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Frontiers in Endocrinology 2023Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones,... (Observational Study)
Observational Study
BACKGROUND
Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses.
METHODS
The observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies.
RESULTS
In the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value <0.001 to 0.003]. Whereas in women, a positive association of free T with FLI (β = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was inversely associated with FLI across sexes [men: -3.45 (-5.13, -1.78); women: -9.23 (-12.19, -6.28)]. No causal association was found between genetically determined sex hormones and liver fat, but higher genetically determined SHBG was associated with lower liver fat in women (β = -0.36, 95% CI: -0.61, -0.12).
CONCLUSION
Our results provide suggestive evidence for a causal association between SHBG and liver fat in women, implicating the protective role of SHBG against liver fat accumulation.
Topics: Male; Humans; Female; Middle Aged; Sex Hormone-Binding Globulin; Mendelian Randomization Analysis; Dihydrotestosterone; Fatty Liver
PubMed: 37900132
DOI: 10.3389/fendo.2023.1223162 -
Journal of Bone and Mineral Research :... Nov 2023Although the impact of sex hormones on bone metabolism is well-documented, effect of their primary modulator, sex hormone-binding globulin (SHBG), remains inconclusive.... (Meta-Analysis)
Meta-Analysis
Genetic Correlation, Shared Loci, and Causal Association Between Sex Hormone-Binding Globulin and Bone Mineral Density: Insights From a Large-Scale Genomewide Cross-Trait Analysis.
Although the impact of sex hormones on bone metabolism is well-documented, effect of their primary modulator, sex hormone-binding globulin (SHBG), remains inconclusive. This study aims to elucidate the genetic overlap between SHBG and heel estimated bone mineral density (eBMD), a widely-accepted tool for osteoporosis management and fracture risk assessment. Using summary statistics from large-scale genomewide association studies conducted for SHBG (N = 370,125), SHBG adjusted for body mass index (SHBGa, N = 368,929), and eBMD (N = 426,824), a comprehensive genomewide cross-trait approach was performed to quantify global and local genetic correlations, identify pleiotropic loci, and infer causal associations. A significant overall inverse genetic correlation was found for SHBG and eBMD (r = -0.11, p = 3.34 × 10 ), which was further supported by the significant local genetic correlations observed in 11 genomic regions. Cross-trait meta-analysis revealed 219 shared loci, of which seven were novel. Notably, four novel loci (rs6542680, rs8178616, rs147110934, and rs815625) were further demonstrated to colocalize. Mendelian randomization identified a robust causal effect of SHBG on eBMD (beta = -0.22, p = 3.04 × 10 ), with comparable effect sizes observed in both men (beta = -0.16, p = 1.99 × 10 ) and women (beta = -0.19, p = 2.73 × 10 ). Replacing SHBG with SHBGa, the observed genetic correlations, pleiotropic loci and causal associations did not change substantially. Our work reveals a shared genetic basis between SHBG and eBMD, substantiated by multiple pleiotropic loci and a robust causal relationship. Although SHBG has been implicated in preventing and screening aging-related diseases, our findings support its etiological role in osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Female; Humans; Male; Bone Density; Genome-Wide Association Study; Mendelian Randomization Analysis; Minerals; Osteoporosis; Phenotype; Sex Hormone-Binding Globulin
PubMed: 37615194
DOI: 10.1002/jbmr.4904 -
ASN Neuro 2023Although transferrin (Tf) is a glycoprotein best known for its role in iron delivery, iron-independent functions have also been reported. Here, we assessed apoTf (aTf)...
Although transferrin (Tf) is a glycoprotein best known for its role in iron delivery, iron-independent functions have also been reported. Here, we assessed apoTf (aTf) treatment effects on Neuro-2a (N2a) cells, a mouse neuroblastoma cell line which, once differentiated, shares many properties with neurons, including process outgrowth, expression of selective neuronal markers, and electrical activity. We first examined the binding of Tf to its receptor (TfR) in our model and verified that, like neurons, N2a cells can internalize Tf from the culture medium. Next, studies on neuronal developmental parameters showed that Tf increases N2a survival through a decrease in apoptosis. Additionally, Tf accelerated the morphological development of N2a cells by promoting neurite outgrowth. These pro-differentiating effects were also observed in primary cultures of mouse cortical neurons treated with aTf, as neurons matured at a higher rate than controls and showed a decrease in the expression of early neuronal markers. Further experiments in iron-enriched and iron-deficient media showed that Tf preserved its pro-differentiation properties in N2a cells, with results hinting at a modulatory role for iron. Moreover, N2a-microglia co-cultures revealed an increase in IL-10 upon aTf treatment, which may be thought to favor N2a differentiation. Taken together, these findings suggest that Tf reduces cell death and favors the neuronal differentiation process, thus making Tf a promising candidate to be used in regenerative strategies for neurodegenerative diseases.
Topics: Mice; Animals; Transferrin; Neurons; Iron; Cell Line; Cell Differentiation
PubMed: 37093743
DOI: 10.1177/17590914231170703 -
Frontiers in Immunology 2021
Topics: Animals; Biomarkers; Complement Activation; Complement Factor H; Disease Susceptibility; Homeostasis; Humans
PubMed: 35095933
DOI: 10.3389/fimmu.2021.831044 -
Frontiers in Endocrinology 2023Type 2 diabetes mellitus (T2DM) is an endocrine-related disease with an increasing incidence worldwide. Male sexual dysfunction is common in diabetic patients....
OBJECTIVE
Type 2 diabetes mellitus (T2DM) is an endocrine-related disease with an increasing incidence worldwide. Male sexual dysfunction is common in diabetic patients. Therefore, we designed a Mendelian randomization (MR) study to investigate the association of type 2 diabetes and 3 glycemic traits with testosterone levels.
METHODS
Uncorrelated single nucleotide polymorphisms (SNPs) associated with T2DM (N = 228), fasting insulin (N = 38), fasting glucose (N = 71), and HbA1c (N = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with testosterone levels (total testosterone, TT, bioavailable testosterone, BT, and sex hormone-binding globulin, SHBG) were obtained from the UK Biobank studies and other large consortia. Two-sample MR analysis was used to minimize the bias caused by confounding factors and response causality. Multivariable MR analysis was performed using Body mass index (BMI), Triglycerides (TG), LDL cholesterol (LDL), and adiponectin to adjust for the effects of potential confounders.
RESULTS
Type 2 diabetes mellitus was associated with the decrease of total testosterone (β: -0.021,95%CI: -0.032, -0.010, p<0.001) and sex hormone binding globulin (β: -0.048,95%CI: -0.065, -0.031, p<0.001). In males, total testosterone (β: 0.058, 95% CI: 0.088, 0.028, p < 0.001) decreased. In females, it was associated with an increase in bioavailable testosterone (β: 0.077,95%CI: 0.058,0.096, p<0.001). Each unit (pmol/L) increase in fasting insulin was associated with 0.283nmol/L decrease in sex hormone-binding globulin (95%CI: -0.464, -0.102, p=0.002) and 0.260nmol/L increase in bioavailable testosterone (95%CI: -0.464, -0.102, p= 0.002). In males, sex hormone binding globulin decreased by 0.507nmol/L (95%CI: -0.960, -0.054, p= 0.028) and bioavailable testosterone increased by 0.216nmol/L (95%CI: 0.087,0.344, p= 0.001). In females, sex hormone binding globulin decreased by 0.714 nmol/L (95%CI: -1.093, -0.335, p<0.001) and bioavailable testosterone increased by 0.467nmol/L (95%CI: 0.286,0.648, p<0.001). Each unit (%) increase in HbA1c was associated with 0.060nmol/L decrease in sex hormone-binding globulin (95%CI: -0.113, -0.007, p= 0.026). In males, total testosterone decreased by 0.171nmol/L (95%CI: -0.288, -0.053, p=0.005) and sex hormone binding globulin decreased by 0.206nmol/L (95%CI: -0.340, -0.072, p=0.003). Total testosterone increased by 0.122nmol/L (95%CI: 0.012,0.233, p=0.029) and bioavailable testosterone increased by 0.163nmol/L (95%CI: 0.042,0.285, p=0.008) in females.
CONCLUSIONS
Using MR Analysis, we found independent effects of type 2 diabetes, fasting insulin, and HbA1c on total testosterone and sex hormone-binding globulin after maximum exclusion of the effects of obesity, BMI, TG, LDL and Adiponectin.
Topics: Female; Humans; Male; Diabetes Mellitus, Type 2; Sex Hormone-Binding Globulin; Glycated Hemoglobin; Adiponectin; Mendelian Randomization Analysis; Testosterone; Insulin; Triglycerides
PubMed: 37900148
DOI: 10.3389/fendo.2023.1238090 -
Frontiers in Endocrinology 2022The role of endogenous androgens in kidney function and disease has not been extensively explored in men and women.
INTRODUCTION
The role of endogenous androgens in kidney function and disease has not been extensively explored in men and women.
RESEARCH DESIGN AND METHODS
We analyzed data from the observational KORA F4 study and its follow-up examination KORA FF4 (median follow-up time 6.5 years) including 1293 men and 650 peri- and postmenopausal women, not using exogenous sex hormones. We examined the associations between endogenous androgens (testosterone [T], dihydrotestosterone [DHT], free T [fT], free DHT [fDHT], and T/DHT), with estimated glomerular filtration rate (eGFR) at baseline and follow-up, prevalent, and incident chronic kidney disease (CKD) adjusting for common CKD risk factors.
RESULTS
At baseline, 73 men (5.7%) and 54 women (8.4%) had prevalent CKD. Cross-sectionally, no significant associations between androgens and kidney function were observed among men. In women, elevated T (β=-1.305, [95% CI -2.290; -0.320]) and fT (β=-1.423, [95% CI -2.449; -0.397]) were associated with lower eGFR. Prospectively, 81 men (8.8%) and 60 women (15.2%) developed incident CKD. In women, a reverse J-shaped associations was observed between DHT and incident CKD (P=0.029), while higher fDHT was associated with lower incident CKD risk (odds ratio per 1 standard deviation=0.613, [95% CI 0.369; 0.971]. Among men, T/DHT (β=-0.819, [95% CI -1.413; -0.226]) and SHBG (P=0.011) were associated with eGFR at follow-up but not with incident CKD. Some associations appeared to be modified by type 2 diabetes (T2D).
CONCLUSION
Suggestive associations are observed of androgens and SHBG with kidney impairment among men and women. However, larger well-phenotyped prospective studies are required to further elucidate the potential of androgens, SHBG, and T2D as modifiable risk factors for kidney function and CKD.
Topics: Male; Humans; Female; Androgens; Diabetes Mellitus, Type 2; Sex Hormone-Binding Globulin; Dihydrotestosterone; Renal Insufficiency, Chronic; Kidney
PubMed: 36601008
DOI: 10.3389/fendo.2022.1000650 -
Cellular and Molecular Life Sciences :... May 2017Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune... (Review)
Review
Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.
Topics: Animals; Complement Factor H; Disease; Humans; Immune Evasion; Immunity, Innate; Polysaccharides; Protein Binding
PubMed: 27942748
DOI: 10.1007/s00018-016-2418-4 -
Journal of Dairy Science Feb 1982beta 2-Microglobulin has been isolated from several species, but only bovine beta 2-microglobulin, previously known as lactollin, has been crystallized. An improved... (Comparative Study)
Comparative Study Review
beta 2-Microglobulin has been isolated from several species, but only bovine beta 2-microglobulin, previously known as lactollin, has been crystallized. An improved method for its isolation from colostrum is described. The bovine homologue exhibits a concentration-dependent aggregation behavior. beta 2-Microglobulin is related to both immune and histocompatibility antigen systems. It exhibits homology with the constant domains of the immunoglobulin-G light and heavy chains and is an integral part of histocompatibility antigens bound to cell surface. beta 2-Microglobulin also occurs in the free state in various body fluids including milk and colostrum. The possible relationship of elevated free beta 2-microglobulin of pathological conditions is suggested for future research.
Topics: Amino Acid Sequence; Animals; Beta-Globulins; Cattle; Colostrum; HLA Antigens; Histocompatibility Antigens; Humans; Milk; beta 2-Microglobulin
PubMed: 6176605
DOI: 10.3168/jds.S0022-0302(82)82193-0 -
Trends in Endocrinology and Metabolism:... Jan 2012Sex hormone-binding globulin (SHBG) has emerged as one of the multiple genetic and environmental factors that potentially contribute to the pathophysiology of type 2... (Review)
Review
Sex hormone-binding globulin (SHBG) has emerged as one of the multiple genetic and environmental factors that potentially contribute to the pathophysiology of type 2 diabetes mellitus (T2DM). In addition to epidemiologic studies demonstrating a consistent relationship between decreased levels of serum SHBG and incident T2DM, recent genetic studies also reveal that transmission of specific polymorphisms in the SHBG gene influence the risk of T2DM. At the molecular level, the multiple interactions between SHBG and its receptors in various target tissues suggest physiologic roles for SHBG that are more complex than the simple transport of sex hormones in serum. Taken together, these data provide support for an expanded role of SHBG in the pathophysiology of insulin resistance and T2DM.
Topics: Animals; Diabetes Mellitus, Type 2; Gene Expression Regulation; Humans; Insulin Resistance; Polymorphism, Genetic; Receptors, Cell Surface; Sex Hormone-Binding Globulin
PubMed: 22047952
DOI: 10.1016/j.tem.2011.09.005 -
Immunology Apr 1967synthesis of β and immune globulins by tissues from foetal, neonatal and adult guinea-pigs, rabbits, mice and rats, was studied using a combination of...
synthesis of β and immune globulins by tissues from foetal, neonatal and adult guinea-pigs, rabbits, mice and rats, was studied using a combination of immunoelectrophoresis and autoradiography. Germ-free (GF) mice and rats of various ages were also included in an effort to evaluate maturation of serum protein formation in an environment free of living bacteria. In all these species IgM is the first immune globulin detected, and its production is most prominent in the spleen. Formation of IgM is correlated with the degree of maturity at birth which in turn is dependent upon the length of the gestation period. In guinea-pigs, and probably also in mice, early IgM synthesis is accompanied by the production of free L chains. In the guinea-pig IgM synthesis is followed by formation of IgG. Production of IgG was first noted at 3–4 weeks of age. In GF animals IgM production by the spleen developed at the same time and to approximately the same degree as in conventional (CVL) animals. Under CVL conditions mesenteric lymph nodes of immature animals developed early and strong synthesis of IgG. In contrast, mesenteric lymph nodes from GF animals remained markedly inactive. Although β was produced by all lymphoid tissue, there was no correlation with immune globulin formation, and the influence of age was evident only in the liver. Liver synthesis of β was low during foetal or neonatal life, depending on the degree of maturity at birth, increased in young animals, and then decreased again in adulthood.
Topics: Animals; Animals, Newborn; Autoradiography; Beta-Globulins; Culture Techniques; Fetus; Germ-Free Life; Guinea Pigs; Immunoelectrophoresis; Liver; Lymph Nodes; Mice; Rabbits; Rats; Spleen; Thymus Gland; Ultracentrifugation; gamma-Globulins
PubMed: 4164675
DOI: No ID Found