Molecular Functions Of Ceruloplasmin in Metabolic Disease Pathology Part 2

Fe is very important to a variety of functions in the body, including DNA synthesis, gene expression, and the synthesis of hemoglobin and various enzymes. An increasing number of studies have found that Fe metabolism disorder leads to insulin resistance and obesity.57,58 

There is an inseparable link between gene expression and memory. Studies have shown that our genes can affect our intelligence and memory. In addition, our behavior and lifestyle can also affect gene expression, thereby affecting our memory ability.

First, genes are the basis of human intelligence and memory. Studies have shown that some genes affect memory formation, storage, and retrieval. For example, some genes encode proteins that help nerve cells connect and store information. Other genes affect synaptic plasticity, which is the ability of neural circuits to change. The expression level and variation of these genes directly affect our intelligence and memory.

Second, our behavior and lifestyle can also affect gene expression and affect our intelligence and memory. For example, lifestyle habits such as exercise, diet, and sleep can affect gene expression. Exercise can not only increase physical health but also improve cognitive ability. Ingredients such as antioxidants, vitamins, and minerals in the diet can promote brain health, thereby improving memory. Adequate sleep can help the brain clear garbage and maintain health.

In addition, mental state can also affect memory. Studies have shown that negative mental states such as stress, depression, and anxiety can damage brain function, thereby affecting memory. Therefore, controlling emotions and maintaining a positive attitude are the keys to promoting memory and intelligence.

In summary, our genes, lifestyles, and mental states can all affect our intelligence and memory abilities. A positive lifestyle and mentality, as well as scientific gene management, can help us achieve better memory and intelligence. This shows that we need to improve our memory, and Cistanche deserticola can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidative and inflammatory responses in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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The Fe in the diet is dominated by Fe3+, which is reduced to Fe2+ by duodenal cytochrome B (DcytB) on the top membrane of intestinal epithelial cells and then transported by divalent metal transporter-1 (DMT1) through intestinal epithelial cells and by TF to the liver through portal vein circulation.59,60 

After entering the liver, Fe is used to synthesize Fe-containing proteins, and the remainder is oxidized.61 As ferrous oxidase, CP plays an important role in the regulation of Fe balance in vivo. 

The transmembrane transport of Fe in vivo requires a specific protein carrier, ferroportin (Fpn). The CP-ferroportin system is the main output pathway of intracellular Fe.62 Although many proteins are involved in the absorption of Fe, the only confirmed output system of Fe in the cell is the CP-Fpn system.63 CP in plasma oxidizes Fe2+ to Fe3+, which could bind to Fpn and then transport it to target cells. 

After endocytosis, Fe is metabolized or stored.62 The liver is the first organ to receive Fe from the intestine, and it is also an important target organ for Fe toxicity. Fe staining in patients with liver cancer shows that excessive Fe is deposited in nontumor tissues,64 and the expression of CP in nontumor tissues is significantly higher than that in tumor tissues. 

Fe deposition occurs in 60–95% of epithelial parenchyma cells of the liver. Histology shows that Fe deposition decreases from the portal vein to the lobular center, and the expression of CP also decreases gradually. 

This indicates that the high expression of CP in Fe deposition is related to the involvement of CP in iron oxidation.64 In addition, Cu levels in individuals with CP-deficient genes and aceruloplasminemia are normal or decreased, but Fe metabolism is seriously dysfunctional, and the use of Fe-chelating agents could play a therapeutic role.65 These results show the indispensable role of CP in the process of Fe transport.

Antioxidant Activities

The antioxidant mechanism of plasma CP is the activity of ferrous oxidase, cuprous oxidase, and glutathione peroxidase and its ability to scavenge ROS. CP is an important antioxidant that can convert divalent Fe into less toxic trivalent Fe without releasing ROS. 

At the same time, CP can further utilize the antioxidant effect, reduce metal toxicity in vivo, and avoid tissue damage and dysfunction in the body.66,67 As early as 1982, Goldstein et al68 found that normal concentrations of CP in serum can inhibit the reduction of n-ferritin C regulated by xanthine oxidase, which is similar to the scavenging effect of superoxide dismutase (SOD) on O2-. 

In general, the Fenton reaction can occur with Fe2+ in H2O2 (Fe2++H2O2→Fe3++OH− +OH+ ), but when CP exists, Fe2+ can be oxidized to Fe3+ through its Fe oxidase activity, so the Fenton reaction can be eliminated and the antioxidant effect can be realized.69 

Compared with the scavenging effect of SOD on free radicals, the effect of CP is weak, but it is relatively constant; even in the case of denaturation of the protein, it still maintains the effect of scavenging free radicals. 

This phenomenon may be the result of a direct chemical reaction between CP and O2-. Both active CP and denatured CP can bind to Cu2+ in blood and tissue fluid, significantly inhibit lipid peroxide, and effectively antagonize erythrocyte hydrolysis induced by Cu2+. 70 In addition, CP can promote the formation of s-nitroso glutathione (GSO). 

When added to cultured monocytes, CP can promote the expression of inducible nitric oxide (NO) synthase. Physiologically, NO can react with hydroxyl radicals (-OH) to form nitrous acid (HONO) and reduce the damage of hydroxyl radicals to the tissue.71 Paradis et al72 believed that this indirect effect may provide cellular protection by protecting mercaptan from irreversible oxidation.

CP Gene Variants

CP gene variants were found and discussed in several recent studies. Gene mutations in CP may disrupt the expression of CP. 

This protein generated by mutant gene expression may degrade immediately after release from the ER, and also may remain within the ER with abnormal structure, but lacks normal physiological functions, such as inability to bind copper atoms, lack of oxidase, etc.73–75 To date, 172 cases of CP gene variants have been reported worldwide, and 56 were considered pathogenic; most of the cases occurred in Japan, without typical clinical symptoms such as neurological involvement and hepatic iron load.76 

At the same time, heterozygous patients with the same mutation may or may not be symptomatic, indicating incomplete penetrance of the CP gene, and that environmental and other genetic factors may affect CP functions. 

Corradini et al77 found that CP gene variants may be the cause of methemoglobinemia and iron overload in patients with non-alcoholic fatty liver disease, but Pelucchi et al78 found that variants may have different effects under other clinical conditions.

CP in Metabolic Disease

Relationship with Type 2 Diabetes

Diabetes is a common metabolic disease characterized by elevated blood glucose levels. Patients often have carbohydrate, fat, and protein metabolic disorders due to insulin deficiency or (and) insulin resistance.79 Diabetes is also a global pandemic. According to the 2017 Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes, the prevalence of diabetes in China soared from 0.67 in 1980 to 10.4 in 2013.80 

Aberrant alterations in CP are seen in patients with type 2 diabetes mellitus (T2DM), and the results are inconsistent. Chacko et al81 found that serum CP levels are elevated in patients with T2DM, and the CP levels in patients with complications are higher than those in patients without complications. At the same time, in a similar population, Sarkar et al82 showed that plasma CP and protein thiols are significantly reduced, but the level of Cu2+ is abnormally elevated. 

Those studies all show a link between CP and diabetes:83,84 diabetes is associated with abnormalities in inflammation, oxidation, and trace elements, and CP is involved in these abnormalities. 

As early as the end of the 20th century, Pickup and Crook proposed that, although the innate immune system recovers quickly after the acute stimulus, activation of the innate immune system, stimulated by the living environment of long-term hyperglycemia, promotes insulin resistance, obesity, diabetes, and its complications instead.85 

Since then, many clinical studies have shown that diabetes is often accompanied by elevated concentrations of a variety of inflammatory factors. A large number of clinical epidemiological investigations further confirmed that a variety of inflammatory factors can predict the occurrence of diabetes. Inflammation mainly acts on the structure and function of endothelial cells and islet B cells and signal transduction of insulin receptors, which affect glucose metabolism and ultimately lead to diabetes.86–88 Anti-inflammatory therapy has been shown to inhibit the development of diabetes.89–91 

CP is an acute-phase reactive protein; its concentration in plasma increases two- to three-fold during infection or injury. CP plays a decisive role in the regulation of innate and specific immune responses, which are the main components of the active immune system and reflect the immune-inflammatory state of the human body. 

It is believed that CP is an anti-inflammatory factor that inhibits the production of harmful substances during inflammation.92 Therefore, as an inflammatory factor, CP may provide new diagnostic and therapeutic effects for diabetes, but more research is needed. Oxidative stress is an important factor in the occurrence and development of T2DM.93 In a physiological state, the human body has antioxidant defense systems that can clear oxidation production, such as ROS and reactive nitrogen species (RNS). 

With these systems, oxidation production will balance production and clearance. Oxidative stress refers to a disruption in that balance that damages tissue and biological macromolecules such as proteins and nucleic acids.94 Oxidative stress can lead to damage of islet B cell function and peripheral insulin resistance, induce diabetes, and even lead to severe complications such as diabetic neuropathy,95 diabetic retinopathy,96, and diabetic cardiovascular disease.97 Experiments in vitro showed that the nonenzymatic glycation reaction in hyperglycemia fragments deactivates CP, and the release of Cu2+ participates in the Fenton reaction to produce ROS. 

At the same time, ROS can deactivate CP again to form a vicious cycle.98 Shukla et al99 suggested that unbound Cu induces excessive ROS production through the Haber–Weiss reaction and Fenton reaction in the aortic tissues of diabetic rabbit models; this phenomenon was not found in nondiabetic rabbit models. 

Sarkar et al82 and Jeppu et al100 found that the level of serum CP is inversely proportional to fasting blood glucose in patients with T2DM. This may indicate that, in the case of hyperglycemia, increased oxidative stress leads to increased availability of transition metals such as Cu released from storage sites, which are more likely to participate in the Fenton and Haber–Weiss reactions to generate ROS.82,100,101 

In recent years, it has been found that trace elements (Cr, Zn, Fe, Se, Mg, Cu) are related to glucose metabolism. Trace elements play an important role in the synthesis, excretion, storage, activity of insulin, and energy metabolism.102 CP is mainly involved in the metabolism of Cu and Fe. Many studies suggest that people with T2DM have elevated levels of Cu and Fe.82,101,103 The redox effect of Cu and Fe is involved in the production of ROS, which is one of the causes of diabetes.93 

In addition to the redox effect, Cu can also affect the action of zinc (Zn). Because Zn and Cu are a pair of antagonistic trace elements, they compete for the same carrier protein, metallothionein, during intestinal absorption. When the level of Cu increases, it will affect the absorption of Zn, which will lead to a large loss of Zn in the body; the reduction of Zn will promote the occurrence of diabetes.46,104 Moreover, Cu and some Cu enzymes are involved in the synthesis of a specific protein on the surface of pancreatic islet B cells, GIUT2, which promotes insulin production. 

When the body is seriously short of Cu, the synthesis of GIUT2 protein is insufficient, affecting the production of insulin. The secretion of insulin is also regulated by the central nervous system. Cu plays an important role in maintaining the functional stability of the central system, and its deficiency can affect nerve transmission and reduce insulin secretion, thus causing or aggravating diabetes.102 

Lee et al and other studies also found that when Cu2+ combines with human amylin (HA), this combination can stabilize the nontoxic conformation of HA and block the polymerization and apoptosis of cells, suggesting that the complex of Cu2+ and HA may protect islet cells.105 An increasing number of studies have shown that Fe overload can increase the risk of diabetes. 

Fe deposition in the liver leads to oxidative stress disorder, increases apoptosis, decreases the expression of IRS2 and GIUT2 in the liver, causes insulin resistance, and eventually leads to abnormal glucose metabolism.106 Moreover, Fe is involved in the synthesis of hemoglobin in vivo, and Fe deficiency can induce anoxia of pancreatic tissue, which can affect the synthesis and release of insulin.107 

There are many proteins involved in Fe transport, not only CP. When CP is dysfunctional, the body has a strong compensation effect on Fe metabolism, but CP is involved in the main process of Fe excretion.63,108 When CP is dysfunctional, it will cause Fe accumulation in tissue and lead to diabetes mellitus. To study the effect of tea polyphenols on glucose metabolism in CP gene knockout mice, it was found that CP gene knockout mice suffer from insulin resistance and abnormal glucose metabolism more easily due to Fe overload.106 

CP also plays an important role in diabetic complications. It has been found that serum CP can be used as an independent predictor of type 2 diabetic nephropathy.109 This may be because the increase in oxidative stress and the oxidative modification of low-density lipoprotein are related to the progression of diabetes,110 and CP can reflect the degree of oxidation.98 

It has also been found that the selective Cu2+-chelating agent trientine can significantly increase ventricular ejection fraction and decrease left ventricular mass index in patients with T2DM complicated by left ventricular hypertrophy. This shows that CP can also improve T2DM with left ventricular hypertrophy, but clinical research is still needed to verify this hypothesis.111 

To summarize the articles on diabetic retinopathy, we found that CP, as a biological enzyme, plays a key role in the pathogenesis of diabetic retinopathy.112 In summary, CP has a close relation with the generation and development of diabetes and may play a protective role in abnormal glucose metabolism, providing a new research direction for the diagnosis and treatment of diabetes.

Relationship with Hyperlipidemia

Hyperlipidemia is a pathological state of lipid metabolism disorder. The clinical manifestations are elevated levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and decreased levels of serum high-density lipoprotein (HDL). 

According to a study, the total prevalence of hyperlipidemia in patients over 18 years old in China is 40.40%; the prevalence of LDL-C was the highest (33.9%), followed by high TG (13.1%).113 Studies indicate that between 2010 and 2030 the number of patients with cardiovascular diseases (CVDs) in China will increase by 9.2 million.114 Hyperlipidemia is divided into primary and secondary categories. 

Primary hyperlipidemia has a familial tendency.115 Secondary hyperlipidemia is dyslipidemia caused by other diseases, such as diabetes and hypertension. In addition, age, weight, and lifestyle factors, such as diet, exercise, and mental stress, can also affect blood lipid levels. 

It is now believed that the pathological mechanism of hyperlipidemia is related to endoplasmic reticulum (ER) stress, gene polymorphism, inflammatory state, oxidative stress, intestinal flora, and trace elements.116 Studies have shown that CP is related to dyslipidemia and can participate in multiple stages of hyperlipidemia. ER stress plays an important role in lipid metabolism and protein synthesis.117 

Various physiological and pathological disturbances can affect the folding process of primary synthetic proteins in the ER cavity, causing the increase and accumulation of unfolded and misfolded proteins, which is ER stress.118 SR-BI is a major receptor for HDL, and ER stress induces downregulation of SR-BI gene expression, leading to lipid metabolism disorders.119,120 GRP78 is a molecular marker of ER stress. 

Zhou et al121 found that the mRNA and protein expression of GRP78 in hyperlipidemic rats was significantly decreased, and, after treatment, serum TC, TG, and LDL-C were significantly decreased, and GRP78 gene expression and protein content were significantly increased. All these studies indicated that ER stress plays an important role in the pathogenesis of hyperlipidemia.121 

Studies on Cu-loaded hepatocytes cultured in vitro showed significant ER stress in hepatocytes, so the damage to Cu-loaded hepatocytes is closely related to excessive ER stress.122 Moreover, Kono et al123 observed that individuals with aceruloplasminemia have ER stress leading to cell death. 

Therefore, we speculated that CP could avoid ER stress caused by increased Cu levels by regulating Cu metabolism, thus reducing the occurrence of hyperlipidemia. However, the preventive effect of CP on hyperlipidemia still needs to be confirmed by relevant studies.

It is now believed that the inflammatory response is accompanied by the occurrence and development of hyperlipidemia, which can accelerate the accumulation of fat in liver cells. 

The accumulation of fat continues to aggravate the inflammatory response in a vicious cycle, resulting in lipid disorders. Studies have shown that the level of related inflammatory factors such as C-reactive protein in patients with hyperlipidemia is significantly increased and is positively correlated with TC, TG, and LDL-C.124 CP, as an acute reactive protein, may play a certain role in predicting the occurrence and prognosis of hyperlipidemia. The exact role of CP in inflammation needs further study. 

In patients with hyperlipidemia, the level of oxidative stress in vivo increases, while the overall antioxidant capacity decreases. Therefore, it is likely that the mechanism of oxidative stress is involved in the occurrence of abnormal lipid metabolism. Hydroxyl radicals, oxidative products, can react directly with lipids, inducing lipid peroxidation and causing structural and functional damage to various biomolecular membranes,125,126 ultimately accelerating the process of atherosclerosis and increasing the risk of coronary heart disease.127 

As an important antioxidant, CP has a therapeutic effect on oxidative stress in the body. Studies have found that CP can significantly eliminate hydroxyl radicals and improve the lipid peroxidation state.128 However, studies still show that oxidative stress may change CP from a protective factor to a vascular pathological factor.129 

These data showed that CP, based on its structure and integrity in combination with Cu, could play an effective oxidant role in LDL rather than having an antioxidant effect. This also proves that the destruction of this combination may change the antioxidant function of CP.130 Therefore, CP may have preventive and predictive effects on hyperlipidemia, but the corresponding pathophysiological mechanism has not been studied.

Relationship with Obesity

Obesity is a chronic metabolic disease that is usually caused by the interaction of heredity, environment, and other factors, such as weight gain caused by abnormal fat distribution or excessive fat accumulation in the body. Obesity can cause a variety of complications and is closely related to the incidence of various acute and chronic diseases and symptoms, such as dyslipidemia, metabolic syndrome, T2DM, atherosclerosis, and CVD. 

According to a 2015 survey, obesity and overweight rates among children aged 6 to 17 in China reached 6.4% and 9.6%, respectively, which were 5.1 and 4.3 percentage points higher than percentages in 2002.131,132 The study found that CP is associated with obesity, and Tajik et al observed a decrease in plasma CP levels in obese women after losing weight through diet.133 

CP can participate in the inflammatory response and oxidative stress in the occurrence and development of obesity, and it can also affect obesity by regulating intestinal flora and complications. Current research suggests that obesity is a chronic low-grade systemic inflammation that results from the interaction between adipocytes, macrophages, and other immune cells that permeate and dilate adipose tissue. 

The inflammatory development of obesity leads to adipocyte hypertrophy, which is the most representative feature of adipose tissue dysfunction, and this feature increases the production of proinflammatory cytokines.134 CP, as an inflammatory factor, can be used to measure the degree of inflammation and distinguish inflammatory diseases. Kim et al,8 using the protein differential display technique, found that an increase in CP is significantly associated with obesity, indicating that CP may be used as a biomarker of obesity. 

Moreover, compared with fibrinogen, C-reactive protein (CRP), and IL-6, CP is a better predictor of long-term prognosis for obesity inflammation.135 However, whether CP plays an important mediating or inducing role in obesity inflammation, whether its increase can affect the status of obesity inflammation, or whether it is only a simple marker still needs research. 

Many studies have shown that the level of oxidative stress in patients with obesity is increased for many reasons, in which mitochondrial function changes play a decisive role. Mitochondrial dysfunction of adipose tissue in patients with obesity is characterized by decreased mitochondrial biosynthesis and activity, excessive production of ROS, and increased autophagy.136–138 

All these factors can adversely affect adipose tissue function. CP can promote metabolism by regulating the metabolism of Cu and Fe, promoting mitochondrial biosynthesis and activity, improving oxidative stress in adipose tissue, and inhibiting autophagy.139 Studies have found that intestinal flora is involved in the metabolic process of human nutrition and energy. 

Intestinal flora can mediate the occurrence and development of obesity not only by affecting the absorption of energy metabolism and intestinal wall permeability but also by participating in the metabolic process of the body and interacting with human tissues and organs.140 The disorder of trace elements such as Cu and Fe can also affect the composition and function of intestinal flora, including the function of lipid metabolism.141,142 However, the role of CP in intestinal flora is still incompletely understood. 

The World Cancer Research Fund concluded in 2007 that obesity is associated with an increased risk of pancreatic (postmenopausal) breast, endometrial, and renal cancer.143 A study found that CP is a novel adipokine with increased expression in the adipose tissue of obese subjects and cells of obesity-related cancers.144 

Whether there is a causal relationship between overexpression of CP and cancer development in patients with obesity still needs further study. When Safavi et al145 observed the relationship between serum CP level and obesity, they found that there was no correlation, but the serum CP level was positively correlated with serum triglyceride level. The relationship between CP and obesity still needs much research.

Relationship with Other Metabolic Diseases

In addition to diabetes and obesity, CP is also associated with other metabolic diseases, such as coronary heart disease (CHD). Göçmen et al146 found that CP levels increase in patients with CHD. In their study, they found that CP level is an independent risk factor for CVD.146 Mori et al147 separated the risk contributed by CP from that of inflammation (α1- antitrypsin, α1-acid glycoprotein, α2-macroglobulin, haptoglobin, fibrinogen, C4b binding protein, lipoprotein, and CRP) and suggested that CP could serve as an independent risk factor for coronary atherosclerosis and as a marker for the severity of disease.147 

Many studies have found an association between CP and CHD, but have not reached a unified conclusion about the mechanisms for the role of CP in CHD. Some studies have suggested that the oxidation of LDL leads to the initiation or acceleration of the process of atherosclerosis, and CP is an effective catalyst for the oxidation of LDL. CP, by influencing NO levels, can reduce the bioavailability of NO in plasma, inhibiting its protective effect on cardiac ischemia and failure. 

However, there are also studies suggesting that CP is an antioxidant that plays a protective role in the development of CHD. For a better observation of achievements about the role of CP in CVD gathered from clinical studies, we report in brief the main points of relevant research in recent years, as shown in Table 1. To explore the latest research trends, Web of Science was used to retrieve CP studies published from 2016 to 2020. The search yielded 2098 original studies and reviews, which were exported to CiteSpace for burst analysis, as shown in Figure 5. As shown, studies on CP in the past five years have focused on in vitro experiments, antioxidation, immune response, and metabolic diseases. Moreover, since 2018, research on immunity and diabetes has become a hot topic and trend for CP. 

At present, an association between CP and metabolic diseases such as diabetes has been found, and it is believed that CP mainly plays a role in diseases by regulating copper and iron metabolism, oxidative stress, and inflammation. Although the mechanism of CP in the metabolism of copper and iron has been thoroughly studied, questions remain. Does CP mainly work as an antioxidant or oxidant in oxidative stress? Does it play an anti-inflammatory role in the inflammatory response? 

Why do studies of CP, using different research methods on similar populations, find different or even opposite research results? Furthermore, the stability of CP's physiological functions has not been determined. Therefore, future research might study the mechanism of CP in metabolic diseases, especially its involvement in oxidative stress and the immune response to uncover the specific link between CP and metabolic disease and find the precise target for its function.

Conclusion

An increasing number of studies have found correlations between CP and metabolic diseases such as diabetes and hyperlipidemia and have observed that CP can be involved in the physiological and pathological processes of these diseases. 

A large number of studies have shown that CP plays an important role in the balance of Cu and Fe through its oxidase activity. CP exhibits antioxidant activity and can protect tissue from oxidative damage. The study found that the level of CP increased in the inflammatory state, and attenuated the activation of neutrophils, indicating that CP can be used as a predictor and antagonist of inflammation.66 

At present, it is believed that CP plays a protective role in metabolic diseases, mainly by participating in oxidative stress and the metabolism of Cu and Fe, and acts as an inflammatory factor to predict those diseases. However, some studies have also found that CP plays the role of an antioxidant. The causal relationship between CP and metabolic diseases in the human body is not clear. While a large number of studies have found a correlation between CP and metabolic diseases, future research should focus on solving the molecular mechanism of CP in metabolic diseases and studying its other roles.

Statement of Ethics

This article does not contain any studies with humans or animals performed by any of the authors.

Acknowledgments

We would like to thank the researchers for their contributions. This paper was supported by the Clinical Research Plan of SHDC (No. SHDC2020CR3028A and No. SHDC12019X16).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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