Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance. Li P et al. (2016) In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.//////////////////
NCBI Summary:
This gene encodes a member of the galectin family of carbohydrate binding proteins. Members of this protein family have an affinity for beta-galactosides. The encoded protein is characterized by an N-terminal proline-rich tandem repeat domain and a single C-terminal carbohydrate recognition domain. This protein can self-associate through the N-terminal domain allowing it to bind to multivalent saccharide ligands. This protein localizes to the extracellular matrix, the cytoplasm and the nucleus. This protein plays a role in numerous cellular functions including apoptosis, innate immunity, cell adhesion and T-cell regulation. The protein exhibits antimicrobial activity against bacteria and fungi. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2014]
General function
Ligand
Comment
Galectin-3 Contributes to Luteolysis by Binding to Beta 1 Integrin in the Bovine Corpus Luteum. Hashiba K 2014 et al.
Luteolysis is characterized by a reduction in progesterone (P4) production and tissue degeneration in the corpus luteum (CL). One of major events during luteolysis is luteal cell death. Galectin-3, a ubiquitously expressed protein involved in many cellular processes, serves as an anti-apoptotic and/or pro-apoptotic factor in various cell types. Although galectin-3 is detected in the bovine CL, its role remains unclear. The expression of galectin-3 in the bovine CL was higher at the regressed stage than at the other luteal stages. Galectin-3 was localized on luteal steroidogenic cells (LSCs). When cultured LSCs were exposed to prostaglandin F2alpha (PGF) for 48 h, the expression and secretion of galectin-3 increased. When the cultured LSCs were treated with galectin-3 for 24 h, cleaved caspase-3 expression was increased and the cell viability was decreased, whereas P4 production did not change. Beta 1 integrin, a target protein of galectin-3, was expressed in bovine CL and possessed glycans which galectin-3 binds. Furthermore, galectin-3 bound to glycans of luteal beta 1 integrin. The decreased cell viability of cultured LSCs by galectin-3 was suppressed by beta1 integrin antibody. The overall findings suggest that the secreted galectin-3 stimulated by PGF plays a role in structural luteolysis by binding to beta 1 integrin.
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Cellular localization
Secreted, Cytoplasmic, Plasma membrane, Nuclear
Comment
Galectin-3 is a potential biomarker to insulin resistance and obesity in women with polycystic ovary syndrome. Alves MT et al. (2020) Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder that affects women in reproductive age. This study aimed to evaluate Gal-3 levels and its role on metabolic parameters in women with PCOS. Gal-3 was measured in 44 PCOS and 25 women recruited as control group for the case-control study. Gal-3 levels were similar between PCOS and control groups (p > 0.05), but showed a positive correlation with glucose levels in the oral glucose tolerance test (OGTT) (r = 0.403, p = 0.037), body mass index (BMI) (r = 0.469, p = 0.027), insulin levels (r = 0.453, p = 0.030) and HOMA-IR (r = 0.738, p = 0.037) in PCOS group. The data suggest that Gal-3 plays a role in the pathophysiology of the insulin resistance and obesity in PCOS group./////////////////////////Galectin-3 as a novel biomarker in women with PCOS. Anik Ilhan G et al. (2018) This study aimed at evaluating galectin-3 levels as a novel metabolic biomarker in women with PCOS. Ninety consecutive women with PCOS fulfilling the inclusion criteria were divided into two groups according to the presence of metabolic syndrome as MetS+ and MetS-. Clinical, hormonal, and metabolic parameters and galectin-3 levels were compared between the groups. Correlation analyses were performed between galectin-3 and clinical and metabolic parameters. Ninety PCOS subjects were enrolled in the study, 25 of which were diagnosed with MetS. Waist-to-hip ratio, systolic and diastolic blood pressures, triglyceride, HOMA-IR, FAI, FGS, and galectin-3 levels were significantly higher in the MetS+ group compared with the MetS- group (13.19 ± 5.63 vs 9.37 ± 3.99 ng/mL, respectively, p = 0.001). HDL cholesterol was significantly higher in the MetS- group than in the MetS+ one. Galectin-3 levels were found to be positively correlated with systolic blood pressure (r = 0.450, p < 0.01), diastolic blood pressure (r = 0.293, p < 0.01), and triglyceride levels (r = 0.218, p < 0.05) in women with PCOS. Galectin-3 may be a promising novel biomarker in women with PCOS. Galectin-3 levels were significantly higher in the MetS+ group compared with the MetS- one and positively correlated with systolic, diastolic blood pressures and triglyceride levels in women with PCOS.//////////////////
Ovarian function
Steroid metabolism, Luteinization
Comment
The loss of luteal progesterone production in women is associated with a galectin switch via a2,6-sialylation of glycoconjugates. Nio-Kobayashi J 2014 et al.
Context: Luteal progesterone is fundamental for reproduction but the molecular regulation of the corpus luteum (CL) in women remains unclear. Galectin-1 and galectin-3 bind to the sugar chains on cells to control key biological processes including cell function and fate. Methods: The expression and localization of LGALS1 and LGALS3 was analyzed by quantitative PCR and histochemical analysis, with special reference to a2,6-sialylation of glycoconjugates, in carefully-dated human CL collected across the menstrual cycle and after exposure to hCG in vivo. The effects of hCG and prostaglandin E2 (PGE2) on the expression of galectins and an a2,6-sialyltransferase, ST6GAL1, in granulosa lutein cells were analyzed in vitro. Results: Galectin-1 was predominantly localized to healthy granulosa lutein cells and galectin-3 was localized to macrophages and regressing granulosa lutein cells. Acute exposure to luteotrophic hormones (hCG and PGE2) up-regulated LGALS1 expression (P<0.001). ST6GAL1, which catalyzes a2,6-sialylation to block galectin-1 binding, increased during luteolysis (P<0.05) as did LGALS3 (P<0.05). Luteotrophic hormones reduced ST6GAL1 and LGALS3 in vivo (P<0.05) and in vitro (P<0.001). There was an inverse correlation between the expression of ST6GAL1 and HSD3B1 (P<0.01), and a distinct cellular relationship among a2,6-sialylation, 3-HSD, and galectin expression. Conclusions: Galectin-1 is a luteotrophic factor whose binding is inhibited by a2,6-sialylation in the human CL during luteolysis. ST6GAL1 and galectin-3 expression is increased during luteolysis and associated with a loss of progesterone synthesis. Luteotrophic hormones differentially regulate galectin-1 and galectin-3/a2,6-sialylation in granulosa lutein cells, suggesting a novel galectin switch regulated by luteotrophic stimuli during luteolysis and luteal rescue.
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Galectins in the Mouse Ovary: Concomitant Expression of Galectin-3 and Progesterone Degradation Enzyme (20{alpha}-HSD) in the Corpus Luteum. Nio J et al. Galectin, an animal lectin which recognizes beta-galactosides of glycoconjugates, is involved in multiple biological functions such as cell growth, differentiation, apoptosis, and signal transduction. The present study employing in situ hybridization revealed the predominant expression of galectin-1 and galectin-3 in the mouse ovary. Galectin-1 mRNA was diffusely expressed in the ovarian stroma, including the interstitial glands and theca interna, and intensely expressed in the corpus luteum (CL) at particular stages of regression. Transcripts of galectin-3 were restricted to CL and always coincident to the expression of 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), a progesterone degradation enzyme. In the non-pregnant ovary, signals for both galectin-1 and galectin-3 were intense in the old, regressing CL formed at previous estrous cycles. In the newly formed CL, the signal intensity of galectin-1 first increased at the starting point of regression followed by increasing galectin-3/20alpha-HSD expressions. Under gestation with active progesterone production, signals for both galectin-1 and galectin-3 in CL completely disappeared. At the perinatal stage, the intense expressions of galectin-3/20alpha-HSD recovered in the remaining CL of gestation with the temporal expression of galectin-1, and continued until weaning. These findings suggest that galectin-1 and galectin-3 may mediate the progesterone production and metabolism in luteal cells via different mechanisms.
Expression regulated by
LH
Comment
Gene expression increased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.
Galectin-1 and galectin-3 in the corpus luteum of mice are differentially regulated by prolactin and prostaglandin F2a Nio-Kobayashi J et al. Galectin-1 and galectin-3, ?galactoside-binding lectins, are specifically expressed in the regressing corpus luteum (CL) of mice, however, their function remains unclear. In this study, we examined the effects of prolactin (PRL) and prostaglandin F(2a) (PGF(2a)), two main regulatory molecules of mouse CL function, on galectin expression. In situ hybridization analysis clearly demonstrated an initial increase of galectin-1 in the CL newly formed (CLN) after postpartum ovulation 48 h after compulsory weaning. This was accompanied by a decline in 3?hydroxysteroid dehydrogenase (3?HSD) and luteinizing hormone receptor (LH-R) expression, suggesting a withdrawal of PRL stimulation. At 72 h after the weaning, the expression of both galectins in CLN was remarkably increased, being associated with an intense expression of progesterone degradation enzyme (20a-HSD). Compulsory weaning did not significantly alter both galectin expression in the remaining CL of pregnancy (CLP), while PGF(2a) strongly up-regulated both galectin expression only in the remaining CLP which lacked LH-R in postpartum mice. Administration of Bromocriptine, an antagonist for PRL secretion, to non-pregnant cyclic mice induced an accumulation of galectin-1 -but not galectin-3- in all CL of various generations, and additional PRL treatment reduced its accumulation, suggesting a direct suppressive effect of PRL on galectin-1 expression. Although the function and regulatory mechanism of galectin in the CL is not fully understood, PGF(2a) is an excellent candidate which regulates galectin expression but its effect may be abolished by LH-R-mediated signal. PRL withdrawal seems to be necessary for an initiation of luteolysis and the following PGF(2a)-induced galectin expression. Cell-type-specific expression of murine multifunctional galectin-3 and its association with follicular atresia/luteolysis in contrast to pro-apoptotic galectins-1 and -7. Lohr M et al. Galectin-3 is a multifunctional protein with modular design. A distinct expression profile was determined in various murine organs when set into relation to homodimeric galectins-1 and -7. Fittingly, the signature of putative transcription-factor-binding sites in the promoter region of the galectin-3 gene affords a toolbox for a complex combinatorial regulation, distinct from the respective sequence stretches in galectins-1 and -7. A striking example for cell-type specificity was the ovary, where these two lectins were confined to the surface epithelium. Immunohistochemically, galectin-3 was found in macrophages of the cortical interstitium between developing follicles and medullary interstitium, matching the distribution of the F4/80 antigen. With respect to atresia and luteolysis strong signals in granulosa cells of atretic preantral but not antral follicles and increasing positivity in corpora lutea upon regression coincided with DNA fragmentation. Labeled galectin-3 revealed lactose-inhibitable binding to granulosa cells. Also, slender processes of vital granulosa cells which extended into the zona pellucida were positive. This study demonstrates cell-type specificity and cycle-associated regulation for galectin-3 with increased presence in atretic preantral follicles and in late stages of luteolysis.
Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with NF-kappaB signaling
Liu L, et al .
Nucling is a novel apoptosis-associated molecule, which is related with cytochrome c /Apaf-1/ caspase-9 apoptosome induction following proapoptotic stress. In the present study, we first show that Nucling is able to interact with galectin-3. Galectin-3 is known to participate in many biological processes including apoptotic cell death. Nucling was found to down-regulate the expression level of galectin-3 mRNA and protein. Nucling-deficient cells, in which galectin-3 expression is up-regulated, appeared to be resistant to some forms of proapoptotic stress as compared to wild-type cells. In addition, the preputial gland from Nucling-deficient mice expressed a significant level of galectin-3 and exhibited a high incidence of inflammatory lesions, indicating that Nucling plays a crucial role in the homeostasis of this gland by interaction with galectin-3 molecule and regulating expression level of galectin-3. Up-regulation of galectin-3 was also observed in heart, kidney, lung, testis and ovary of the Nucling-deficient mice. In order to confirm the functional interaction between Nucling and galectin-3, a well-documented candidate for the mediator of galectin-3 expression, NF-kappaB, was investigated as well. Nucling was shown to interfere with NF-kappaB activation through the nuclear translocation process of NF-kappaB-p65, thus inhibiting the expression of galectin-3. Taken together, we propose that Nucling mediates apoptosis by interacting and inhibiting expression of galectin-3.
Expression and immunohistochemical localization of galectin-3 in various mouse tissues. Kim H et al. The expression and immunohistochemical localization of galectin-3, a beta-galactoside-binding protein, was studied in several mouse tissues. Galectin-3 expression was low in the cerebrum, heart, and pancreas, and moderate in the liver, ileum, kidney, and adrenal gland. High expression of galectin-3 was found in the lung, spleen, stomach, colon, uterus, and ovary. The results of Western blot analysis largely matched the immunohistochemical findings for galectin-3. These findings suggest that galectin-3 is differentially expressed in a variety of organs in the mouse. This study provides valuable information for research on galectin-3.
Follicle stages
Primordial, Corpus luteum
Comment
Unilaminar follicular cells transiently express galectin-3 during ovarian folliculogenesis in pigs. Heo SD et al. (2016) The localization of galectin-3, a β-galactoside-binding animal lectin, was immunohistochemically studied in the ovaries of pigs to determine its expression in ovarian folliculogenesis. Various stages of ovarian follicles were identified in the ovaries of adult pigs. Galectin-3 was immunostained in the squamous follicular cells surrounding oocytes in primordial follicles and in the unilaminar granulosa cells of primary follicles, but not in oocytes of multilaminar follicles (including primary, secondary, and tertiary Graafian follicles). As in adult ovaries, galectin-3 immunoreactivity was prominent in the unilaminar follicles in neonatal ovaries. Galectin-3 was also immunolocalized in the luteal cells in the corpus luteum and granulosa cells of atretic follicles as well as in interstitial macrophages in porcine ovaries. Collectively, these results suggest that galectin-3 is transiently expressed in follicular cells in the unilaminar ovarian follicles (primordial and primary) but not in multilaminar ovarian follicles (primary to tertiary), implying that galectin-3 is embryologically involved in ovum generation.//////////////////
Expression of galectin-3 in gonads and gonadal sex cord stromal and germ cell tumors. Devouassoux-Shisheboran M et al. Galectin-3, a beta-galactoside-binding lectin, has been implicated in many human malignancies, but has seldom been studied in human gonads and gonadal tumors. The aim of our study was to investigate galectin-3 mRNA and protein expression in normal ovaries and testes as well as in a variety of 51 gonadal sex cord stromal and germ cell tumors, and two testicular seminomatous and non-seminomatous cell lines, using either real-time PCR or immunohistochemistry. In human testes, galectin-3 is specifically expressed in mature Sertoli cells and Leydig cells, and is absent from fetal and pre-pubertal testes, suggesting a hormone-dependence of this gene. In human ovaries, galectin-3 is absent from granulosa cells, as well as from granulosa cell and Sertoli-Leydig cell tumors, and is not a useful marker in distinguishing granulosa cell from Sertoli-Leydig cell tumors. In testicular tumorigenesis, galectin-3 has a dual function according to the histological type of tumors and their hormone dependency. In malignant testicular Sertoli cell tumors, the expression of galectin-3 is down-regulated while, in benign Leydig cell tumors, this expression is maintained, indicating the possible implication of this gene in the development of more aggressive testicular sex cord stromal tumors. In contrast to sex cord stromal tumors, galectin-3 expression is up-regulated in testicular germ cell tumors. By real-time PCR, we demonstrated a significant elevation of the galectin-3 mRNA level in non-seminomatous testicular germ cell tumors and cell line as compared to normal testes and seminomas (p=0.0432 and p=0.0247, respectively), indicating the possible role of this gene in the non-seminomatous differentiation of germ cell tumors.