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Sex hormone-binding globulin as a potential drug candidate for liver-related metabolic disorders treatment (2022)
Nabila Bourebaba, ThuHa Ngo, Agnieszka Smieszek, Lynda Bourebaba, Krzysztof Marycz
ABSTRACT
Sex hormone-binding globulin (SHBG) is a hepatokine that binds to circulating steroid hormones (testosterone, oestradiol) to regulate their concentration in the bloodstream. Recently SHBG was recognized as an essential biomarker for metabolic syndrome (MetS) and hepatic steatosis development. At the hepatic level, the production of SHBG is mainly regulated by sex steroids and thyroxine. Studies of various research groups, including ours, showed that SHBG could be considered a reliable marker of insulin resistance and, therefore, can serve as a predictor of type 2 diabetes. Moreover, increased levels of circulating pro-inflammatory mediators strongly correlate with lowered serum levels of SHBG. This review paper emphasizes the role of SHBG as a potential drug candidate in the course of various metabolic dysfunctions, including non-alcoholic fatty liver disease (NAFLD), obesity, diabetes mellitus, and insulin resistance. The studies related to SHBG and its role in the course of metabolic disorders are very limited. Here, we have summarized the most current knowledge about SHBG and its mechanism of action, indicating a novel concept for its possible therapeutic application in the management framework of commonly occurring metabolic dysfunctions.
1. Introduction
Non-alcoholic fatty liver disease (NAFLD) represents a group of liver disorders affecting several extrahepatic organs and regulatory pathways. It is characterized by excess fat and steatosis in the liver, occurring independently from alcoholic intake in more than 5 % of hepatocytes. It is estimated that about 20/10,000 people are affected by NAFLD per year. The statistics show that NAFLD prevalence reaches 30–40 % of the male against 15–20 % of the female population. For unclear reasons, men are more prone to NAFLD than women. Additionally, the estimates are higher in people with type 2 diabetes mellitus (T2DM), occurring in up to 70 % of this group of patients [1]
The involvement of insulin resistance, oxidative stress and subsequent lipid peroxidation, pro-inflammatory cytokines, adipokines, and mitochondrial dysfunction in the pathological assent of NAFLD has been repeatedly demonstrated, which supports the link between this pathology and metabolic syndrome (MetS). Although the data are primarily epidemiological, the etiology of NAFLD and MetS appear to underline common pathophysiological mechanisms, emphasizing insulin resistance as a key factor during the development of both conditions. Thus, NAFLD is considered a hepatic representation of metabolic syndrome [2]. Insulin resistance is just as linked to the eventuality of the onset of type 2 diabetes mellitus (T2DM) as the accumulation of fat in the liver and this phenomenon is greatly increased in the presence of NAFLD. In addition, in patients with T2DM, the predominance of NAFLD (55–60 %) and non-alcoholic steatohepatitis (NASH) (± 37 %) is increased, which confers to T2DM the role of a predictor of hepatic disorders, morbidity, and mortality in patients with NAFLD [3].
Indeed, one of the main features of NAFLD associated with obesity is the hepatic absorption of fatty acids from blood plasma. The de novo synthesis of fatty acids becomes more significant than the oxidation and the export of fatty acids including lipotoxicity, which causes insulin resistance and pancreatic beta-cell dysfunction. In fact, increased circulating lipid levels and alterations in fatty acid utilization and intracellular signaling have been linked to hepatic insulin resistance [4, 5].
Infiltration of fat into the liver outcomes is associated with hepatocellular inflammation and the occurrence of fibrosis. Several factors mediate this process, including tumor necrosis factor (TNF-α). This pleiotropic cytokine is produced by cells of monocytic lineage and by immunomodulatory stromal cells. The overexpression of TNF-α leads to increased oxidative stress, as well as cell death in the liver. Consequently, this potentiates the development of hepatic fibrosis and ultimately progresses to a more severe condition, i.e. non-alcoholic steatohepatitis (NASH). In the course of NAFLD, the expression of TNF-α also increases at the hepatic level, highlighting the link between the development of insulin resistance and hepatic steatosis [6].
The liver is responsible for the production of fasting plasma glucose and very-low-density lipoprotein (VLDL) serum triglycerides. In patients suffering from NAFLD, the ability of insulin to suppress the production of glucose and VLDL is impaired [7]. In addition, NAFLD is not only limited to advanced liver disease but also affects other extrahepatic organs leading to severe complications. In fact, patients with NAFLD die more frequently from cardiovascular diseases and extrahepatic malignancies than from NAFLD or other resulting liver conditions [8]. In analogy to the functional proteins released from adipose tissue and skeletal muscle, liver-derived proteins are known as hepatokines. Ongoing studies aimed at hepatokines molecular mechanism of action may lead to the selection of novel promising biomarkers for new regiments of treatment dedicated to metabolic disorders and type 2 diabetes management.
Several proteins are exclusively or predominantly secreted by the liver and are now known to play a crucial role in maintaining metabolic homeostasis. Among them, sex-hormone-binding globulin (SHBG), which had been identified as a protective molecule against metabolic syndrome, acts on macrophages and adipocytes suppressing inflammation and lipid accumulation [9–11].
SHBG, also known as the sex steroid-binding protein (SBP) or estradiol testosterone binding globulin, is mainly secreted by hepatocytes. However, as an extracellular plasma glycoprotein, SHBG binds to circulating steroid hormones, including testosterone, dihydrotestosterone, and estradiol, in order to regulate their free concentrations in blood plasma; where this glycoprotein will act as a transporter of these sex steroids in order to regulate their bioavailability and access to target tissues and cells [12]. Epidemiological studies indicate that serum levels of SHBG are altered in the course of various metabolic dysfunctions including obesity, diabetes mellitus, and insulin resistance and that patients suffering from obesity excrete low levels of SHBG compared to normal-weight patients. This allows considering SHBG a good molecular predictor of MetS and hepatic steatosis development [12]. At the hepatic level, the production of SHBG is mainly regulated by sex steroids and thyroxine; it was suggested that insulin also acts as an important regulator and that low levels of SHBG can be considered a marker of insulin resistance and therefore a predictor of type 2 diabetes; furthermore, previous studies showed that overweight people, with a high BMI index, exhibited higher insulin levels and lowered circulating SHBG levels [13,14]. The molecular mechanism of T2DM lies in the dysfunction of phosphoinositide 3-kinase (PI3K) activation, which plays a key role in signal transduction during metabolism. Negative regulation of insulin receptor substrate 1/ insulin receptor substrate 2 (IRS1/IRS2) is therefore linked to a reduction in insulin sensitivity leading to a significant drop in the expression of SHBG. Besides hormone transportation (testosterone and estradiol), SHBG also acts as a signal transduction factor by regulating the expression of phosphoinositide 3-kinase/serine-threonine-protein kinases (PI3K/AKT) pathway components and consequently participating in the modulation of insulin signaling [14]. Recent epidemiological studies have demonstrated a reversed correlation between the plasma levels of several cytokines and SHBG in people with inflammatory diseases such as obesity and type 2 diabetes. In addition, when circulating pro-inflammatory cytokines levels increases, the plasma levels of SHBG decrease as well. This phenomenon is governed by pro-inflammatory cytokines (Tumor necrosis factor-alpha (TNF-α)) which are decreasing SHBG expression at the mRNA level through the suppression of its specific hepatocyte nuclear factor 4 alpha (HNF-4α) promotor activity in liver cells. However, the effect of TNF-α is indirect and is mediated by the nuclear factor kappa B (NF-kB) [15].
Many lines of evidence indicate that low circulating levels of SHBG can be considered an appropriate biomarker for insulin resistance and inflammation diagnosis. What is more, it could be a promising agent in terms of new therapeutic strategies aiming at regulating various metabolic pathways. In this review, we will discuss the main physiological functions of SHBG glycoprotein, with particular attention to its implication in cellular metabolism. We will also discuss its differential circulating levels in the body under normal and pathologic conditions. We will then focus on the implication of SHBG in the course of metabolic syndrome development (i.e., insulin resistance, liver inflammation, and NAFLD) and consider the possible therapeutic use of SHBG in the framework of metabolic disorders management.
The review was prepared based on 38 original experimental studies and 23 review papers. The articles were selected in the PubMed collection based using the keywords: "NAFLD", "metabolic syndrome", "SHBG’’ and their combinations. To this date, no review study has been published highlighting the link between the phenomena mentioned above. The present review will provide an overview of common pathophysiological mechanisms underlying NAFLD and MetS development. It will also show the role of SHBG as a hepatokine hampering the onset of insulin resistance, lipotoxicity as well as chronic low-grade inflammation. Moreover, the possible use of SHBG as a therapeutic candidate in the treatment of MetS-related liver diseases, notably NAFLD will be emphasized.
2. Sex hormone-binding globulin (SHBG): a hepatokine mainly produced by the liver
SHBG is a homodimeric plasma glycoprotein with a molecular mass of approximately 95 kDa, which is largely synthesized in the liver and secreted into the bloodstream. Its molecular weight depends partly on its glycosylation status. This extracellular plasma glycoprotein consists of two laminin G (LG)-type domains [10]. Two subunits are encoded by a gene located on the short arm of chromosome 17. The non-dimerized SHBG subunit comprises 373 amino acids, with three oligosaccharide side chains and two disulfide bonds. The homodimeric SHBG has two active and distanced steroid sites whose role is to bind to DHT, testosterone, or estradiol. Each monomer is composed of two β sheets, linked by eight hydrogen bonds, essential for forming the two continuous 14-strand b sheets of the mature homodimer [16].
2.1. SHBG synthesis pathway: transcription regulators
2.2. Physiological role of SHBG: a crucial hormone transporter
2.3. SHBG levels in the course of metabolic disorders
3. Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) crosstalk
4. Perspectives in the use of SHBG as a new therapeutic lead in NAFLD and MetS treatment
In this review, we have emphasized the vital role of SHBG and its regulation in the course of metabolic disorders. We have shown that SHBG is hampering ER stress in insulin-resistant hepatocytes, decreasing type 2 diabetes and counteracting the occurrence of high-fat diet-induced obesity, SHBG improved insulin sensitivity through stimulation of hepatic DNL. Collected data and our previous studies shed promising light on the potential significance of SHBG as a novel therapeutic target in the treatment of MetS and NAFLD.
Nabila Bourebaba, ThuHa Ngo, Agnieszka Smieszek, Lynda Bourebaba, Krzysztof Marycz
ABSTRACT
Sex hormone-binding globulin (SHBG) is a hepatokine that binds to circulating steroid hormones (testosterone, oestradiol) to regulate their concentration in the bloodstream. Recently SHBG was recognized as an essential biomarker for metabolic syndrome (MetS) and hepatic steatosis development. At the hepatic level, the production of SHBG is mainly regulated by sex steroids and thyroxine. Studies of various research groups, including ours, showed that SHBG could be considered a reliable marker of insulin resistance and, therefore, can serve as a predictor of type 2 diabetes. Moreover, increased levels of circulating pro-inflammatory mediators strongly correlate with lowered serum levels of SHBG. This review paper emphasizes the role of SHBG as a potential drug candidate in the course of various metabolic dysfunctions, including non-alcoholic fatty liver disease (NAFLD), obesity, diabetes mellitus, and insulin resistance. The studies related to SHBG and its role in the course of metabolic disorders are very limited. Here, we have summarized the most current knowledge about SHBG and its mechanism of action, indicating a novel concept for its possible therapeutic application in the management framework of commonly occurring metabolic dysfunctions.
1. Introduction
Non-alcoholic fatty liver disease (NAFLD) represents a group of liver disorders affecting several extrahepatic organs and regulatory pathways. It is characterized by excess fat and steatosis in the liver, occurring independently from alcoholic intake in more than 5 % of hepatocytes. It is estimated that about 20/10,000 people are affected by NAFLD per year. The statistics show that NAFLD prevalence reaches 30–40 % of the male against 15–20 % of the female population. For unclear reasons, men are more prone to NAFLD than women. Additionally, the estimates are higher in people with type 2 diabetes mellitus (T2DM), occurring in up to 70 % of this group of patients [1]
The involvement of insulin resistance, oxidative stress and subsequent lipid peroxidation, pro-inflammatory cytokines, adipokines, and mitochondrial dysfunction in the pathological assent of NAFLD has been repeatedly demonstrated, which supports the link between this pathology and metabolic syndrome (MetS). Although the data are primarily epidemiological, the etiology of NAFLD and MetS appear to underline common pathophysiological mechanisms, emphasizing insulin resistance as a key factor during the development of both conditions. Thus, NAFLD is considered a hepatic representation of metabolic syndrome [2]. Insulin resistance is just as linked to the eventuality of the onset of type 2 diabetes mellitus (T2DM) as the accumulation of fat in the liver and this phenomenon is greatly increased in the presence of NAFLD. In addition, in patients with T2DM, the predominance of NAFLD (55–60 %) and non-alcoholic steatohepatitis (NASH) (± 37 %) is increased, which confers to T2DM the role of a predictor of hepatic disorders, morbidity, and mortality in patients with NAFLD [3].
Indeed, one of the main features of NAFLD associated with obesity is the hepatic absorption of fatty acids from blood plasma. The de novo synthesis of fatty acids becomes more significant than the oxidation and the export of fatty acids including lipotoxicity, which causes insulin resistance and pancreatic beta-cell dysfunction. In fact, increased circulating lipid levels and alterations in fatty acid utilization and intracellular signaling have been linked to hepatic insulin resistance [4, 5].
Infiltration of fat into the liver outcomes is associated with hepatocellular inflammation and the occurrence of fibrosis. Several factors mediate this process, including tumor necrosis factor (TNF-α). This pleiotropic cytokine is produced by cells of monocytic lineage and by immunomodulatory stromal cells. The overexpression of TNF-α leads to increased oxidative stress, as well as cell death in the liver. Consequently, this potentiates the development of hepatic fibrosis and ultimately progresses to a more severe condition, i.e. non-alcoholic steatohepatitis (NASH). In the course of NAFLD, the expression of TNF-α also increases at the hepatic level, highlighting the link between the development of insulin resistance and hepatic steatosis [6].
The liver is responsible for the production of fasting plasma glucose and very-low-density lipoprotein (VLDL) serum triglycerides. In patients suffering from NAFLD, the ability of insulin to suppress the production of glucose and VLDL is impaired [7]. In addition, NAFLD is not only limited to advanced liver disease but also affects other extrahepatic organs leading to severe complications. In fact, patients with NAFLD die more frequently from cardiovascular diseases and extrahepatic malignancies than from NAFLD or other resulting liver conditions [8]. In analogy to the functional proteins released from adipose tissue and skeletal muscle, liver-derived proteins are known as hepatokines. Ongoing studies aimed at hepatokines molecular mechanism of action may lead to the selection of novel promising biomarkers for new regiments of treatment dedicated to metabolic disorders and type 2 diabetes management.
Several proteins are exclusively or predominantly secreted by the liver and are now known to play a crucial role in maintaining metabolic homeostasis. Among them, sex-hormone-binding globulin (SHBG), which had been identified as a protective molecule against metabolic syndrome, acts on macrophages and adipocytes suppressing inflammation and lipid accumulation [9–11].
SHBG, also known as the sex steroid-binding protein (SBP) or estradiol testosterone binding globulin, is mainly secreted by hepatocytes. However, as an extracellular plasma glycoprotein, SHBG binds to circulating steroid hormones, including testosterone, dihydrotestosterone, and estradiol, in order to regulate their free concentrations in blood plasma; where this glycoprotein will act as a transporter of these sex steroids in order to regulate their bioavailability and access to target tissues and cells [12]. Epidemiological studies indicate that serum levels of SHBG are altered in the course of various metabolic dysfunctions including obesity, diabetes mellitus, and insulin resistance and that patients suffering from obesity excrete low levels of SHBG compared to normal-weight patients. This allows considering SHBG a good molecular predictor of MetS and hepatic steatosis development [12]. At the hepatic level, the production of SHBG is mainly regulated by sex steroids and thyroxine; it was suggested that insulin also acts as an important regulator and that low levels of SHBG can be considered a marker of insulin resistance and therefore a predictor of type 2 diabetes; furthermore, previous studies showed that overweight people, with a high BMI index, exhibited higher insulin levels and lowered circulating SHBG levels [13,14]. The molecular mechanism of T2DM lies in the dysfunction of phosphoinositide 3-kinase (PI3K) activation, which plays a key role in signal transduction during metabolism. Negative regulation of insulin receptor substrate 1/ insulin receptor substrate 2 (IRS1/IRS2) is therefore linked to a reduction in insulin sensitivity leading to a significant drop in the expression of SHBG. Besides hormone transportation (testosterone and estradiol), SHBG also acts as a signal transduction factor by regulating the expression of phosphoinositide 3-kinase/serine-threonine-protein kinases (PI3K/AKT) pathway components and consequently participating in the modulation of insulin signaling [14]. Recent epidemiological studies have demonstrated a reversed correlation between the plasma levels of several cytokines and SHBG in people with inflammatory diseases such as obesity and type 2 diabetes. In addition, when circulating pro-inflammatory cytokines levels increases, the plasma levels of SHBG decrease as well. This phenomenon is governed by pro-inflammatory cytokines (Tumor necrosis factor-alpha (TNF-α)) which are decreasing SHBG expression at the mRNA level through the suppression of its specific hepatocyte nuclear factor 4 alpha (HNF-4α) promotor activity in liver cells. However, the effect of TNF-α is indirect and is mediated by the nuclear factor kappa B (NF-kB) [15].
Many lines of evidence indicate that low circulating levels of SHBG can be considered an appropriate biomarker for insulin resistance and inflammation diagnosis. What is more, it could be a promising agent in terms of new therapeutic strategies aiming at regulating various metabolic pathways. In this review, we will discuss the main physiological functions of SHBG glycoprotein, with particular attention to its implication in cellular metabolism. We will also discuss its differential circulating levels in the body under normal and pathologic conditions. We will then focus on the implication of SHBG in the course of metabolic syndrome development (i.e., insulin resistance, liver inflammation, and NAFLD) and consider the possible therapeutic use of SHBG in the framework of metabolic disorders management.
The review was prepared based on 38 original experimental studies and 23 review papers. The articles were selected in the PubMed collection based using the keywords: "NAFLD", "metabolic syndrome", "SHBG’’ and their combinations. To this date, no review study has been published highlighting the link between the phenomena mentioned above. The present review will provide an overview of common pathophysiological mechanisms underlying NAFLD and MetS development. It will also show the role of SHBG as a hepatokine hampering the onset of insulin resistance, lipotoxicity as well as chronic low-grade inflammation. Moreover, the possible use of SHBG as a therapeutic candidate in the treatment of MetS-related liver diseases, notably NAFLD will be emphasized.
2. Sex hormone-binding globulin (SHBG): a hepatokine mainly produced by the liver
SHBG is a homodimeric plasma glycoprotein with a molecular mass of approximately 95 kDa, which is largely synthesized in the liver and secreted into the bloodstream. Its molecular weight depends partly on its glycosylation status. This extracellular plasma glycoprotein consists of two laminin G (LG)-type domains [10]. Two subunits are encoded by a gene located on the short arm of chromosome 17. The non-dimerized SHBG subunit comprises 373 amino acids, with three oligosaccharide side chains and two disulfide bonds. The homodimeric SHBG has two active and distanced steroid sites whose role is to bind to DHT, testosterone, or estradiol. Each monomer is composed of two β sheets, linked by eight hydrogen bonds, essential for forming the two continuous 14-strand b sheets of the mature homodimer [16].
2.1. SHBG synthesis pathway: transcription regulators
2.2. Physiological role of SHBG: a crucial hormone transporter
2.3. SHBG levels in the course of metabolic disorders
3. Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) crosstalk
4. Perspectives in the use of SHBG as a new therapeutic lead in NAFLD and MetS treatment
In this review, we have emphasized the vital role of SHBG and its regulation in the course of metabolic disorders. We have shown that SHBG is hampering ER stress in insulin-resistant hepatocytes, decreasing type 2 diabetes and counteracting the occurrence of high-fat diet-induced obesity, SHBG improved insulin sensitivity through stimulation of hepatic DNL. Collected data and our previous studies shed promising light on the potential significance of SHBG as a novel therapeutic target in the treatment of MetS and NAFLD.
