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Hyperlipidemia, a chronic disorder of abnormal lipid metabolism, can induce obesity, diabetes, and cardiovascular and cerebrovascular diseases such as coronary heart disease, atherosclerosis, and hypertension. Increasing evidence indicates that phytochemicals may serve as a promising strategy for the prevention and management of hyperlipidemia and its complications. At the same time, the concept of synergistic hypolipidemic and its application in the food industry is rapidly increasing as a practical approach to preserve and improve the health-promoting effects of functional ingredients. Due to the complexity of the lipid metabolism regulatory network, the synergistic regulation of different metabolic pathways or targets may be more effective than single pathways or targets in the treatment of hyperlipidemia.
- synergistic hypolipidemic effect
- phytochemicals
- structure-bioactive relationship
- lipid metabolic pathways
- action mechanism
1. Introduction
Hyperlipidemia is a disorder in which abnormal lipid metabolism results in a higher-than-normal level of one or more lipids in the serum, and the common symptoms are high levels of total serum cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) or low levels of high-density lipoprotein cholesterol (HDL-C), which is called dyslipidemia in modern medicine [1,2,3]. Hyperlipidemia can cause some serious cardiovascular diseases, such as coronary heart disease (CHD) and atherosclerotic cardiovascular disease (ASCVD), which are responsible for millions of deaths in the world every year [4]. Alarmingly, a study of early subclinical atherosclerosis showed that 63% of participants have symptoms of subclinical atherosclerosis [5]. Although considerable progress has been made in the treatment of hyperlipidemia, the incidence rate and risk associated with this disease are still rising. Therefore, the prevention and treatment of hyperlipidemia are extremely important. Currently, the main treatment of hyperlipidemia is chemical drugs, and the classical lipid-lowering drugs include statins, fibrates, and nicotinic acids [6]. The above-mentioned chemical drugs have definite clinical effects and obvious effects in lowering blood lipid, but similar to other chemical drugs, long-term use of statins may also cause a series of potential side effects, for example, they may lead to liver and kidney function damage, gastrointestinal reactions and other adverse reactions [7,8,9]. In addition, the regulation of lipid metabolism is a complex process involving multiple pathways and targets, and it is difficult for the current single-target lipid-lowering drugs to achieve both primary and secondary effects [10]. Therefore, safe and effective substitutes are urgently needed to treat hyperlipidemia and its related complications. In this context, phytochemicals have received considerable attention for their safety and therapeutic potential [11,12].
Studies have shown that the natural active ingredients in some plants have unique advantages in treating hyperlipidemia and preventing the development of cardiovascular disease [13]. Furthermore, many studies have emphasized the hypolipidemic benefits of phytochemicals, which are multi-component, multi-targeted, and have relatively low toxic effects [14]. In fact, plants are natural sources of medicines, and their roots, stems, leaves and seeds are rich in polysaccharides, flavonoids, saponins, phytosterols, fatty acids, phenols, polypeptides and other small molecular compounds, which are active ingredients in drugs for cardiovascular diseases [15,16]. Many in vitro and animal studies have shown that the consumption of these bioactive phytochemicals significantly improves hypertension, low-density lipoprotein oxidation, lipid peroxidation, total plasma antioxidant capacity and dyslipidemia [17]. After years of verification of hypolipidemic phytochemicals, the structural properties of their main components are becoming clearer, and the mechanism of action is becoming clearer. For example, it has been suggested that plants contain many biologically active phytochemicals that can act on multiple targets in complex disease networks. In addition, different phytochemicals act synergistically at each target to intervene in the development of disease and ultimately achieve therapeutic effects [18,19]. Interestingly, it is not clear which specific components produce the actual effects, which makes the study of synergistic effects among phytochemicals a hot topic of interest.
2. Synergistic Hypolipidemic Effects between Phytochemicals of the Same Category
Increasing evidence suggests that combinations of phytochemicals from the same category may have a stronger hypolipidemic effect than a single phytochemical.
2.1. Synergistic Hypolipidemic Effects of Flavonoids
Flavonoids are a very rich and diverse category of natural phytochemicals with important biological activities, which are composed of a common diphenylpropane (C6-C3-C6) skeleton in which two aromatic rings are linked by a three-carbon chain [38]. Most flavonoids can be sub-classified into the following categories, namely flavones, flavonols, flavanones, flavanols, isoflavones, and anthocyanins [39]. Flavonoids are widely distributed in our daily diet and are the major phytochemicals in foods such as vegetables, fruits, tea, and cocoa [40], and they can exist as free aglycones but are usually combined with glycosides and dissolve in water in this form [41]. Because of the potential health care value, safety and medicinal significance, it is considered to be an indispensable ingredient in all kinds of medicines and dietary supplements [42].
Studies have shown that eating foods rich in flavonoids is associated with lower cardiovascular risk because of a significant reduction in cholesterol levels and free radical scavenging activity [43,44]. Flavonoids can regulate the imbalance of lipid metabolism by inhibiting lipid peroxidation and endogenous lipid biosynthesis and promoting lipid redistribution and exogenous lipid metabolism, significantly reducing TG, TC and LDL-C levels [45]. For example, to investigate the interrelationship among flavonoids in the antioxidant and hypolipidemic effects, Qin et al. used ever-red and ever-green leaves during the development of crabapple cultivars. They identified a total of 16 flavonoids from them and predicted a positive interaction of flavonoids in ever-red by principal component analysis, and the experimental results also showed that the total antioxidant capacity was significantly higher than the sum of the antioxidant capacity of individual compounds [46].
Quercetin and kaempferol (different flavonoids), found in high levels in fruits and vegetables, have been shown to protect against cardiovascular diseases by regulating lipid levels [47]. Yusof et al. evaluated the lipid-lowering potential of quercetin and kaempferol by LDL-C uptake on HepG2 cells. They found that the mixture of quercetin and kaempferol (1:1,2:1 and 1:2) decreased the cell viability more than treatment individually, and the combination of quercetin and kaempferol in a ratio of 1:1 had the best effect on the LDL-C uptake of HepG2 cells. The conclusion just shows that quercetin and kaempferol have some synergistic effects [29].
In addition, Ma et al. isolated 12 flavonoids (jaceosidin, kaempferol, chrysoeriol, quercetin, apigenin, hispidulin, luteolin, quercitrin, rutin, isorhamnetin, genkwanin, and acacetin) from Artemisia sacrorum, which were arranged into 11 combinations to investigate their synergistic inhibitory effects on lipid accumulation in 3T3-L1 cells, respectively. Combined analysis of oil-red O staining, triglyceride levels, and lipid accumulation assays showed that the combination of acacetin and apigenin (1:1) had a more significant synergistic inhibitory effect on lipid accumulation compared to the compounds used alone [30]. In addition, the combinations of the plant flavonoids rutin and epicatechin (1:3) were tested on alloxan-induced diabetic mice for 28 days. The combination showed impressive anti-diabetic, anti-oxidant and anti-inflammatory activity without any observed signs of toxicity, and the formulation is considered to be a potentially safe, multi-target drug alternative [31].
Sea buckthorn is rich in flavonoids, which have hypolipidemic and hypoglycemic effects in mice fed with a high-fat diet [48]. To investigate the ameliorative effect of sea buckthorn flavonoids on obesity and hyperlipidemia, a network of component-target-disease was constructed by screening 12 biologically active flavonoids and 60 target sites using network pharmacological analysis and in vitro experimental methods. It has been shown that four bioactive flavonoids, including quercetin, catechin, hesperidin and isorhamnetin, may synergistically improve hyperlipidemia by promoting the conversion of cholesterol to bile acids and cholesterol efflux, inhibiting the de novo synthesis of cholesterol, and accelerating fatty acid oxidation [32].
The combination of plant flavonoids may have diverse biological activities such as antioxidant, antibacterial, hypolipidemic, immune regulation, and liver protection [49]; we can obtain a new, safe and multi-objective combination of plant flavonoids by optimizing the combination and proportion of them, and the synergy of these phytochemicals will have broad application prospects in the fields of medicine and plant-based functional foods.
2.2. Synergistic Hypolipidemic Effects of Polysaccharides
Polysaccharides are carbohydrates composed of more than 10 monosaccharides linked by glycosidic bonds [50] and are one of the important active components of plants. They have the activities of hypolipidemic, hypoglycemic, enhancing immunity, anti-oxidation, anti-inflammation, anti-atherosclerosis and so on [51,52]. In general, polysaccharides can be divided into two categories: homo-polysaccharides and hetero-polysaccharides. A typical homo-polysaccharide is defined as having only one monosaccharide repeating on the chain, while a hetero-polysaccharide is composed of two or more categories of monosaccharides [53]. Polysaccharides have the characteristics of strong polarity, large molecular weight and difficulty to confirm the structure [54]. It has been suggested that polysaccharides can inhibit the absorption of exogenous lipids and accelerate the hepatic catabolism of TC by physically binding to lipid molecules or bile salts in the gastrointestinal tract. The larger the relative molecular mass, the greater the characteristic viscosity or hydrophobicity of polysaccharides, and the stronger the corresponding binding ability [55]. Zhang et al. [56] claimed that some polysaccharide compounds can bind to each other to enhance the affinity between the receptor and the polysaccharide or to activate more polysaccharide binding sites on the receptor, thus resulting in a synergistic effect.
To investigate the physicochemical properties, anti-inflammatory and hypolipidemic effects of different polysaccharides in lipopolysaccharide-induced RAW264.7 macrophages, a multifactorial test was conducted using three different concentrations (0, 50 and 100 μg/mL) of high molecular weight dextran (885.2 kDa) and low molecular weight heteropolysaccharide (24.5 kDa). The results showed that high molecular weight dextran and low molecular weight heteropolysaccharide alone did not have significant effects compared to the control group, while the combination showed significant inhibitory effects, indicating a significant synergistic effect between them [33]. Similarly, Deng et al. analyzed the effect of complex polysaccharides and their combinations on RAW 246.7 macrophages, showing that complex polysaccharides with molecular weights between 100 and 1000 kDa had higher activity compared to the corresponding single-component polysaccharides, which also suggests a synergistic effect of different polysaccharides [57].
In addition, Li et al. investigated the effects of dietary fiber from bamboo shoots on hyperlipidemia mice induced by a high-fat diet. After 6 weeks of treatment with the combination of soluble dietary fiber (SDF) and insoluble dietary fiber (IDF), the body weight, body fat and adipose tissue mass of rats were significantly reduced (p < 0.05), and TC, TG and LDL-C levels were reduced by 30.20%, 53.28%, and 35.63%, respectively, compared with the model group. SDF + IDF (1:1) treatments had a better ability of lowering blood lipid and showed synergistic effects in preventing hyperlipidemia [34]. This synergistic effect of the combination may be related to their vast array and saccharide-based complex structures [58].
The studies of the active mechanism and the structure–activity relationship are the basis of the application of polysaccharides. However, compared with other biomolecules, polysaccharide structures are more complex, resulting in many polysaccharide structures with significant activity that cannot be easily identified. Moreover, the absorption, transport, distribution and metabolic processes of polysaccharides in vivo are difficult to investigate, which greatly limits the development of polysaccharides in the direction of hypolipidemia. At present, the hypolipidemic activity is mainly aimed at plant crude polysaccharides, containing a mixture of polysaccharides, oligosaccharides, polysaccharide proteins and other components, which makes researchers face certain difficulties in the study of their synergistic effects. In recent years, with the development of new science and technology, the derivatization modification of natural polysaccharides or the artificial synthesis of polysaccharides with well-defined structures are expected to be used to investigate the structure–activity relationship and activity mechanisms of polysaccharides [59]. Therefore, in the future, strengthening the research on the structure, active groups and structure–activity relationship of polysaccharide molecules will be the key to elucidating the synergistic effects of different plant-derived polysaccharides.
2.3. Synergistic Hypolipidemic Effects of Polyphenols
Polyphenols are secondary metabolites produced by many edible plants and have anti-diabetic, anti-inflammatory, anti-oxidant and hypolipidemic capabilities [60]. As an anti-oxidant, polyphenols are able to reduce oxidative damage to lipids, proteins, enzymes, carbohydrates and DNA in living cells and tissues, which is mainly attributed to the ability to scavenge free radicals, provide hydrogen atoms or chelate metal ions [61]. The combination of several polyphenol components could improve antioxidant and hypolipidemic efficiency, which can expand their applications in nutrition and biomedicine. For example, Heo et al. found that individual phenolic compounds showed their specific antioxidant capacity, and the sum of the antioxidant capacity of phenolic compounds resulted in an increase in total antioxidant capacity [62].
Proanthocyanidins and pterostilbene are natural phenolic antioxidants with hypolipidemic effects [63,64,65]. Hannan et al. studied their hypolipidemic effects combined with nicotinic acid in cholesterol-fed rabbits. The results showed that the LDL/HDL ratio and atherogenic index were suppressed significantly in blend therapies with maximum effects of 59.3 and 25% (p > 0.001) observed in 50:30:20 ratios of OPC, NA and PT compared to individual therapies 37 and 18% max respectively [35]. This study provides important evidence for the synergistic advantage of polyphenols in the hyperlipidemia effect and its complications. In addition, four phenolic compounds, including catechin, hesperidin, ferulic acid and quercetin, were also exhibiting synergistic effects in the prevention of low-density lipoprotein oxidation in humans [36].
At present, there are few studies on the synergistic effects of polyphenols on lowering blood lipid, which is mainly because there are many hydroxyl groups in the structure of polyphenols, which makes it very unstable in light, heat, and alkaline conditions [66]. Furthermore, many polyphenols are poorly soluble and have low bioavailability in humans [67], which limits their commercial use in functional foods.
2.4. Synergistic Hypolipidemic Effects of Other Phytochemicals
In addition to the above synergistic hypolipidemic effects among the same phytochemicals category, other phytochemicals such as amides have also been found to have synergistic effects in the treatment of hyperlipidemia and related diseases. Chen et al. investigated the synergistic effects of different mass ratios of numb-tasting components of Zanthoxylum bungeanum and capsaicin on lipid levels in hyperlipidemic mice. Compared with the control group, feeding three different mass ratios (1:8, 2:7, and 3:6) of numb-tasting components of Zanthoxylum bungeanum and capsaicin reduced the serum levels of TC, TG, and LDL-C in mice (p < 0.05) and the symptoms of fatty liver in rats. Among them, the best effect was achieved at 3:6, without affecting the normal development of the mouse liver [37].
The basic structures of reported other phytochemicals with synergistic hypolipidemic effects from plants are shown in Figure S1.
In summary, a certain amount of studies have reported on the synergistic hypolipidemic effects of the same category of phytochemicals, especially flavonoids and polysaccharides. Nevertheless, there are still some unresolved aspects; for example, the phytochemical synergistic effects are usually studied based on observations in animal models, while in-depth and systematic analyses at the molecular level are still pending. In addition, we can search for new combinations of phytochemicals with clear molecular structures and active groups showing synergistic hypolipidemic effects, which should serve as the focus of further investigations.
3. Synergistic Hypolipidemic Effects between Different Categories of Phytochemicals
Nowadays, a large number of researchers indicated that different categories of phytochemicals could show synergistic hypolipidemic effects.
3.1. Synergistic Hypolipidemic Effects of Flavonoids with Other Categories of Phytochemicals
Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a flavonol compound with a wide distribution in the plant kingdom that has a variety of biological activities [81]. Resveratrol (3,5,4′-trihydroxytrans-stilbene) is considered as a natural antioxidant and is known for its anti-atherosclerotic properties, inhibiting lipid peroxidation and enhancing cholesterol efflux [82]. Arias et al. investigated the additive or synergistic effects of resveratrol and quercetin on fat accumulation and triglyceride metabolism in mice fed a high-fat diet. Mice were treated with resveratrol (15 mg/kg/d), quercetin (30 mg/kg/d), or a combination of them for 6 weeks, respectively. The results showed that the combination with quercetin or resveratrol resulted in a significant reduction in lipid accumulation compared to treatment alone, and the reduction percentage was greater than the calculated additive effect [83].
Similarly, Yang et al. observed that in maturing preadipocytes, resveratrol and quercetin individually suppressed intracellular lipid accumulation by 9.4% and 15.9%, respectively, and the combination of them at the same dose decreased lipid accumulation by 68.6% [84]. Furthermore, a gas chromatography-mass spectrometry (GC-MS)-based metabolomic approach was used to assess the potential role and mechanisms of quercetin and resveratrol combination (2:1) at different doses (45, 90 and 180 mg/kg) in high-fat diet (HFD)-induced obese rats. A total of 22 differential metabolites were found at the transcriptional and metabolic levels in the HFD group compared to the normal group, involving amino acid, galactose and pyruvate metabolism, pantothenic acid and coenzyme a biosynthesis, citric acid cycle, and lysine degradation, respectively, while the combination of quercetin and resveratrol reversed some of the differential metabolite changes [68]. In addition, Zhao et al. also reported that a combination of quercetin and resveratrol (2:1) significantly reduced TC, TG, and LDL-C levels in HFD-fed rats [85]. These results suggest that quercetin and resveratrol have significant synergistic hypolipidemic effects.
Park et al. investigated the combined effects of quercetin, resveratrol, and genistein on adipogenesis and apoptosis in human primary adipocytes (HAS) and 3T3-L1 mouse adipocytes (MAS). If these active substances were used to treated HAS alone, lipid accumulation was reduced by 16.8%, 20.3%, and 17.4%, respectively, while combined treatment (2:2:1) reduced lipid accumulation by 80.3%. The combination showed a greater inhibition of lipogenesis compared with the predicted superimposed effect based on individual compounds, indicating a synergistic hypolipidemic effect of a certain proportion of quercetin, resveratrol and genistein combination therapy [69]. Similarly, to assess the synergistic lipid-lowering effects of Hawthorn phytochemicals, Huang et al. used a combination of quercetin, hyperoside, rutin, and chlorogenic acid (6:9:2:1). They measured the inhibition of 3-hydroxy-3-methylglutaric acid monoacyl coenzyme A reductase before and after treatment with this combination therapy. The results showed that the inhibition rate of the combination was 58.9% higher than the sum of their individual inhibition rates, indicating that there was indeed a synergistic effect between the four active ingredients [70].
In addition, kaempferol, a flavonol in edible plants, has various effects such as antioxidant, anti-inflammatory and hypolipidemic effects, and it can be used as a therapeutic agent for diabetes and cardiovascular diseases [86]. Cinnamaldehyde, a natural flavoring, inhibits glycolysis while enhancing glucose storage [87]. Their combination has been reported to significantly reduce serum TC, TG and LDL-C levels and increase HDL-C levels in mice [71]. The nontargeted metabolomics results also confirmed the simultaneous obstruction of glucose and amino acid metabolism by kaempferol and cinnamaldehyde, showing synergistic hypolipidemic effects.
3.2. Synergistic Hypolipidemic Effects of Polysaccharides with Other Categories of Phytochemicals
It has been reported that polysaccharides and polyphenols in green tea can effectively reduce serum leptin levels and inhibit fatty acid absorption in rats, and the combination can reduce lipid accumulation more than their individual effects, which implies that polysaccharides and polyphenols may have synergistic effects in lowering blood lipids [72]. In addition, pumpkin polysaccharides and puerarin both showed lipid-lowering activity by lowering TC, TG and LDL-C levels and improving HDL-C levels [88,89]. Chen et al. investigated the hypoglycemic and hypolipidemic effects of pumpkin polysaccharides and puerarin in the type II diabetes mellitus mice model. After eight weeks of treatment, blood samples were taken from the tail vein of mice that had fasted overnight for the study. The results showed that pumpkin polysaccharide, gerberoside and their combination all improved the blood glucose levels in diabetic mice. Furthermore, compared with pumpkin polysaccharide and puerarin alone, the combination (2:1) treatment more significantly reduced serum TC, TG and LDL-C levels and increased serum HDL-C levels, indicating that they have synergistic hypoglycemic and hypolipidemic potential [73].
In addition, oat β-glucan and phytosterols have been recognized as adjunct or alternative lipid modulating therapies for optimizing dyslipidemia control as they are safe, effective and easily compliable for individuals with dyslipidemia [90,91]. Ferguson et al. reported that oat β-glucan and phytosterols can reduce blood cholesterol levels through different mechanisms and have the potential synergistic hypolipidemic effects. This has also been demonstrated through clinical studies that high molecular weight oat β-glucan and phytosterols have synergistic effects in lowering cholesterol in hypercholesterolemic adults. Specifically, TC and LDL-C decreased significantly by 11.5% and 13.9% (p < 0.0001), respectively, after their combined treatment, but they were significantly higher than phytosterols, which were 4.6% and 7.6% (p < 0.05), and oat β-glucan, which were 5.7% and 8.6% (p < 0.01) [74].
3.3. Synergistic Hypolipidemic Effects of Polyphenols with Other Categories of Phytochemicals
Apples are rich in polyphenols and pectin. In order to determine the role of apple components in lipid lowering, mice were fed diets containing 5 g/100 g apple pectin and 10 g/100 g high polyphenol freeze-dried apples or both. The combination was more effective in reducing circulating cholesterol and triglyceride concentrations than feeding alone, suggesting a positive interaction between apple pectin and polyphenols on lipid metabolism [75]. In addition, Ker et al. reported that peeled apples contain a large amount of inositol and uronic acid, which may play a synergistic role in lowering blood lipids, and suggested that phenolics may also have a potential contribution [92].
Epigallocatechin-3-gallate (EGCG) is the main polyphenol in green tea and has high antioxidant, hypolipidemic and anti-inflammatory activities [93,94]. Yang and Zhu et al. found that the combination of EGCG and caffeine was more effective in inhibiting fat accumulation than the same dose alone [95]. In another experiments, they demonstrated that the combination of low-dose EGCG and caffeine (2:1) had synergistic lipid-lowering effects. Specifically, mice were fed with low-dose EGCG (40 mg/kg/d), low-dose caffeine (20 mg/kg/d), high-dose EGCG (160 mg/kg/d), and a combination (40 mg/kg/d EGCG and 20 mg/kg/d caffeine). Compared to single treatment, the combination had more significant effects in reducing hepatic TC and TG levels, preventing weight gain, and inhibiting perirenal and epididymal fat accumulation. In addition, the combination of low-dose EGCG and caffeine resulted in better lipid-lowering effects than high-dose EGCG [76]. Similarly, Sugiura et al. reported that combined treatment with EGCG and caffeine (2:1) had overall stronger inhibitory effects on fat accumulation in mice than either alone [96]. In addition, a recent study reported that the combination of hydrophilic EGCG and lipophilic lycopene synergistically reduced TG and TC levels in serum and liver [77].
Curcuminoid is a natural polyphenol compound, which has good anti-inflammatory and hypolipidemic effects [97,98]. Hasimun et al. evaluated the effects of curcuminoid, S-methyl cysteine and their combination on the regulation of cholesterol levels in serum, liver, and feces. They established an animal model of rats with cholesterol metabolism abnormality induced by propylthiouracil for 7 days. The results showed that curcuminoid, S-methyl cysteine and their combination (1:1) could maintain the normal level of serum cholesterol by inhibiting the absorption of liver cholesterol. Furthermore, the combination resulted in the conversion of cholesterol into feces at a rate three times higher than that of the control group, which was superior to the effect of curcumin and S-methyl cysteine alone. This demonstrated that the combination of curcumin and s-methyl cysteine had synergistic hypolipidemic effects [78].
3.4. Synergistic Hypolipidemic Effects of other Different Categories of Phytochemicals
Ursolic acid is a naturally occurring triterpenoid found in many plants which has anti-oxidative, anti-inflammatory and hypolipidemic properties [99]. Artesunate is one of many derivatives of artemisinin extracted from Artemisia annua. Researchers investigated the hypolipidemic effects of ursolic acid and artesunate in rabbits with Western-diet induced hyperlipidemia. Rabbits received ursolic acid (25 mg/kg) or artesunate (25 mg/kg) alone or in combination (12.5 + 12.5 mg/kg). The results showed that ursolic acid or artesunate alone significantly reduced plasma triglyceride levels but had no effect on cholesterol levels. The combination reduced triglyceride and cholesterol levels with stronger synergistic effects than their individual effects [79]. This synergistic effect may be attributed to the different hypolipidemic mechanisms of artesunate and ursolic acid [100].
In addition, both policosanol and 10-dehydrogingerdione are natural phytochemicals and have shown the ability to lower the level of blood lipids [101,102]. It has been reported that the combination (1:1) significantly decreased serum levels of TC, LDL-C and TG and increased HDL-C levels in mice compared to single treatment, indicating synergistic hypolipidemic effects [80].
This entry is adapted from the peer-reviewed paper 10.3390/foods11182774
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