madman
Super Moderator
Sex hormone-binding globulin (SHBG) is a homodimeric glycoprotein produced by the human liver and secreted into the systemic circulation where it binds with high affinity sex steroids regulating their availability in blood and accessibility to target tissues. Plasma SHBG levels are altered in metabolic disorders such as obesity, anorexia, and insulin resistance. Several reports have shown that diets in terms of total calories or fat, fiber, or protein content can alter plasma SHBG levels. However, there are many components in a diet that can affect SHBG gene expression in the liver. In order to unravel the molecular mechanisms by which diets regulate SHBG production, it would be necessary to analyze single diet components and/or nutritional factors. This review summarizes the recent advances in identifying different nutritional factors regulating SHBG production and the related molecular mechanism, as well as the clinical implications.
1. Sex Hormone-Binding Globulin Background
1.1. Human Sex Hormone-Binding Globulin Gene
The human SHBG gene is located on chromosome 17p13.1 and it spans up to 11-kb containing two known transcription units: a) first transcription unit or proximal promoter (4.3-kb) that is responsible for driving the expression of the SHBG gene in the hepatocytes that secrete SHBG protein into the circulation[1]; b) second transcription unit containing an alternative promoter which drives the expression of the SHBG gene in germ cells of the testes producing a smaller isoform than the plasmatic SHBG that accumulates in the acrosome of human sperm[1] (Figure 1)
1.2. Transcription Factors Regulating Hepatic SHBG Gene Expression
The human SHBG proximal promoter isa TATA-less promoter that contains different footprint (FP) regions which have been well characterized during the last decade (Figure 1):
• FP1 region: chicken ovalbumin upstream promoter transcription factor (COUP TFI) and hepatocyte nuclear factor 4 alpha (HNF-4), which represses and activates SHBG transcription, respectively.[2]
• FP3 region: HNF-4, estrogen receptor alpha (ER), and constitutive androstane receptor (CAR) activate SHBG transcription, while peroxisome proliferator activated receptor gamma (PPAR) inhibits SHBG transcription.[2,3]
• FP4 region: upstream stimulatory factor 1/2 (USF1/2) activates SHBG transcription.[4]
1.3. SHBG Function and Role as Biomarker of Metabolic Disturbances
1.4. Dietary Composition and SHBG
2. SHBG Regulation by Nutritional Factors and Associated Molecular Mechanisms
2.1. Carbohydrates
2.2. Olive Oil
2.3. Red Wine (Resveratrol)
2.4. Caffeine
3. Clinical Implications and Future Perspectives
One of the most important lessons of recent years has been that apart from a carrier of sex hormones, SHBG is a reliable biomarker of metabolic dysfunctions in which insulin resistance plays an essential role such as metabolic syndrome, obesity, fatty liver disease, type 2 diabetes (T2D), gestational diabetes, and polycystic ovary syndrome.[6–8,67] In addition, low plasma SHBG concentrations in overweight individuals are predictive T2D and cardiovascular disease (CVD) risk.[10–14,67] Although the potential role of SHBG per se in the pathogenesis of the above-mentioned diseases remains to be elucidated, several reports have suggested its contribution to the development and progression of obesity.[68]
The new insights from SHBG research related to nutrition reported in recent years, are based on fact that a single dietary component can potentially regulate plasmatic SHBG levels in humans. Consumption of added sugars has been related to an increased risk of several chronic diseases, including obesity, CVD, T2D, nonalcoholic fatty liver disease (NAFLD), cognitive decline, and even some cancers.[69–71] The fact that monosaccharides reduced human SHBG gene expression by altering hepatic HNF-4 levels provide a molecular mechanism explaining the link between the low plasma SHBG levels and the metabolic extremes in people suffering from obesity and anorexia. Interestingly, monosaccharides induced hepatic de novo lipogenesis which increased the hepatocyte palmitate content reducing HNF-4 protein levels.[28] This is important since, among the monosaccharides, fructose is the most potent inducer of de novo lipogenesis[28] and therefore explains why the SHBG gene expression is remarkably responsive to fructose consumption. Studies in different human cohorts have shown that elevated liver fat content strongly correlated with circulating SHBG in humans.[35,36] These findings suggest that plasma SHBG levels may represent a useful biomarker of metabolic disturbances associated with excess sugar consumption.
MedDiet is a well-known and characterized diet distinguished by high intakes of vegetables, legumes, fruits, nuts, grains, fish, protein sources from seafood and poultry, olive oil and low-to moderate intake of red wine, as well as low intake of dairy products, red and processed meat, cream, and sugar drinks.[72,73] TheMedDiet is the most studied diet in the world and it has been associated with important health benefits. In this regard, several studies provided strong evidences of the MedDiet benefits on cardiovascular health, which not only includes reduction in the cardiovascular incident outcomes, but also in the associated risk factors such as obesity, hypertension, metabolic syndrome,and dyslipidemia. The MedDiet has been also related with a reduction of the risk in the development of developing T2D, a reduction in mortality and therefore an increase in longevity.[73,74] It is remarkable that olive oil and red wine, two of the most important components of MedDiet increased plasma SHBG levels, thus linking epidemiologically studies showing that subjects with low plasma SHBG levels have higher risk of suffering both CVD and T2D.[75,76] Therefore, specific studies addressed to examine the role of SHBG as an independent mediator of the relationship between olive oil and red wine consumption and the cardiovascular protective effects of the Mediterranean diet seem warranted.
Coffee is one of the most popular beverages in the world; although its impact on health outcomes and adverse effects is not fully understood. It is widely accepted that coffee consumption contributes to the prevention of inflammatory and oxidative stress-related diseases, such as obesity, metabolic syndrome, and T2D.[77] Recent results showed that caffeine upregulates hepatic SHBG expression by increasing adiponectin production through AKT/FOXO1 pathway in the adipose tissue.[61] Therefore, this could be one of the key mechanisms involved in the beneficial effects of caffeine in the prevention of metabolic diseases.
Overall, all these findings point to SHBG not only as a sex steroid carrier but also as a useful biomarker of type of diet consumption and metabolic diseases. Future research is needed in order to determine whether SHBG plasma levels could be a reliable biomarker of the success of dietary interventions in patients suffering from metabolic diseases.
1. Sex Hormone-Binding Globulin Background
1.1. Human Sex Hormone-Binding Globulin Gene
The human SHBG gene is located on chromosome 17p13.1 and it spans up to 11-kb containing two known transcription units: a) first transcription unit or proximal promoter (4.3-kb) that is responsible for driving the expression of the SHBG gene in the hepatocytes that secrete SHBG protein into the circulation[1]; b) second transcription unit containing an alternative promoter which drives the expression of the SHBG gene in germ cells of the testes producing a smaller isoform than the plasmatic SHBG that accumulates in the acrosome of human sperm[1] (Figure 1)
1.2. Transcription Factors Regulating Hepatic SHBG Gene Expression
The human SHBG proximal promoter isa TATA-less promoter that contains different footprint (FP) regions which have been well characterized during the last decade (Figure 1):
• FP1 region: chicken ovalbumin upstream promoter transcription factor (COUP TFI) and hepatocyte nuclear factor 4 alpha (HNF-4), which represses and activates SHBG transcription, respectively.[2]
• FP3 region: HNF-4, estrogen receptor alpha (ER), and constitutive androstane receptor (CAR) activate SHBG transcription, while peroxisome proliferator activated receptor gamma (PPAR) inhibits SHBG transcription.[2,3]
• FP4 region: upstream stimulatory factor 1/2 (USF1/2) activates SHBG transcription.[4]
1.3. SHBG Function and Role as Biomarker of Metabolic Disturbances
1.4. Dietary Composition and SHBG
2. SHBG Regulation by Nutritional Factors and Associated Molecular Mechanisms
2.1. Carbohydrates
2.2. Olive Oil
2.3. Red Wine (Resveratrol)
2.4. Caffeine
3. Clinical Implications and Future Perspectives
One of the most important lessons of recent years has been that apart from a carrier of sex hormones, SHBG is a reliable biomarker of metabolic dysfunctions in which insulin resistance plays an essential role such as metabolic syndrome, obesity, fatty liver disease, type 2 diabetes (T2D), gestational diabetes, and polycystic ovary syndrome.[6–8,67] In addition, low plasma SHBG concentrations in overweight individuals are predictive T2D and cardiovascular disease (CVD) risk.[10–14,67] Although the potential role of SHBG per se in the pathogenesis of the above-mentioned diseases remains to be elucidated, several reports have suggested its contribution to the development and progression of obesity.[68]
The new insights from SHBG research related to nutrition reported in recent years, are based on fact that a single dietary component can potentially regulate plasmatic SHBG levels in humans. Consumption of added sugars has been related to an increased risk of several chronic diseases, including obesity, CVD, T2D, nonalcoholic fatty liver disease (NAFLD), cognitive decline, and even some cancers.[69–71] The fact that monosaccharides reduced human SHBG gene expression by altering hepatic HNF-4 levels provide a molecular mechanism explaining the link between the low plasma SHBG levels and the metabolic extremes in people suffering from obesity and anorexia. Interestingly, monosaccharides induced hepatic de novo lipogenesis which increased the hepatocyte palmitate content reducing HNF-4 protein levels.[28] This is important since, among the monosaccharides, fructose is the most potent inducer of de novo lipogenesis[28] and therefore explains why the SHBG gene expression is remarkably responsive to fructose consumption. Studies in different human cohorts have shown that elevated liver fat content strongly correlated with circulating SHBG in humans.[35,36] These findings suggest that plasma SHBG levels may represent a useful biomarker of metabolic disturbances associated with excess sugar consumption.
MedDiet is a well-known and characterized diet distinguished by high intakes of vegetables, legumes, fruits, nuts, grains, fish, protein sources from seafood and poultry, olive oil and low-to moderate intake of red wine, as well as low intake of dairy products, red and processed meat, cream, and sugar drinks.[72,73] TheMedDiet is the most studied diet in the world and it has been associated with important health benefits. In this regard, several studies provided strong evidences of the MedDiet benefits on cardiovascular health, which not only includes reduction in the cardiovascular incident outcomes, but also in the associated risk factors such as obesity, hypertension, metabolic syndrome,and dyslipidemia. The MedDiet has been also related with a reduction of the risk in the development of developing T2D, a reduction in mortality and therefore an increase in longevity.[73,74] It is remarkable that olive oil and red wine, two of the most important components of MedDiet increased plasma SHBG levels, thus linking epidemiologically studies showing that subjects with low plasma SHBG levels have higher risk of suffering both CVD and T2D.[75,76] Therefore, specific studies addressed to examine the role of SHBG as an independent mediator of the relationship between olive oil and red wine consumption and the cardiovascular protective effects of the Mediterranean diet seem warranted.
Coffee is one of the most popular beverages in the world; although its impact on health outcomes and adverse effects is not fully understood. It is widely accepted that coffee consumption contributes to the prevention of inflammatory and oxidative stress-related diseases, such as obesity, metabolic syndrome, and T2D.[77] Recent results showed that caffeine upregulates hepatic SHBG expression by increasing adiponectin production through AKT/FOXO1 pathway in the adipose tissue.[61] Therefore, this could be one of the key mechanisms involved in the beneficial effects of caffeine in the prevention of metabolic diseases.
Overall, all these findings point to SHBG not only as a sex steroid carrier but also as a useful biomarker of type of diet consumption and metabolic diseases. Future research is needed in order to determine whether SHBG plasma levels could be a reliable biomarker of the success of dietary interventions in patients suffering from metabolic diseases.
