Hyperuricemia is a chronic metabolic disease caused by excessive uric acid production or insufficient excretion, which leads to an abnormal increase in the uric acid level in serum and is characterized by purine metabolism disorder (1). It is a worldwide issue related to public health, connected with a wide range of other conditions, affecting people of different ages, and has been trending towards a younger age group in recent years (2, 3). Several recent findings have revealed the prevalence of hyperuricemia appears to be on the rise worldwide. The incidence of hyperuricemia is about 20% in the United States (4). Hyperuricemia is often preceded by gouty attacks and gout stone formation, which greatly reduces people’s quality of life, although asymptomatic patients do exist (5). However, even in asymptomatic patients, hyperuricemia remains an independent risk factor for metabolic syndrome, hypertension, many chronic kidney diseases, and even death (6–9), which seriously jeopardizes people’s health. Uric acid represents the terminal metabolite of purine catabolism in humans, with approximately two-thirds derived from endogenous purine metabolism and the remaining one-third attributable to the ingestion of purine-rich dietary sources (10, 11). The absence of urate oxidase in humans precludes the further metabolic breakdown of uric acid into the more water-soluble allantoin, thereby elevating serum uric acid levels approximately five- to sixfold higher than those observed in other mammals (12). The renal system is the predominant route for uric acid excretion, accounting for approximately 70% of total clearance, while the remaining 30% is cleared through extra-renal mechanisms (13, 14). Within the kidneys, specific uric acid transporters, such as URAT1 (urate transporter 1) and GLUT9 (glucose transporter 9), are instrumental in mediating the reabsorption and secretion of uric acid, thereby regulating its overall renal handling (15).

Low-density lipoprotein cholesterol (LDL-C) is undoubtedly a critical component in the lipoprotein profile. However, with the popularity of statins, the focus of research has shifted to triglyceride-rich lipoproteins (TRL), which are the hallmark component of dyslipidemia and are not affected by statins (16, 17). Residual cholesterol (RC), which reflects the level of cholesterol in triglyceride-rich lipoproteins (TRLs), is an emerging nontraditional marker of lipids and consists of celiac remnants, intermediate-density lipoproteins (IDLs), and very-low-density lipoproteins (VLDLs) (18). Actually, RC is essentially a form of cholesterol, and studies have shown that elevated levels of cholesterol in triglyceride-rich lipoproteins (TRLs) pose a more direct and significant risk to the incidence of cardiovascular and metabolic diseases than traditional lipid markers such as LDL-C & TG (19–21). Although TG levels are often used as a clinical surrogate for TRLs or RC, increasing emphasis is being placed on RC in current lipid management practices (22). The metabolism of RC primarily involves the synthesis, transport, and catabolism of lipids, with its levels being influenced by multiple factors, including dietary fat intake, hepatic lipid synthesis, and lipoprotein metabolism (23). Elevated RC levels have been associated with increased cardiovascular risk, as these lipoproteins can penetrate the endothelium and contribute to atherosclerotic plaque formation (24).

There is a marked divergence in the metabolic pathways of residual cholesterol and uric acid. The metabolism of uric acid is predominantly centered around the purine metabolic pathway, with its production and excretion regulated by enzymes and transport proteins in the liver and kidneys (25). In contrast, the metabolism of residual cholesterol encompasses the synthesis, transport, and breakdown of lipoproteins, which are primarily governed by lipid metabolic pathways in the liver and small intestine (26). Despite their distinct metabolic pathways, both are closely associated with metabolic syndrome and cardiovascular diseases (27). The ratio of Residual Cholesterol to High-Density Lipoprotein Cholesterol (RC/HDL-C) is an important indicator of lipid metabolite interactions, reflecting the balance between atherogenic and anti-atherogenic lipoproteins (28). Thus, exploring the potential connections between the two holds significant clinical importance. In recent years, with the increasing research on proteomics, metabolomics and genomics, many molecular markers are emerging to provide important information for disease diagnosis, prognosis and therapeutic targets (29). However, limited research has been conducted on the correlation between increased RC/HDL-C and the likelihood of hyperuricemia, particularly in the broader US population. We conducted the following cross-sectional study using data related to the 2005-2018 National Health and Nutrition Examination Survey (NHANES) to prove the connection with RC/HDL-C and hyperuricemia.

Our investigation primarily examined the association between the prevalence of hyperuricemia and RC/HDL-C index and using the NHANES database. The research involved in a sample size of 11915 individuals. Weighted multifactorial logistic regression analysis revealed, after all covariates with control, the positive and statistically significant association observed between RC/HDL-C and hyperuricemia. Besides, RCS curves revealed a non-linear positive correlation between hyperuricemia and RC/HDL-C. In addition, the incidence of hyperuricemia progressively elevated with rising quartiles of RC/HDL-C. The statistical association between RC/HDL-C and hyperuricemia remained stable among participants who self-reported CVD and hyperlipidemia. To be emphasized, subgroup analyses revealed that the relevance between RC/HDL-C and hyperuricemia might be altered because of gender, educational levels, hypertension and diabetes.

In the adult population, a growing body of research suggests that hyperuricemia is a frequent condition. Hyperuricemia has a significant influence on the quality of survival and healthy condition of the patient, as well as a remarkable influence on the psychological well-being of individuals. The positive correlation of RC/HDL on the occurrence of hyperuricemia varies in certain subgroups, firstly, at the gender level, there are differences in lifestyle between males and females, where males have a tendency to be regular smokers and drinkers of alcohol, habits that have a negative impact on lipid levels. In addition to this, estrogen may increase HDL-C levels, while androgens may decrease HDL-C levels (32). Secondly, differences in education levels may affect an individual’s lipid levels, and thus the prevalence of hyperuricemia, through a number of pathways. In general, well-educated individuals may have a better understanding of health, including awareness of hyperuricemia and dyslipidemia. They may be more aware of how to manage these health problems through diet, exercise, and other lifestyle changes (33). Education level is often correlated with economic income, which may affect an individual’s ability to access healthy foods and healthcare resources. Individuals with higher educational attainment typically possess greater financial capacity to procure nutritious foods and secure routine health checkups. Moreover, hypertension and diabetes are commonly associated with metabolic syndrome, which can precipitate dyslipidemia, including alterations in HDL-C levels. Dyslipidemia itself can induce vascular wall damage, subsequently leading to elevated blood pressure (34, 35). Collectively, these conditions can contribute to an unstable prevalence RC/HDL-C) relative to hyperuricemia.

However, the pathophysiological mechanisms of hyperuricemia have not yet been fully elaborated. Although the prevalence of hyperuricemia in the U.S. population has remained stable over the last decade, the overall incidence and public health impact of the condition remains quite significant given the rising population size (36), which may indirectly reflect trends in the development of hyperuricemia in other countries around the globe. This exacerbates the strain on healthcare systems and increases the direct and indirect healthcare costs associated with the condition. In addition, hyperuricemia is connected to varieties of chronic diseases including cardiovascular and kidney disease, further increasing the urgency for public health interventions. Elevated RC/HDL-C, a crucial indicator of lipid metabolite interactions, has been associated with the prevalence of hyperuricemia, and this relationship may involve multiple mechanisms. First, studies have shown that dyslipidemia may lead to elevated blood uric acid levels, which increase with increasing TG levels and decreasing HDL levels (37). In the obese state, purine catabolism is enhanced in the body due to increased adipose tissue, leading to increased uric acid production, as has been demonstrated in mouse model studies (38). And the Western dietary pattern is characterized by its composition of high fats and carbohydrates, which may lead to an increased inflammatory response in the body and elevation of various lipid metabolites (39, 40). Based on the analysis of large-scale population statistics, dietary inflammation holds a pivotal position for serum uric acid levels and significantly influences the progression of health status in hyperuricemia (41). Secondly, oxidative stress in adipose tissue is the principally etiological factor for metabolic syndrome and obesity-related inflammation (42, 43). In the pathogenesis of metabolic disorders, for instance, hypertriglyceridemia and nonalcoholic fatty liver disease, hepatic fatty acid oxidation may induce hypoxia-inducible factor-1α (HIF-1α), which in turn transcriptionally activates xanthine dehydrogenase (XDH) and cytoplasmic-5´-nucleotidase-II (NT5C2) in the uric acid synthesis pathway and promotes hepatic uric acid synthesis (43, 44). In addition, the kidneys perform a crucial function in sustaining the homeostasis of uric acid in the body and are responsible for the majority of uric acid excretion, with approximately 70% of uric acid excreted in urine throughout the kidneys (45). Abnormal lipid profile can lead to renal pathology, cholesterol can be ectopically deposited in the kidney, and the presence of cholesterol accumulation in the podocytes without effective intervention will induce oxidative stress, skeletal disorders, and mitochondrial function abnormalities in the podocytes, which will directly activate autophagy of the podocytes, cause the apoptosis of podocyte, and accelerate the damage of glomerular filtration barrier (46). Moreover, dyslipidemia increases the disease susceptibility of coronary heart disease and accelerates the onset of atherosclerosis, as well as being a potential hazard to the kidneys. Elevated lipids can damage the kidneys, leading to enlarged glomeruli, changes in renal tissue, and even glomerulosclerosis, which ultimately affects the excretion of uric acid and accelerates the progression of hyperuricemia under the combined effect of several mechanisms (47). Currently, substantial research has confirmed that when cholesterol levels in triglyceride-rich lipoproteins (TRLs) are elevated, the effect on the development of cardiovascular and other diseases has a more pronounced and direct correlation (48).

According to studies in recent years, the current rate of obesity in the global population continues to rise, affecting people’s physical and mental health in various ways. The universal prevalence of hyperuricemia also keeps escalating year by year, and lipid metabolism is closely associated with hyperuricemia problems. Our investigation confirms a novel demonstration of a remarkable association between the occurrence of hyperuricemia and RC/HDL-C, which has significant implications for the future diagnosis as well as treatment of hyperuricemia. The present study has some strengths, based on the NHANES database, the investigation is the primarily cross-sectional investigation to research the correlation between RC/HDL-C and hyperuricemia. At the same time, our study is representative because it contains basic data from a large number of US respondents. However, it is worth noting that we still have some limitations, firstly some of the disease information in the NHANES database was obtained through self-reporting by the respondents, including disease information. And the self-reporting deviation could lead to imprecise messages, which may affect the accuracy of the results. Second, this investigation could not establish the direct sequential association between hyperuricemia and RC/HDL-C, but only inferred a correlation, due to the cross-sectional study. In conclusion, this study suggests that there is the significantly positive relationship between the hazard of hyperuricemia and the RC/HDL-C.

The research revealed the positively remarkable relationship between hyperuricemia and RC/HDL-C in the American population. Higher RC/HDL-C is associated with higher prevalence of hyperuricemia. The founding suggests that lipid metabolism might be an influenced factor for hyperuricemia. The clinical importance of our research is that assessing RC/HDL-C may help identify those at higher prevalence for hyperuricemia. Incorporation of the RC/HDL-C into common clinical assessment could contribute to inchoate detection of hyperuricemia and direct personalized care strategies.