madman
Super Moderator
Over the past decade, there have been important breakthroughs in our understanding of the regulation and function of sex hormone-binding globulin (SHBG). A recent genome-wide association and Mendelian randomization study have provided new insights at the population level. A thorough study of genetic variants affecting serum SHBG has identified de novo lipogenesis as one of the mechanistic links between metabolic syndrome and reduced serum SHBG levels in humans. Furthermore, careful deduction of the Mendelian randomization results suggests a direct, causal role for SHBG in the pathogenesis of type 2 diabetes, as a hepatokine, in women. These findings prompt the development of SHBG-raising therapies as a means to prevent or treat disorders such as type 2 diabetes and polycystic ovary syndrome.
*The traditional view on sex hormone-binding globulin
Since its discovery by Mercier et al. in 1966 [1], sex hormone-binding globulin (SHBG) has been viewed as the principal protein that binds circulating sex hormones with high affinity, primarily 5- alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol [2,3]. As such, according to the free hormone hypothesis (see Glossary), SHBG regulates the bioavailability of these sex hormones at the target site [4,5].
A recent genome-wide association study (GWAS) and Mendelian randomization analysis have provided new insights into the regulation and function of SHBG in humans [6]. On the basis of these outcomes, we postulate that SHBG is both a biomarker of metabolic derangements, such as de novo lipogenesis, and a protein that exerts systemic metabolic effects by itself, a so-called hepatokine. In this opinion, we provide an extensive description of this landmark study and elaborate on the interpretation and clinical implications of the outcomes.
*Current knowledge of the regulation and function of SHBG
SHBG is synthesized primarily in the liver as a homodimeric glycoprotein [7–10]. The expression of the SHBG gene, located on chromosome 17p13.1 [11], is under transcriptional control of hepatocyte nuclear factor 4 alpha (HNF-4α) and constitutive androstane receptor (both stimulatory), as well as peroxisome proliferator-activated receptor gamma and chicken ovalbumin upstream promoter transcription factor (both inhibitory) [12–14]. These transcription factors are affected by several hormonal, metabolic, nutritional, and inflammatory factors, among others thyroid hormone [15], adiponectin [16], and several cytokines, including tumor necrosis factor-alpha, which downregulates HNF-4α through nuclear factor-κB [17], and interleukin-1β, which downregulates HNF-4α through mitogen-activated protein kinase (MAPK)/extracellular signaling regulated kinase 1/2 and c-Jun N-terminal kinase MAPK signaling [18]. The complex regulation of SHBG synthesis has been extensively reviewed elsewhere [19–22].
There is abundant epidemiological evidence that serum SHBG levels are reduced in several metabolic disorders, including obesity, type 2 diabetes (T2D), and polycystic ovary syndrome (PCOS) [21,23,24]. Furthermore, serum SHBG levels are inversely associated with metabolic syndrome [25,26] and its individual components, except for blood pressure [27]. For a long time, it was widely accepted that the common denominator of these entities, hyperinsulinemia, accounted for the reduced serum SHBG levels [28–32]. However, growing evidence pleads against a direct role of insulin in the regulation of SHBG [19,33–35]. For instance, streptozotocin-induced insulin deficiency in transgenic mice carrying human SHBG led to a decrease rather than an increase in SHBG levels [33].
*New insights into the regulation of SHBG in humans: SHBG as a biomarker
*New insights into the causal role of SHBG in T2D and PCOS: SHBG as a hepatokine
*Clinical implications: SHBG-raising therapies
Concluding remarks and future directions
A recent large-scale GWAS and Mendelian randomization study revealed that SHBG has an appreciably greater role in metabolic disorders than it has previously been given credit for, functioning as both a biomarker of metabolic derangements, including de novo lipogenesis and a mediator (either primary or secondary) in the pathogenesis of metabolic disorders such as T2D and PCOS.
A thorough study of genetic variants that affect serum SHBG levels suggests that de novo lipogenesis is one of the mechanistic links between metabolic syndrome and SHBG levels. Furthermore, in women, SHBG not only acts as a carrier protein but also appears to be a true hepatokine involved in the pathogenesis of T2D, independent of its effects on free testosterone. Together, this warrants the development of drugs that raise serum SHBG to treat and prevent T2D and PCOS. Although trials are still in the early stages, THRβ agonists provide an interesting avenue of research (see Outstanding Questions).
*The traditional view on sex hormone-binding globulin
Since its discovery by Mercier et al. in 1966 [1], sex hormone-binding globulin (SHBG) has been viewed as the principal protein that binds circulating sex hormones with high affinity, primarily 5- alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol [2,3]. As such, according to the free hormone hypothesis (see Glossary), SHBG regulates the bioavailability of these sex hormones at the target site [4,5].
A recent genome-wide association study (GWAS) and Mendelian randomization analysis have provided new insights into the regulation and function of SHBG in humans [6]. On the basis of these outcomes, we postulate that SHBG is both a biomarker of metabolic derangements, such as de novo lipogenesis, and a protein that exerts systemic metabolic effects by itself, a so-called hepatokine. In this opinion, we provide an extensive description of this landmark study and elaborate on the interpretation and clinical implications of the outcomes.
*Current knowledge of the regulation and function of SHBG
SHBG is synthesized primarily in the liver as a homodimeric glycoprotein [7–10]. The expression of the SHBG gene, located on chromosome 17p13.1 [11], is under transcriptional control of hepatocyte nuclear factor 4 alpha (HNF-4α) and constitutive androstane receptor (both stimulatory), as well as peroxisome proliferator-activated receptor gamma and chicken ovalbumin upstream promoter transcription factor (both inhibitory) [12–14]. These transcription factors are affected by several hormonal, metabolic, nutritional, and inflammatory factors, among others thyroid hormone [15], adiponectin [16], and several cytokines, including tumor necrosis factor-alpha, which downregulates HNF-4α through nuclear factor-κB [17], and interleukin-1β, which downregulates HNF-4α through mitogen-activated protein kinase (MAPK)/extracellular signaling regulated kinase 1/2 and c-Jun N-terminal kinase MAPK signaling [18]. The complex regulation of SHBG synthesis has been extensively reviewed elsewhere [19–22].
There is abundant epidemiological evidence that serum SHBG levels are reduced in several metabolic disorders, including obesity, type 2 diabetes (T2D), and polycystic ovary syndrome (PCOS) [21,23,24]. Furthermore, serum SHBG levels are inversely associated with metabolic syndrome [25,26] and its individual components, except for blood pressure [27]. For a long time, it was widely accepted that the common denominator of these entities, hyperinsulinemia, accounted for the reduced serum SHBG levels [28–32]. However, growing evidence pleads against a direct role of insulin in the regulation of SHBG [19,33–35]. For instance, streptozotocin-induced insulin deficiency in transgenic mice carrying human SHBG led to a decrease rather than an increase in SHBG levels [33].
*New insights into the regulation of SHBG in humans: SHBG as a biomarker
*New insights into the causal role of SHBG in T2D and PCOS: SHBG as a hepatokine
*Clinical implications: SHBG-raising therapies
Concluding remarks and future directions
A recent large-scale GWAS and Mendelian randomization study revealed that SHBG has an appreciably greater role in metabolic disorders than it has previously been given credit for, functioning as both a biomarker of metabolic derangements, including de novo lipogenesis and a mediator (either primary or secondary) in the pathogenesis of metabolic disorders such as T2D and PCOS.
A thorough study of genetic variants that affect serum SHBG levels suggests that de novo lipogenesis is one of the mechanistic links between metabolic syndrome and SHBG levels. Furthermore, in women, SHBG not only acts as a carrier protein but also appears to be a true hepatokine involved in the pathogenesis of T2D, independent of its effects on free testosterone. Together, this warrants the development of drugs that raise serum SHBG to treat and prevent T2D and PCOS. Although trials are still in the early stages, THRβ agonists provide an interesting avenue of research (see Outstanding Questions).
