with six known withanolides (1, 3-7), was identified as a potential GLUT1 inhibitor. Physagulide Y was the most potent GLUT1 inhibitor, and its antitumor activity and possible mechanism of action were explored in MCF-7 human cancer cells. These findings advance the development of technologies for the targeted separation of natural products and identify a new molecular framework for the investigation of natural GLUT1 inhibitors.

Hypoxia promotes the growth and metastasis of ovarian cancer cells by suppressing ferroptosis via upregulating SLC2A12.

BACKGROUND: Ovarian cancer has been a worldwide health burden for women and its progression is highly hypoxia-independent. Here, we investigated the exact mechanisms by which hypoxia contributes to the malignant progression of ovarian cancer. METHOD: MTT, transwell, colony formation, and scratch wound healing assays were carried out for cellular functions. The underlying mechanism by which hypoxia functions was explored by RNA-seq, enrichment analysis, western blotting, qRT-PCR, flow cytometry, ChIP, luciferase reporter, and ELISA. Finally, animal experiments including the xenograft model and tumor metastasis model were constructed to validate the role of SLC2A12 in vivo. RESULTS: Hypoxia treatment promoted the cell proliferation, mobility, and colony growth abilities of the two ovarian cancer cell lines HO-8910 and A2780. RNA-seq and enrichment analysis showed that SLC2A12 was hyper-expressed under hypoxia condition and it may be related to glutathione and lipid metabolism. Besides, the expression of SLC2A12 was negatively correlated with overall survival. Hypoxia suppressed ferroptosis by SLC2A12 because silencing SLC2A12 declined the cell viability of HO-8910 and A2780 cells under hypoxia conditions, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) breached that result and upregulated the expression of glutathione peroxidase 4 (GPX4). Moreover, hypoxia increased the expression of hypoxia inducible factor 1 A (HIF-1A), and the accumulated HIF-1A binds to hypoxia inducible factor 1 B (HIF1B) to form HIF-1 complex, then promoted the binding of hypoxic response elements (HRE) to SLC2A12 promoter by HIF-1/HRE signal. Subsequently, SLC2A12 regulated glutathione metabolism and in turn inhibited ferroptosis. The animal experiments indicated that silencing SLC2A12 could significantly inhibit tumor growth and metastasis in vivo. CONCLUSION: Hypoxia promoted ovarian cancer progression by upregulating SLC2A12 and then regulating glutathione metabolism to inhibit ferroptosis.

Brain energetics and glucose transport in metabolic diseases: role in neurodegeneration.

OBJECTIVES: Neurons and glial cells are the main functional and structural elements of the brain, and the former depends on the latter for their nutritional, functional and structural organization, as well as for their energy maintenance. METHODS: Glucose is the main metabolic source that fulfills energetic demands, either by direct anaplerosis or through its conversion to metabolic intermediates. Development of some neurodegenerative diseases have been related with modifications in the expression and/or function of glial glucose transporters, which might cause physiological and/or pathological disturbances of brain metabolism. In the present contribution, we summarized the experimental findings that describe the exquisite adjustment in expression and function of glial glucose transporters from physiologic to pathologic metabolism, and its relevance to neurodegenerative diseases. RESULTS: A exhaustive literature review was done in order to gain insight into the role of brain energetics in neurodegenerative disease. This study made evident a critical involvement of glucose transporters and thus brain energetics in the development of neurodegenerative diseases. DISCUSSION: An exquisite adjustment in the expression and function of glial glucose transporters from physiologic to pathologic metabolism is a biochemical signature of neurodegenerative diseases.

Comment on, "Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat".

Wu et al. (2021) investigated the neuroprotective effects of hypoxia preconditioning (HPC) in a rat model of traumatic brain injury (TBI). The study demonstrated that HPC enhances brain resilience to TBI by upregulating glucose transporters GLUT1 and GLUT3 through the HIF-1α signaling pathway. Comprehensive molecular and histological analyses confirmed increased expression of these transporters, correlating with reduced neuronal apoptosis and cerebral edema. The robust methodology, including rigorous statistical validation and time-course assessments, underscores HPC's potential therapeutic role in mitigating neuronal loss and improving glucose transport post-injury. However, the study could be strengthened by incorporating additional preconditioning controls, comparative analyses with other neuroprotective strategies, and exploring downstream metabolic effects in greater detail. Furthermore, expanding the research to include diverse animal models and examining sex-dependent responses would enhance the generalizability and translational relevance of the findings. Future studies should also integrate metabolic flux analysis and advanced imaging techniques to further elucidate HPC's mechanisms of action.

The genetics and evolution of eye color in domestic pigeons (Columba livia).

The eye color of birds, generally referring to the color of the iris, results from both pigmentation and structural coloration. Avian iris colors exhibit striking interspecific and intraspecific variations that correspond to unique evolutionary and ecological histories. Here, we identified the genetic basis of pearl (white) iris color in domestic pigeons (Columba livia) to explore the largely unknown genetic mechanism underlying the evolution of avian iris coloration. Using a genome-wide association study (GWAS) approach in 92 pigeons, we mapped the pearl iris trait to a 9 kb region containing the facilitative glucose transporter gene SLC2A11B. A nonsense mutation (W49X) leading to a premature stop codon in SLC2A11B was identified as the causal variant. Transcriptome analysis suggested that SLC2A11B loss of function may downregulate the xanthophore-differentiation gene CSF1R and the key pteridine biosynthesis gene GCH1, thus resulting in the pearl iris phenotype. Coalescence and phylogenetic analyses indicated that the mutation originated approximately 5,400 years ago, coinciding with the onset of pigeon domestication, while positive selection was likely associated with artificial breeding. Within Aves, potentially impaired SLC2A11B was found in six species from six distinct lineages, four of which associated with their signature brown or blue eyes and lack of pteridine. Analysis of vertebrate SLC2A11B orthologs revealed relaxed selection in the avian clade, consistent with the scenario that during and after avian divergence from the reptilian ancestor, the SLC2A11B-involved development of dermal chromatophores likely degenerated in the presence of feather coverage. Our findings provide new insight into the mechanism of avian iris color variations and the evolution of pigmentation in vertebrates.

Molecular parallelisms between pigmentation in the avian iris and the integument of ectothermic vertebrates.

Birds exhibit striking variation in eye color that arises from interactions between specialized pigment cells named chromatophores. The types of chromatophores present in the avian iris are lacking from the integument of birds or mammals, but are remarkably similar to those found in the skin of ectothermic vertebrates. To investigate molecular mechanisms associated with eye coloration in birds, we took advantage of a Mendelian mutation found in domestic pigeons that alters the deposition of yellow pterin pigments in the iris. Using a combination of genome-wide association analysis and linkage information in pedigrees, we mapped variation in eye coloration in pigeons to a small genomic region of ~8.5kb. This interval contained a single gene, SLC2A11B, which has been previously implicated in skin pigmentation and chromatophore differentiation in fish. Loss of yellow pigmentation is likely caused by a point mutation that introduces a premature STOP codon and leads to lower expression of SLC2A11B through nonsense-mediated mRNA decay. There were no substantial changes in overall gene expression profiles between both iris types as well as in genes directly associated with pterin metabolism and/or chromatophore differentiation. Our findings demonstrate that SLC2A11B is required for the expression of pterin-based pigmentation in the avian iris. They further highlight common molecular mechanisms underlying the production of coloration in the iris of birds and skin of ectothermic vertebrates.

Opisthorchis viverrini excretory-secretory products suppress GLUT8 of cholangiocytes.

Opisthorchis viverrini infection and the subsequent bile duct cancer it induces remains a significant public health problem in Southeast Asia. Opisthorchiasis has been reported to cause reduced plasma glucose levels among infected patients. The underlying mechanism for this phenomenon is unclear. In the present study, evidence is presented to support the hypothesis that O. viverrini exploits host cholangiocyte glucose transporters (GLUTs) in a similar manner to that of rodent intestinal nematodes, to feed on unabsorbed glucose in the bile for survival. GLUT levels in a cholangiocyte H69 cell line co-cultured with excretory-secretory products of O. viverrini were examined using qPCR and immunoblotting. GLUT 8 mRNA and expressed proteins were found to be downregulated in H69 cells in the presence of O. viverrini. This suggests that O. viverrini alters glucose metabolism in cells within its vicinity by limiting transporter expression resulting in increased bile glucose that it can utilize and potentially explains the previously reported anti-insulin effect of opisthorchiasis.