The estrogen receptor and metabolism

Abstract

Across the globe, metabolic syndrome, hyperuric acid, and their related diseases, such as cardiovascular disease, diabetes, and insulin resistance, are increasing in incidence due to metabolic imbalances. Due to the pathogenesis, women are more prone to these diseases than men. As estrogen levels decrease after menopause, obesity and metabolic disorders are more likely to occur. Men are also affected by hyperuric acid. To provide ideas for the prevention and treatment of metabolic syndrome and hyperuricemia, this article reviews and analyzes the relationship between estrogen receptors, metabolic syndrome, and hyperuricemia.

Plain language summary

Influence of estrogen receptor on metabolic syndrome and hyperuricemia

A narrative review discusses the mechanism of estrogen and estrogen receptors for metabolic syndrome and hyperuric acid, and highlights the important for prevention and treatment of metabolic balances.

Introduction

Metabolic syndrome (MS) has become a new epidemic of this century, and various factors such as age, lifestyle, and gender all play a role in promoting the prevalence of MS.^1,2 The incidence of MS-related diseases is rapidly increasing, such as cardiovascular, type-2 diabetes, and abdominal obesity. Furthermore, MS increases the risk of cancer, depression, Alzheimer’s disease, and stroke.^{3 –7} MS has become a disease that cannot be ignored and should be prevented resolutely. Women are more likely to develop MS after menopause, especially. As estrogen levels decrease and estrogen receptors (ERs) become less sensitive, women’s normal metabolism is severely affected. ⁸ Obesity, insulin resistance, and hypertension are also on the rise, making everyday life challenging. As an introduction to MS, we will discuss ERs. We will also summarize how ERs contribute to glucose homeostasis, insulin resistance, and hyperuric acid, anticipating new insights into pharmacology. Several aspects of MS are discussed, in an effort to facilitate understanding, prevention, and early detection of the hazards of the disease. Moreover, we also discussed the intrinsic link between ERs and hyperuric acid, hoping to uncover its pathogenesis, as hyperuric acid also has obvious effects on people, especially men.

Definition of MS

MS refers to a pathological state in which the metabolism of proteins, fats, carbohydrates, and other substances in the human body is disordered. It is a complex syndrome of metabolic disorders that is a risk factor for cancer, diabetes, and depression, among other diseases. Various definitions have been developed by different organizations to better determine whether a patient has MS. As shown in Table 1, the World Health Organization, the National Cholesterol Education Program’s Adult Treatment Panel III (ATP III), International Diabetes Federation, and the European Group on Insulin Resistance have defined the criteria, respectively.^3–6 As the criteria of the World Health Organization, when the patient’s symptoms meet the conditions of glucose regulation or hyperinsulinemia and the two necessary criteria will it be diagnosed as MS. However, in the European Group on Insulin Resistance, the MS is diagnosed and just needs to meet hyperinsulinemia and the other two necessary criteria. There are differences between these standards, which may be due to the different data objects collected. It needs to be judged by the actual condition of patients for better and more precise treatment.

Table 1.

The criteria of the World Health Organization, the National Cholesterol Education Program’s ATP III, International Diabetes Federation, and the European group on insulin resistance, respectively.

Risk factors	The World Health Organization (impaired glucose regulation or hyperinsulinemia and two of criteria necessary)	The National Cholesterol Education Program’s ATP III (three of five criteria necessary)	International Diabetes Federation (increased waist circumference plus any two of other four criteria)	The European group on insulin resistance (hyperinsulinemia and two of criteria necessary)
Fasting glucose (mg/dL)	⩾110	⩾110	⩾110	⩾110
Prandial glucose	>140 mg/dL	–	–	–
Hyperinsulinemia	Fasting serum insulin: third quartile for the control group	–	–	Fasting serum insulin third quartile for the nondiabetic control group
Hypertriglyceridemia (mg/dL)	⩾150	⩾150	⩾150	–
High-density lipoprotein (mg/dL)
Men	<35	<40	<40
Women	<39	<50	<50
Abdominal obesity
Men	>0.9 in	> 02 cm	⩾94 cm	⩾80 cm
Women	>0.85 in	>88 cm	⩾80 cm	⩾80 cm
Hypertension (mm Hg)	⩾140/ 90	⩾130/g85	⩾130/g85	⩾140/g90
Microalbuminuria	⩾20 μg/min	–	–	–

ATP III: adult treatment panel III.

The effects of MS and hyperuric acid

As the definition of MS describes, MS means that the health index of people has deteriorated and there is a metabolic imbalance. ⁷ Intuitively, the fasting glucose and prandial glucose both will be increased. In addition, several or more other indicators are also high, such as hyperinsulinemia, hypertriglyceridemia, high-density lipoprotein, abdominal obesity, and hypertension. The imbalance of single or multiple indicators leads to the appearance of MS. More importantly, the accumulation of these metabolic disorders not only cause MS but also underlies the pathological basis of other diseases, such as diabetes, cardiovascular disease, and cancer.

Obesity and insulin resistance are the most common symptoms and manifestations of MS. ⁹ At present, it is believed that insulin resistance and hyperinsulinemia are caused by obesity, especially central obesity. It can also cause various diseases, such as hypertension, coronary heart disease, and stroke. Hence, obesity is the most major and most prone influence of MS.

In addition, epidemiological studies have found that MS also will enhance the risk of cancer. ⁸ Sex hormone-related endometrial cancer, prostate cancer, digestive system-related pancreatic cancer, liver cancer, gallbladder cancer, colon cancer, and so on all have relationships with MS. Most components of MS are somehow linked to the development of cancer. Therefore, MS almost affects many common and prone diseases, which undoubtedly need to be paid attention to.

Furthermore, similar to MS, hyperuricemia is also a common disease.^10,11 Changes in dietary structure make its incidence higher and higher. Gout, urate deposition, and other symptoms are troublesome and affect people’s normal life. However, effective treatment methods have not been found. Hence, understanding the impact and harm of MS and hyperuricemia has far-reaching significance for us to prevent these diseases.

Main factors affecting MS

MS is a complex disorder whose etiology is unclear. It is currently considered to be the result of multigene and multi-environmental interaction, and is closely related to heredity and immunity. ¹² In addition, the disease is affected by a variety of environmental factors, focusing on high-fat, high-carbohydrate diets, increasing the occurrence of insulin resistance, and less exercise, leading to the occurrence and development of MS.

For heredity, genes are the material basis of inheritance and the code of life, recording and transmitting genetic information. All life phenomena such as the birth, growth, disease, aging, and death of organisms are related to genes. Genes also will influence the development of MS in multiple ways.^13,14 One of these ways is extracellular signal-regulated kinase-1 (ERK-1) and extracellular signal-regulated kinase-2 (ERK-2). ERK-1 and ERK-2 play an important role in transmitting signals from the cell surface into the cell and are involved in many cell processes, including cell adhesion, migration, proliferation, and differentiation and maintenance of the cell cycle. ERK-1 and ERK-2 pathways are one of the largest signaling networks in the cell and are closely related to insulin metabolism. Genetic problems that are seen in this pathway may cause MS. It is stated that this pathway is related to polycystic ovary syndrome (PCOS) syndrome and PCOS is related to ER density. Considering that PCOS is associated with MS, it is quite logical that genetic problems that may be seen in the ERK-1 and ERK-2 pathways are associated with MS. ¹⁵ As shown in Table 1, these key components of MS all have a genetic basis. Candidate genes of insulin resistance, dyslipidemia, hyperinsulinemia, and high-density lipoprotein all have been identified. In addition, genetic variants are consistently association with the risk of developing the disease. For example, the basal insulin receptor substrate-1 (IRS1) is a key component of the insulin signaling pathway, which will initiate the activation of phospho-inositide 3-kinase (PI3K) in response to insulin.^{16 –18} Both lower IRS1 protein levels and reduced activity of PI3K will influence the expression of insulin.^18,19 In addition, genome-wide association studies have identified that at least 56 loci are reproducibly associated with obesity. In total, 157 with lipids and more than 90 loci are associated with hypertension as well as the numerous loci are associated with type 2 diabetes. ²⁰ In addition, the occurrence of these individual component diseases is affected by these loci variants. The associations might facilitate the development of the MS.

Lifestyle also is a risk factor for MS. ² A balanced diet, regular exercise, optimal sleep, stress relief, and maintenance of appropriate weight are the foundations for maintaining optimal health, which will effectively reduce the occurrence of diseases, including MS, diabetes, and cancer. In addition, poor dietary habits and lack of exercise are easily led to obesity and the incidence rate of MS. The studies have demonstrated that the western diet, which is enriched in protein, alcohol, and n-6 fatty acid, is associated with a higher risk for obesity, cardiovascular diseases, diabetes, and cancer. Furthermore, poor dietary habits, such as snacking and drinking alcohol, will obviously influence the metabolic balance and normal hormone levels, which are associated with a high risk of these diseases.

Age, diet, family history, and exposure to environmental toxins all will influence the occurrence and development of MS. Oxidative stress, alterations in glutamate homeostasis, neuroinflammation, accumulation of toxic peptides, and loss of synapse may all promote the development of MS. Therefore, we need to maintain a healthy lifestyle to reduce the incidence of MS.

Types, production, and distribution of ERs

Up to now, estrogen and ERs have been studied and proved that they have a significant impact on MS, which can be found in perimenopausal women. In addition, women extensively suffer from MS after menopause. The symptoms, such as obesity, insulin resistance, and hypertension, are more likely to occur. The main reason is associated with the expression of estrogen and ERs, leading to the disorder of energy balance, glucose homeostasis, and the abnormal distribution of adipose tissue. ²¹

Estrogen and ERs play important roles in the preservation of disease-free health. Estrogen is a female steroid compound secreted by ovary, placenta, and other organs, which has a wide range of important physiological roles. ²² There are mainly two forms of estrogen, including estradiol and estriol. It not only promotes and maintains the physiological effects of female reproductive organs and secondary sexual characteristics, but also has obvious effects on endocrine, cardiovascular, metabolic systems, bone growth and maturation, skin, and so on. Estrogen is essential in regulating various physiological processes of cell growth, reproduction, development, and differentiation.

ERs are transcription factors for the estrogen and also play indispensable roles in human tissues, which are composed of NH₂-terminal domain (NTD), DNA-binding domain (DBD), and COOH-terminal ligand-binding domain (LBD), and these are the three functional domains.^23,24 According to different NTD, ERs can be divided into two types, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), which have multiple splice variants with unknown functions and exhibit tissue specificity in expression and function. Between the two isoforms, there is only 16% similarity in NTD. In addition, the DBD is highly consistent between ERα and ERβ with 97% amino acid identity. For LBDs, the overall amino acid sequence identity between the two isoforms is 59%, and the ligand-binding pockets of the two isoforms show only minor structural differences. Based on the alternative splicing of ER-mRNAs, three ERα isoforms and at least four ERβ isoforms have been identified.

The ERα gene is located on the long arm of chromosome 6 (6q24-27), and the ERβ gene is located on the long arm of chromosome 14 (14q22-24). ²³ ERα is mainly distributed in breast, uterus, and vagina to play a dominant role, while ERβ plays an important role in hypothalamus, thymus, spleen, lung, ovary, prostate, and testis. ²⁵ The classic mechanism of ERs is the diffusion of estrogen and tight binding of receptor. It regulates gene expression by binding to estrogen response elements on target genes or interacting with essential transcription factors to activate or inhibit target gene expression. These two types of receptors are expressed in adipose tissue, skeletal muscle, liver and pancreas, and other metabolic tissues, as well as in the central nervous system, and are involved in the regulation of multiple functions. For these two ERs, studies have shown that ERα has a relatively large correlation with the occurrence of MS. ²⁶ The expression of ERα has a significant impact on human energy intake, fat distribution, insulin sensitivity, and metabolism. The follow-up dissertation reviews the effects of ERs on obesity, insulin resistance, glucose metabolism, and hyperuric acid.

The mechanisms of ER

Estrogen has been clearly demonstrated that play an important role in the regulation of many complex physiological processes in humans via ERα and ERβ. ²⁷ In this process, ERα and ERβ as transcription factors have a pivotal role. Both estrogen deficiency and abnormal ER signaling will promote metabolic dysfunction predisposing to MS, insulin resistance, and hyperuric acid. The main causes for the above three diseases are energy accumulation and the changes in fat distribution, in which ERα and ERβ play distinct and important roles.

ERα plays a crucial role in controlling energy balance and maintains normal body weight. There is a high level of expression of ERα in the ventromedial nucleus of hypothalamic neurons due to a high density of estrogen-binding sites. ²⁸ A follow-up study using ovariectomized and gonad-intact female mice and rats has been proved this phenomenon. ²⁹ After ERα knockdown, mice developed several features, such as weight gain, increased visceral adiposity, hyperphagia, and hyperglycemia, which correspond to symptoms of MS. Compared with the controlled mice, ERα-silenced animals consumed more food. Food intake in ERα silenced female mice never decreased after implantation of 17-estradiol-3-benzoate particles. ³⁰

Consistent with this finding, hyperphagia was also observed in gonad-intact females after ERα silencing. Moreover, energy expenditure was reduced in ERα-silenced mice. Furthermore, leptin is a powerful catabolic signal, which suppresses food intake and increases energy expenditure. Leprb is associated with ERα, which is expressed by ERα in the brain.

Excessive food intake and low energy consumption will undoubtedly lead to high levels of blood glucose, which will give rise to the accumulation of lipid in the long term. ERα plays an important role in maintenance of glucose homeostasis. ERα is a positive regulator of glucose transporter 4 (GLUT4) and can increase levels of GLUT4 to regulate the entry of extracellular glucose into cells. ³¹ In addition, inappropriate expression can lead to consequently impaired glucose homeostasis and insulin resistance. Studies have revealed that the regulation of glucose homeostasis is obviously affected by estrogen signaling pathway via ERα. The deficiency of ERα will reduce the sensitivity of insulin and result in insulin resistance, which will increase the glucose level in the whole body. ³² Experiment with ovariectomized female mice and estrogen receptor alpha knockout (ERαKO) mice has demonstrated the importance of ERα. Compared with the control mice, islets of ovariectomized female mice insulin secretion were significantly less in response to glucose. In addition, there were no changes in glucose-induced insulin release in isolated ERαKO mice islets. With the treatment of estradiol and progesterone, the effect of the ERαKO mice was abolished.

In the field of food intake, energy expenditure, and glucose, ERα exhibits important regulatory functions. In addition, ERα plays a more important role in insulin regulation, which will be discussed in the section on insulin resistance. Based on different transcriptional activities and promoter contexts from ERα, ERβ expresses distinct estrogenic signals during general physiologic processes via its tissue-specific biological actions. For glucose homeostasis, ERβ also plays an important role, and it has a suppressive role in GLUT4. ³³ With the reduction in GLUT4, the absorption and conversion of glucose will be decreased, which interacts with ERα plays a key role in the balance of energy metabolism. Compared with ERαKO mice, the body weight of ERβKO mice did not increase significantly and was similar to that of wild-type (WT) mice. In addition, ERβ also has the function of metabolic regulation of lipid metabolism and fat subdivision. Overall, compared with ERα, ERβ may play a limited role in MS. In addition, the physiological functions of ERβ have not been revealed clearly, which need be further investigated for full knowledge and understanding.

Obesity and ER

Obesity can be defined as excess body fat, indicating a high percent body fat. ³⁴ Body mass index (BMI) is usually used to assess body fat and has a higher feasibility and lower cost than the test of percent body fat. ³⁴ A BMI of 25–29 kg/m² is called overweight, and a higher BMI (⩾30 kg/m²) is called obesity. In today’s society, bad living habits and overeating make people more prone to obesity. Obesity is an important and common manifestation of MS, and it can also cause cardiovascular disease, diabetes, and other diseases. ER has a significant effect on obesity, the presence of obesity, and the division of fat.^{35 –37}

ERα and ERβ have been revealed that they have regulating effects on weight gain, fat partitioning, and associated comorbidities.^36,38,39 This study has proved that ablation of estrogen signaling in hypothalamic neurons leads to weight gain. In neurons of the ventromedial hypothalamus, steroidogenic factor-1 (SF1) is an important factor in the compensatory increase after exposure to a hypercaloric diet. In addition, the expression of SF1 will suppress ERα expression, resulting in increased adipocyte size and triglyceride content in gonadal and visceral adipose tissue. ⁴⁰ Furthermore, based on tissue-specific suppression of ERα, which is also important for food intake, affects the expression of pro-opiomelanocortin (POMC). ⁴¹ In addition, POMCs are important for the regulation of food intake. Therefore, for women, after entering menopause, body fat accumulation will increase significantly due to the reduced expression of ERα. Meanwhile, depending on the different distribution of ERα, fat accumulates in different tissues. The abdominal fat easily accumulates when the body fat is increased. In addition, affected by menopause, women are more prone to develop abdominal obesity than men.

Furthermore, ERβ does have an effect on obesity. In ERαKO mice, removal of ERβ signaling can decrease body and fat-pad weights and adipocyte size.^29,42 This study also suggested that ERβ has an opposite impact on adipose tissue than ERα. The interaction of ERs affects body weight and fat distribution.

Hence, ERs play an important role in obesity and adipose distribution of humans. We need to analyze and understand the mechanism by which ERs induced obesity to better treat and prevent obesity and MS.

Insulin resistance and ER

Insulin resistance has been defined as the inability of insulin to stimulate glucose uptake and disposal. It is one of the main symptoms of MS and the pathogenesis of type II diabetes, which is a disease prone to perimenopausal women. However, no effective treatment method has been found, which has troubled doctors and patients for many years. The main cause of insulin resistance is high level of blood glucose caused by obesity. As for pathogenesis, ERs are involved in and closely related to the cause of insulin resistance.

Research has shown that the absence of ERα has a high probability of causing insulin resistance. ³⁸ ERα-dependent mechanisms involved in insulin resistance have been widely studied for therapy. In ERα-deficient animals, insulin is all significantly elevated. As we know, insulin is a biological signal to increase glucose transport in adipocytes and myocytes by stimulating the translocation of GLUT4 for the balance of glucose. When glucose concentration is high, the body compensates by secreting excess insulin, leading to hyperinsulinemia, to maintain glucose stability. In ERαKO mice which is without ERα, the content GLUT4 is very low and insufficient to regulate the entry of extracellular glucose into the cell. Meanwhile, the phosphorylation concentration of Adenosine monophosphate (AMP-activated protein kinase (AMPK)) is also decreased, which can enhance glucose transport. ⁴³ After using ER subtype-selective ligand propylpyrazoletriyl (PPT), which can activate ERα, the insulin signaling pathway is potentiated, AMPK is activated, and GLUT4 protein is also increased. The glucose concentration of ERαKO mice naturally returned to normal levels. In the case of sufficient insulin, without the presence of ERα, the glucose content will not decrease obviously. ERα plays an important role in the transport and conversion process of glucose.

In addition, ERα also influences insulin sensitivity, and low insulin sensitivity also is a factor in insulin resistance. In ERα-deficient animals, the adiponectin also will markedly decrease, which is an adipokine positively associated with insulin sensitivity. AMPK is signaling pathways to activate adiponectin, which is also influenced by ERα. ⁴³ In the absence of ERα, the signaling pathways will not be expressed to enhance insulin sensitivity. Apart from adiponectin, there are other adipokines that are thought to be associated with MS, one of which is endotrophin. Endotrophin is secreted secondarily to a metabolic problem, especially in adipose tissue, and plays a key role in many events such as inflammation, chemotaxis, apoptosis, angiogenesis, and regulation of myofibroblast accumulation. Endotrophin accumulation in the extracellular environment causes fibrosis which leads to secretion of proinflammatory cytokines, and these proinflammatory cytokines are associated with MS, diabetes mellitus, atherosclerosis, and some cancers such as breast and colon cancers. ⁴⁴

Herein, ERα has an important function in glucose uptake of the insulin signaling pathway. ERα activation may explain the protection effect against insulin resistance. The relationship between ERα and insulin may provide new therapeutic ideas for maintaining glucose metabolism and MS. However, comparing with ERα, there are few reports about ERβ with glucose tolerance. In addition, researchers need to explore more to clarify the relationship, so as to regulate insulin resistance and treat MS.

Hypertension

Hypertension is usually defined as a chronic increase in systemic arterial pressure above a certain threshold, which is more than 140/90 mm Hg. In today’s society, the prevalence of hypertension has been increasing. In China, 23.2% of Chinese adult (⩾18 years of age) population had hypertension, which is in pessimistic situation. More importantly, hypertension has serious impact and health hazards on multiple sclerosis and cardiovascular diseases. There are many causes of hypertension, such as increased sympathetic nervous system activity, overproduction of sodium-retaining hormones, and deficiencies of vasodilators. In addition, ERs also have a significant effect on hypertension.

In postmenopausal women, the incidence of hypertension tends to increase, because of the deficiency of estrogen and endogenous estrogen, which are mediated via ERs.^45,46 There are about 75% of postmenopausal women are hypertensive in the United States. ⁴⁶ ERs are involved in multiple functional mechanisms in humans. For example, ERs can regulate the endothelium-independent vasodilation and inhibit the vascular renin–angiotensin–aldosterone system, keeping a normal blood pressure.^{46 –48} Meanwhile, recent studies have proved that ERα-mediated estrogen protection against angiotensin II (Ang II)-induced hypertension in conscious female mice. ⁴⁹ Compared with ERαKO female mice, the WT female mice have a low blood pressure induced by chronic infusion of Ang II. In addition, in ERαKO mice, the response to Ang II remains the same irrespective of estrogen levels. In addition, ERβ also has an important role in blood pressure regulation in female mice, and it can suppress elevated blood pressure by the reduction in hypertension induced by Ang II.^50,51 Hence, both ERα and ERβ play an important role in hypertension, and we need to urgently analyze the mechanism of ERs in lowering blood pressure to better prevent and treat hypertension.

Hypertension is one of indicators of MS and has seriously influenced people’s life. We not only need to understand the regulation mechanism of estrogen and ERs on it, but also must pay attention to standardizing the normal diet and habits, which can prevent the occurrence of hypertension, such as low intake of salt and more exercise.

Hyperuric acid

Current research suggests that hyperuric acid exhibits an increased risk of MS in human. For women, the incidence of hyperuric acid greatly increases after menopause. ⁵² Hyperuric acid leads to an increase in blood pressure, serum triglycerides, hyperinsulinemia, weight gain, and the risk of kidney disease, which have seriously affected people’s health. In addition, ERs play an important role in regulating uric acid metabolism, which has been proved in the symptoms of patients with hyperuric acid and animal experiments. ⁵³

Uric acid is mainly produced during the metabolism of fructose in the liver, and the mechanism has been previously studied. Fructose enters liver cells, where it is rapidly phosphorylated to fructose 1-phosphate by fructokinase. During this reaction, ATP (α, β-methylene ATP) will transform to ADP (α, β-methylene ADP), which is further metabolized to uric acid. In addition, the kidney plays an important role in the regulation of uric acid levels, where uric acid is filtered via the glomeruli into renal tubule. By urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9), most of uric acid will be reabsorbed to regulate blood uric acid levels. ⁵⁴ In the process of production and reabsorption, estrogen and ERβ are involved in signal translation and regulation. Because ERβ, but not ERα, is expressed on renal tubular epithelial cells.^55,56 ERβ may mediate the regulation of estrogen on GLUT9, which may be achieved through ERβ-induced autophagy in renal tubular epithelial cells. ⁵⁷

The uric acid transporters are the most important and tightly regulate for the excretion and reabsorption of uric acid. The URAT1/SLC22A12, OAT4/SLC22A11, and OAT10/SLC22A13 amino acid sequences are the gene promoter sequences of the uric acid reabsorption transporters. ⁵⁸ Among the three amino acid sequences, the URAT1/SLC22A12 gene promoter is conserved by estrogen response. By intervening in the ER modulators, 27-hydroxycholesterol, it can effectively promote the expression of URAT1/SLC22A12 and the upregulation of serum uric acid levels. ⁵⁹

Epidemiological studies have shown that enhancing the serum estrogen levels can decrease serum uric acid levels in male-to-female transsexuals, which is by renal uric acid excretion. ⁶⁰ In addition, in ovariectomized mice, the estradiol will induce the downregulation of urate resorptive transporters URAT1 and GLUT9 to increase the urate excretion. By transcribing the signal of estrogen, ERα and ERβ both have regulated the metabolism of uric acid.^53,56 ERα has been proven that it is associated with hyperuricemia. In addition, the ERβ affects GLUT9 transport activity in the kidney. However, relatively little has been explained about the mechanism of ERs regulating uric acid metabolism. The correlation between hyperuric acid and ERs needs to be further investigated and provides potential treatments for hyperuricemia-related diseases.

The treatment of the MS

Over the past few decades, the prevention and treatment of MS has been an important target for improving people’s health.^61,62 However, after people with MS, the change of life style to regulate the body metabolism to improve the health is inefficient and no quick results. Through the combination of case analysis and experiments, researchers continue to uncover the etiology of MS, to reveal the pathogenesis of MS and formulate efficient treatment and prevention methods. According to the definition criteria of MS, the management of diabetes, hyperlipidemia, hypertension, and uric acid is very important for MS. These indicators can serve as main targets of treatment, which is an effective method. We can prevent and treat individual symptoms to prevent MS, such as regulating glucose levels, preventing insulin resistance, and reducing uric acid levels. Under the usual concentration of estrogen and ERs, sugar intake, energy consumption, and fat storage can be effectively regulated to prevent the occurrence of obesity. At the same time, it can prevent insulin from resisting and control blood sugar levels, preventing diabetes. In addition, for the high incidence hypertension and hyperuric acid, the regulation of estrogen and ERs can effectively target the endothelium-independent vasodilation, Ang II, GLUT9, and other function organizations to maintain blood pressure and uric acid. By regulating estrogen and ERs, the corresponding hormones that regulate insulin, uric acid, and hypertension can be further autonomously regulated to lower blood sugar, uric acid levels, and blood pressure. As shown in Figure 1, through treating each individual condition, the incidence of MS can be effectively prevented and reduced. The influence of estrogen and ERs on MS is constantly being analyzed and revealed, and methods to treat MS through these factors are continuously developed, which is more effective and less negative.

Figure 1.

Schematic diagram of mechanism of estrogen and estrogen receptors on metabolic syndrome.

Hormone therapy is currently used to treat MS and to restore metabolic balance in human body. However, hormones will cause other adverse effects. For example, the sensitivity of hormones will continue to decline, and the body’s metabolism will continue to rely on hormones. Therefore, a healthy lifestyle is the best way to prevent and treat MS. A healthy diet and exercising are important to maintain normal blood glucose, insulin levels, and blood pressure. Without excessive food uptake, obesity can be effectively prevented. The incidence of insulin resistance, hyperuricemia, and diabetes all will be effectively reduced, because obesity is the main cause of these diseases. Furthermore, bad habits should be resisted, which can increase the risk of heart disease and heart attacks, such as smoking and alcohol.

This review was focused on providing an overview of the available literature on the pathology of MS and hyperuricemia, as such it has a few limitations. This review does not focus on clinical recommendations nor does it cover the evidence behind specific impact of behavioral factors on the impact of MS and hyperuricemia. This review does show that the pathology, harm, and prevention of MS, hoping to contribute our efforts to the treatment of MS.

Conclusion

MS and hyperuric acid cause many complications and risks. Now, the incidence of MS is increasing, especially for menopausal women, and men are also plagued by hyperuric acid. Therefore, it is important to reveal the pathogenesis and find treatment methods. Meanwhile, the harmfulness of MS and hyperuric acid also needs to be informed, which will enhance the awareness of prevention. People need a healthy lifestyle to prevent diseases and keep healthy. Here, we briefly outline the definition, harm, and treatment of MS, and the relationship between the ER and MS, hoping to contribute our efforts to the treatment of MS. Similarly, we also want to find effective methods to treat and prevent hyperuricemia by analyzing the role of ER in the pathogenesis of hyperuricemia.