Hyperlipidemia is a metabolic disorder in which there is an abnormally high level of lipids in the blood and is clinically classified as hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, and low HDL cholesterolemia, depending on the type of elevated lipoprotein (1, 2). Hyperlipidemia has been a widespread concern in Europe, America, and other developing countries. According to epidemiologic surveys, it was found that in the United States, about 12% of adults ≥20 years of age had total cholesterol levels higher than 240 mg/dL, and about 17% had high-density lipoprotein (HDL) cholesterol levels <40 mg/dL between 2015 and 2018 (3). Hyperlipidemia is one of the risk factors for several vascular diseases (4). Thus, it increases the risk of disease in the elderly (5). The prevalence of hyperlipidemia continues to grow as the world faces an increasingly aging population (6). Hyperlipidemia is associated with a variety of diseases such as stroke, diabetes, coronary heart disease, and other chronic diseases (7), severely reducing the quality of life, shortening the lifespan of the patients, and causing a substantial economic burden. Based on this fact, finding effective treatments to address this problem is essential.

Current research has identified the key to oxidative stress as reactive oxygen species (ROS), and the overproduction of ROS has been linked to pathological diseases such as obesity, insulin resistance, hyperglycemia, chronic inflammation and dyslipidemia (8–10). During physiological circumstances, ROS are readily modulated by counter-oxidants. However, counter-oxidants can be obtained in vivo and in vitro (11). When antioxidant deficiencies and malnutrition result in the body being more susceptible to oxidative stress, thus improving the risk of an adverse reaction (12). There is evidence of an association between hyperlipidemia and oxidative stress (13). Vitamin A (VA) as a dietary antioxidant, Wang et al. (14). In an intervention experiment in diabetic adipose rats, administration of VA for 8 weeks was able to improve fat metabolism to reduce hyperlipidemia. Vitamin E (VE) derives its antioxidant activity mainly from α-tocopherol and γ-tocopherol. In a study in children and adolescents, administration of micronutrients VE and VA was shown to reduce blood lipids through antioxidant properties (15). Administration of zinc alone in type 2 diabetic rats improved lipid levels (16), in addition to dietary zinc reducing oxidative stress (17). It is apparent that numerous studies have confirmed the effect of single antioxidants on hyperlipidemia, but the relationship between combined dietary antioxidant intake and hyperlipidemia still needs to be explored.

In recent years, the role of antioxidants has become prominent in global dietary patterns, and the impact of total nutritional antioxidant capacity on health has become increasingly common in all sectors (18). Dietary antioxidant supplementation through consuming fruits, vegetables, whole grains, nuts, and legumes has been suggested (19), and the intake of adequate antioxidants may help reduce the burden of oxidative stress (20). CDAI was proposed by Wright et al. (21) as a composite score reflecting antioxidant capacity of one’s diet, which includes vitamins A, C, and E, zinc, selenium, and carotenoids. Previous studies have found that CDAI improves heart failure, hypertension, depression, and atherosclerotic cardiovascular disease and reduces the risk of morbidity (18, 22–24). However, there are no studies on the relationship between CDAI and hyperlipidemia.

In this study, we explored the association between CDAI and hyperlipidemia for the first time using a large-sample cross-sectional design. Based on previous studies, it was hypothesized that there may be a negative association between CDAI and hyperlipidemia, intending to prevent hyperlipidemia and reduce the risk of its onset through diet, with important clinical implications.

The study analyzed the most representative US population data and, after adjusting for several covariates, found that CDAI was negatively associated with the prevalence of hyperlipidemia in the population, which confirms our hypothesis. These results suggest that appropriate dietary modification and increased antioxidant intake can help prevent and treat hyperlipidemia. Although previous studies have demonstrated the effect of dietary antioxidants such as VA, VE, and zinc on hyperlipidemia, most of them applied a single class of antioxidants for correlation analysis and did not consider them in combination. However, the intake of a single antioxidant is difficult to achieve in the daily diet, and it is more likely that a wide range of foods and a wide range of antioxidants will be consumed. In addition, there is no single antioxidant component in foods that are rich in multiple antioxidants. Therefore, there is a need to investigate the relationship between combined dietary antioxidant intake and hyperlipidemia.

Oxidative stress plays a vital role in hyperlipidemia. Wu et al. (31) found that the substrates of G. frondosa decreased glutathione (GSH) and catalase activity, increased GSH peroxidase activity, inhibited oxidative stress, and increased bile acid synthesis to improve hypercholesterolemia. Feng et al. (32) administered hawthorn fructofuranic acid (HFA) to rats. Found that activation of Nrf2/HO-1 signaling pathway could inhibit oleic acid (OA)-induced oxidative damage in a hepatocellular carcinoma cell line (HepG2), which in turn reduced oxidative stress damage in rats, effectively reduced triglyceride and cholesterol levels, attenuated hepatic steatosis and intervened in hyperlipidemia. Pretreatment with M. charantia polysaccharides for 25 days in a rat model was found to inhibit oxidative stress via nuclear factor κB (NF-kB), lowering lipid indices, and consequently ameliorating hyperlipidemia (33). Ji et al. (34) further found that consumption of propolis by rabbits with hypercholesterolemia lowered the lipid levels and enhanced antioxidant activity by a mechanism which may be the inhibition of the TLR4-mediated NF- κB signaling pathway. Puerarin was found to reduce ROS production and increase antioxidant capacity by modulating the phosphorylated Jun N-terminal kinase (JNK)/phosphorylated c-Jun protein/cholesterol 7a-hydroxylase (CYP7A1) pathway in mouse liver, which in turn inhibited hyperlipidemia (35). Fan et al. (36) used baicalein to intervene in hyperlipidemic rats and showed results of enhanced activation of PI3K/AKT and activation of Nrf2, thereby increasing the expression of HO-1 and NQO1, inhibiting oxidative stress and preventing hyperlipidemia. Honey pretreatment given to rats before feeding them a high-fat diet was found to be able to attenuate oxidative stress and exert anti-hyperlipidemia effects more significantly by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (37). Antunes et al. (38) experimented with different combinations of phenolic compounds from purple grape bark, both in vitro and in vivo, and all of the results showed an antioxidant effect, thereby reducing hypercholesterolemia. Administration of p-coumaric acid (p-CA) in mouse experiments revealed an increase in the expression of Nrf2, HO-1, glutathione peroxidase (Gpx), and superoxide dismutase (SOD-1), which in turn exerted an antioxidant and potentially therapeutic effect in the treatment of hyperlipidemia (39). In conclusion, inhibition of oxidative stress, which can treat hyperlipidemia, is the same as the conclusions of cross-sectional studies on the relationship between CDAI and hyperlipidemia.

This study also found that the prevalence of hypertension, diabetes mellitus, and coronary heart disease decreased progressively with increasing CDAI. Previous analyses of the NHANES database found that the prevalence of hypertension, coronary heart disease, and diabetes mellitus were negatively correlated with CDAI (18, 23, 40), which is consistent with our findings. Control variables such as energy, carbohydrates, total fat, and cholesterol, which may affect the results of the study, were added to the previous ones. In addition, instead of using the traditional Dietary Antioxidant Quality Score (DAQS) for assessing dietary antioxidant indices in this study, the more accurate CDAI was used for correlation analyses because of its applied advantages and validity proved in epidemiological studies.

Diet is essential in treating hyperlipidemia by containing antioxidants that reduce oxidative stress damage and promote health (41). Antioxidants are biologically active compounds that neutralize free radicals and reduce oxidative damage (42). Although there are no studies on the relationship between CDAI and hyperlipidemia, the use of dietary antioxidant properties to intervene in hyperlipidemia has become a hot research topic. The vitamins (A, D, and E) and carotenoids in CDAI are fat-soluble and vitamin C is water-soluble, which is relevant for absorption, transport and action. Feeding a VA-rich (52 mg/kg) diet for 20 weeks in hypercholesterolemic obese rats increased plasma lecithin cholesterol acyltransferase activity and expression of ATP-binding cassette transporter protein A1, which, in turn, led to normalization of plasma HDL-C levels (43). Vitamin C (VC) is an essential nutrient for humans and the effect of administration is highly dose dependent (44), maximizing neutrophil concentration, reducing ROS production and inhibiting LDL-C oxidation through dietary intake (45, 46). Kumar et al. (47) administered VC (0.5 g/kg) once daily for 30 days in a male rat model of hyperlipidemia. It showed a decrease in triglycerides, cholesterol, ROS, malondialdehyde (MDA), and reduced GSH, the mechanism of which may be to prevent hyperlipidemia by inhibiting oxidative stress and maintaining redox balance. In a randomized double-blind crossover study, VC (1,000 mg) in combination with dietary nitrates given to untreated hypercholesterolemic subjects for 4 weeks was found to reduce oxidized low-density lipoprotein (oxLDL), triglycerides and inhibit oxidative stress by increasing the total plasma NO metabolites (48). Selenium was able to maintain the anti-oxidative stress function of glutathione peroxidation and selenoprotein P (49). Guo et al. (50) fed selenium nanoparticles (SeNPs) 50 μg/d in apolipoprotein E-deficient (ApoE) mice, and showed that it was able to alleviate hyperlipidemia in ApoE mice by regulating cholesterol metabolism through antioxidant selenoenzymes/selenoproteins and reducing oxidative stress, and additionally metabolomics selenium-enriched kiwifruit was also found to be able to treat hyperlipidemia (51). Carotenoids (Crt) act as antioxidants in lipid-rich environments (52), mainly through (i) electron transfer between free radicals (R-) and Crt, leading to the formation of Crt radical cation (Crt-+) or Crt radical anion (Crt-); and (ii) radical adducts (R-), leading to the formation of Crt radical cation (Crt-+) or Crt radical anion (Crt-). (-); (ii) radical adduct formation (RCrt-); and (iii) hydrogen atom transfer leading to neutral Crt radicals (Crt-) three pathways to scavenge free radicals, which can also effectively scavenge ROS and play an antioxidant role (53). Lycopene, a water-soluble carotenoid, intervenes in hyperlipidemia by down-regulating oxidative stress induced by the preprotein convertase Bacillus subtilis protease/kexin type 9 (PCSK-9) targeting lipopolysaccharide (LPS) (54). This study concluded that the difference between single serum antioxidant and hyperlipidemia was statistically significant, and the more intake, the greater the CDAI and the lower the prevalence of hyperlipidemia, which is in line with the results of the above study.

The following four limitations exist in this research. First, the study was a cross-sectional analysis, and we could not determine a causal relationship between CDAI and hyperlipidemia. Second, since the population studied was Americans, special people such as minors were omitted. Third, some unknown covariates may affect the relationship between CDAI and the risk of hyperlipidemia. Fourth, CDAI data are self-reported and will be subject to recall bias.

There is a linear negative association between CDAI and the risk of hyperlipidemia. Therefore, intake of foods rich in CDAI components, which are mainly rich in VC and VE, may reduce the risk of hyperlipidemia. In the future, prospective studies and basic experiments are needed to further explore the mechanism of action, tap into the diet of each component of CDAI to exclude the effect of individual variability, and additionally explore the relationship between more antioxidants in the diet and hyperlipidemia to guide the diet. Living with balanced nutrition, reasonable diet, strengthening physical exercise, improving body metabolism, strengthening hyperlipidemia prevention and reducing the occurrence of the disease.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by The Research Ethics Review Board at the National Center for Health Statistics (NCHS). The patients/participants provided their written informed consent to participate in this study. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

HZ: Data curation, Formal analysis, Methodology, Software, Validation, Writing – original draft, Writing – review & editing. TL: Conceptualization, Data curation, Formal analysis, Methodology, Writing – review & editing. JL: Conceptualization, Methodology, Visualization, Writing – review & editing. DZ: Formal analysis, Software, Visualization, Writing – review & editing. JY: Conceptualization, Methodology, Validation, Visualization, Writing – review & editing. XZ: Data curation, Supervision, Visualization, Writing – review & editing.