The Effect of Tomato Extract,Tomato Puree and Lycopene on Lipid Profile of Albino Rats and in Silico Simulation in Human

Abstract

Background

Cardiovascular disorders, including atherosclerosis, are the leading causes of mortality worldwide, and prophylactic measures to combat these disorders deserve special attention.

Objective

This study was designed to determine the effects of pure lycopene, raw tomato, and tomato puree on the lipid profile of albino rats fed a high-fat diet in vivo in rats and in silico in humans.

Materials and methods

Twenty-five albino rats were divided into five groups of five rats each: the group fed a normal diet; the group fed a high-fat diet; the group fed a high-fat diet plus pure lycopene; the group fed a high-fat diet plus freeze-dried raw tomato; and the group fed a high-fat diet plus freeze-dried tomato puree. After six weeks of treatment, blood samples were collected from the rats, and the serum lipid profile was determined using an enzymatic colorimetric method.

Result

The total serum cholesterol levels (TC), total triglycerides (TG), low-density lipoprotein (LDL), and cholesterol-to-HDL ratio levels were significantly (p < .05) increased in the group fed a high-fat diet compared to the group fed a normal diet. However, the mean TC, TG, LDL, and cholesterol/HDL ratio of the groups fed with high-fat diet plus pure lycopene, those fed a high-fat diet plus freeze-dried raw tomato, and those fed with high-fat diet plus freeze-dried tomato puree were significantly (p < .05) lower compared to the group fed with high-fat diet and the group fed with normal diet. The high-density lipoprotein (HDL) levels were significantly lower in the group fed with high-fat diet compared to the treatment groups fed with high-fat diet plus freeze-dried raw tomato and those fed with high-fat diet plus freeze-dried tomato puree. Interestingly, the group fed with high-fat diet plus freeze-dried raw tomato apparently had the lowest mean values of TC, TG, LDL, and TC/HDL ratio and the highest value of HDL among the treatment groups. The in-silico analysis in human showed the PPARA protein as the hub gene involved in lipid metabolism of tomatoes, primarily implicating the PPAR signaling pathway, adipocytokine signaling pathway, and thyroid hormone signaling pathway. 9-Octadecenoic acid, Cis 9-Octadecanoic acid, Methyl cis-9-octadecenoate were the three most active compounds involved.

Conclusion

These findings can enhance our understanding of the supplementation of lycopene and tomato products as potential measures to protect against hyperlipidemia, excessive abdominal fat deposition, and associated diseases in mammals, including humans.

Keywords

Tomato anti-hyperlipidemic property of tomato PPARA PPARA signalling pathway lipid metabolism

Introduction

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, thus, preventative strategies to reduce their prevalence should receive particular focus.¹ The majority of the time, atherosclerosis is the primary sign of cardiovascular diseases. It can progress silently for a long time until it causes serious adverse events, such a heart attack or stroke, at that point.² Public health measures currently in use are mostly concentrated on improving lifestyles through medicine or medical treatments, and lowering serum cholesterol to minimize the risk of coronary heart disease. The development of metabolic syndrome, a group of illnesses that includes insulin resistance, hypertension, and hyperlipidaemia, is one of the most worrisome features of obesity.³ When combined, these illnesses raise the chance of experiencing more serious health problems like heart attacks and strokes.⁴ Comprehensive and frequently expensive healthcare measures are needed to manage the comorbidities associated with obesity. These therapies include medication, lifestyle modifications, and even surgical procedures.⁵ The prevalence of obesity is still rising despite these measures, suggesting that the public health strategies in place may not be adequate.⁶ Effective preventive and therapeutic measures are desperately needed, as the burden of obesity and its associated comorbidities rises. Promoting healthy dietary practices, boosting physical activity levels, and putting laws in place that support healthier surroundings are just a few of the many strategies needed to address this public health emergency.⁷ Furthermore, more investigation is required to look at cutting-edge therapy alternatives, such as the advantages of functional foods, bioactive substances, and other non-pharmacological therapies that might supplement current treatment.⁸

The risk of complications can be decreased by using several types of treatment strategies to help prevent and/or cure cardiovascular diseases.^9,10 Previous research has demonstrated that a lower cholesterol level is linked to a lower risk of cardiovascular diseases.¹¹ Furthermore, triacylglycerol and low-density lipoproteins (LDL) have been found to share some additional similarities as important lipid risk factors for cardiovascular diseases.¹² Diet has a significant impact on reducing these levels of circulating lipids and has a long-term effectiveness that is on par with the majority of existing medication treatments. Supplementing the diet with dietary antioxidants, like lycopene, which is naturally found in tomatoes and tomato-derived products, is one diet plan that might be advantageous for enhancing the lipid profile.^1,13 Furthermore, tomatoes (Solanum lycopersicum) as widely consumed fruits have a high nutritional profile that includes vitamins, minerals, antioxidants, and bioactive substances, all of which add to their many health advantages.¹⁴ Of these advantages, tomatoes’ ability to lower blood cholesterol has attracted a lot of attention lately. Elevated blood lipid levels, or hyperlipidaemia, are a key risk factor for cardiovascular diseases (CVDs).¹⁵

The main pigment that gives tomatoes their red colour, lycopene, has been the subject of much research due to its potential to decrease cholesterol and its role in lipid metabolism.¹⁶ Lycopene has been shown in numerous studies to lower low-density lipoprotein (LDL) cholesterol, which is commonly known as “bad” cholesterol because it plays a part in the development of atherosclerosis. For instance, Zhang et al's meta-analysis¹⁷ of 12 clinical studies revealed that supplementing with lycopene significantly lowered LDL cholesterol levels in hypercholesterolaemia patients. The antioxidant qualities of lycopene, which shield lipids from oxidation, may be a factor in the compound's ability to decrease cholesterol, according to the authors.

Tomatoes’ antioxidant and anti-inflammatory qualities also contribute to their anti-hyperlipidemic benefits.¹⁸ Chronic inflammation and oxidative stress are linked to hyperlipidaemia and both of these factors play a role in the development of CVDs.¹⁵ Tomatoes are rich in antioxidants such as beta-carotene, lycopene, and vitamin C, which are important in lowering inflammation and oxidative stress.¹⁸

The use of plant parts to moderate human conditions and ailments is as old as man.^19,20 Consuming tomatoes and their products have been linked to a lower incidence of degenerative diseases, such as cardiovascular problems, according to empirical research.²¹ It has been proposed that in healthy males, consuming large amounts of tomato juice can inhibit the production of thiobarbituric reactive species (TBARS) and LDL oxidation.²¹ Lycopene is a carotenoid that gives fruits and vegetables their red color and has antioxidant qualities.

This study aimed at finding out how albino rats’ lipid profiles were affected by lycopene, tomato extract, and tomato puree as well simulate in silico activity in homo sapiens.

Materials and Methods

Study Design and Location

This experimental study was conducted in the Department of Medical Laboratory Science, Ebonyi State University, Abakaliki, Nigeria.

Preparation of Tomato Products and Pure Lycopene

This study utilized fresh raw tomatoes, tomato puree, and pure lycopene. Approximately 50 kilograms of mature, ripe tomatoes (Solanum lycopersicum) were procured from the International Market in Abakaliki, Ebonyi State, Nigeria. All tomatoes were selected at peak ripeness to ensure maximal lycopene content, as recommended by Rao and Rao.²² To prepare tomato juice, the fresh tomatoes were thoroughly washed to remove dirt and contaminants, homogenized using a mechanical blender, and then gently simmered in a small quantity of olive oil at low heat to enhance lycopene bioavailability through lipid-mediated absorption.²³

Tomato puree was purchased from a local grocery store in Abakaliki and was industrially processed through sequential steps including sorting, seed removal, crushing, heating at 65-75 °C, and preservation. Pasteurization was carried out under controlled conditions at 80-85 °C and 560-745 hPa. Post-processing, the puree was deep-frozen at −70 °C to retain phytonutrient stability. It was later subjected to freeze-drying for 48 h at a chamber temperature of −20 °C and a condenser temperature of −80 °C, following the procedure adapted from Zhang and colleagues.²⁴ Dried extracts were stored at 4 °C in opaque containers to prevent photodegradation. Pure lycopene (≥90% purity) was purchased as a red crystalline powder from Clanol Pharmaceutical Stores, Abakaliki, Nigeria. This compound was manufactured by Sigma-Aldrich, USA, a globally recognized supplier of research-grade chemicals.

Standardized Preparation of Tomato Extract

To ensure reproducibility and accuracy, the preparation of tomato extract was performed using a modified protocol from George et al²⁵ and Nara et al.²⁶ Only unblemished, vine-ripened tomatoes of the same cultivar were selected to maintain consistency in lycopene concentration. The tomatoes were first washed with distilled water to remove surface contaminants. Enzyme deactivation was achieved via blanching—submerging tomatoes in boiling water for 2-3 min, followed by immediate cooling in an ice bath. This process inhibits enzymatic degradation of carotenoids and other phytochemicals.

For homogenization, the tomatoes were chopped into smaller fragments and blended into a smooth puree. A solvent extraction method was employed using 95% ethanol in a 1:3 ratio (one part tomato paste to three parts ethanol) based on the protocol by Sadek and colleagues.²⁷ The mixture was stirred continuously and left to stand at ambient temperature (25 °C) for 24 h to ensure optimal extraction of bioactive compounds. Following maceration, the extract was filtered through multiple layers of sterile cheesecloth to eliminate particulate matter. The resulting filtrate, rich in lycopene and other phytonutrients was stored in sterile amber bottles at 4 °C until further analysis.

Experimental Animals

Twenty-five male albino rats, with ages between 5-7 months, weighing between 178-182 g, all in good health, and obtained from the Animal Farm of Faculty of Agriculture and Natural Sciences, Ebonyi State University, Abakaliki, Ebonyi State, were used in this study. They were bred in the animal housing section of College of Health Sciences, Ebonyi State University, Abakaliki, Nigeria. The animals were placed in plastic cages with metal net covers, and were subjected to a standardized laboratory condition of ventilation, temperature, (26 ± 2) °C and natural light throughout the study. The animals were fed with standard forage and water which was available ad libitum until the end of the experiment.

Experimental Design

The study involved in vivo analysis on Albino Wistar rats, and in silico simulation for humans. The twenty-five Wistar albino rats were placed in five groups (A, B, C, D, and E), each with five rats of similar weights, and placed in separate cages. The groups are defined as follows:

Negative Control Group; Fed with standard forage and normal tap water daily ad libitum.

Positive Control Group; Fed with a high-fat diet (basal diet + 5% tallow + 1% cholesterol + 0.02% bile salt).

Group of induced Hyperlipidemia and treated with pure lycopene; fed with high-fat diet (basal diet + 5% tallow + 1% cholesterol + 0.02% bile salt) plus 0.1% lycopene.

Group of induced Hyperlipidemia and treated with raw tomato; fed with high-fat diet (basal diet + 5% tallow + 1% cholesterol + 0.02% bile salt) plus 24% of the raw tomatoes powder.

Group of induced Hyperlipidemia and treated with tomato puree: fed with a high-fat diet (basal diet + 5% tallow + 1% cholesterol + 0.02% bile salt) plus 24% of tomato puree.

Groups D and E were all supplemented as to have the same quantity of lycopene (100 mg per kg of diet). Cholesterol powder and bile salts were obtained from the UC Biochemicals, Enugu, Nigeria. The duration of the experiment was for six weeks (42 days) and the experiment was terminated on the 43^rd day. Note, the dosage calculation and administration of tomato extract, tomato puree, and lycopene to the experimental animals were based on the predetermined protocol by Khayat-Nouri and Namvaran-Abbas.^28,29

Blood Sample Collection and Biochemical Analysis

At the end of experimental period, blood samples were collected from the rats after a 12 h period of fasting into clean dry plain tubes at room temperature and centrifuged at 3000 rpm for 10 min. The serum was aspirated and stored at −20 °C, until it was used for biochemical analysis. The lipid profile such as serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were determined using an enzymatic colorimetric method,³⁰ Randox kit, made in Crumlin-Northern Ireland but purchased from Cjay reagents Abakaliki, Ebonyi State. Procedures for biochemical analyses were as per the manufacturer's protocols.

Randomisation: To guarantee similar baseline features and reduce selection bias, albino rats were selected at random to one of five study groups using simple randomisation techniques. Every albino rat had a special identifying number issued to it. Using a randomisation process, the identifying numbers were then assigned at random to each of the study groups

Blinding: To avoid bias in the administration of diets and the evaluation of lipid profiles in each group, the study used single-blinding. The labels for the food and treatment were coded, and the code keys were kept secret until the trial was over.

Gas Chromatography-Mass Spectrometry Analysis of Dichloromethane of Tomato Extract

The protocol followed previous method. Briefly, the GC-MS analysis was carried out with a Clarus 500 Perkin Elmer gas chromatograph outfitted with an Elite-5 capillary column (5% phenyl, 95% dimethyl polysiloxane) (30 nm × 0.25 mm ID × 0.25 mm df) and a mass detector turbo-mass gold of the company that was operated in EI mode. The injector worked at 290 °C, and the oven temperature was controlled in the following order: 50 °C at 8 °C/min to 200 °C (5 min) at 7 °C/min to 290 °C (10 min). Helium served as the medium for the gas at the rate of flow of 1 ml/min. The National Institute of Standards and Technology (NIST) database, which contains more than 62 000 patterns, was used for the interpretation of the mass spectrum. The names and molecular weights of the extract's constituents were determined using the retention time and peak area acquired from the mass spectra of the unknown compounds and those of the known compounds stored in the library.³¹

In Silico Simulation

To further understand and extrapolate the findings of this study to human, we performed the underlisted analysis:

ADMET Analysis

We performed the ADMET and physicochemical analysis of the compounds using Swiss ADME.

Putative Gene, Protein-Protein Interaction, Gene Ontology and KEGG Pathway Evaluation

We curated putative genes associated with the identified compound using SwissTargetPrediction. We curated genes associated with lipid metabolisms using NCBI and OMIM. Venny 2.1 was used to identify common genes. STRING database was used for protein-protein interaction as well as gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway. We used Cytoscape to visualization. Cytohubba plug in was used for identification of hub genes and most important compounds and pathways.

Ethical Consideration

All experiments were conducted in accordance with the guidelines provided by the University Research Ethics Committee on the Use of Laboratory Animals. Prior to the study, the ethical approval was obtained from the Experiments and Ethics Committee of the College of Health Sciences, Ebonyi State University, Abakaliki, Nigeria (EBSU/REC/BMS/2210/04/003).

The reporting of this study conforms to ARRIVE guidelines 2.0.³²

Statistical Analysis

Data generated from this study was analyzed using Statistical Package for Social Sciences (SPSS) version 25 for windows, SPSS Inc, Chicago, IL, USA. The data are presented in terms of mean ± SD. The differences between the groups were determined by one-way analysis of variance (ANOVA). Level of significance was established at p < .05 with 95% Confidence interval.

Results

The result of the Gas chromatography-mass spectrometry analysis of dichloromethane of tomato extract as well as the physicochemical properties/ADMET properties of the identified compounds is represented in table 1.

Table 1.

Physicochemical (ADMET) Properties of the Compounds Found in the Tomato.

Compound	Formular	MW	Heavy Atoms	Aromatic Heavy Atoms	Rotatable Bonds	H-bond Acceptors	H-bond Donors	GI Absorption	BBB Permeant	Pgp Substrate	CYP1A2 Inhibitor	CYP2C19 Inhibitor	CYP2C9 Inhibitor	CYP2D6 Inhibitor	CYP3A4 Inhibitor	Bioavailability Score
2-Ethylhexane (3-methylheptane)	C8H18	114.23	8	0	4	0	0	Low	Yes	No	No	No	No	No	No	0.55
Ethylcyclohexane	C8H16	112.21	8	0	1	0	0	Low	Yes	No	No	No	No	No	No	0.55
2-Methyl-4,6-octadiyn-3-one	C9H10O	134.18	10	0	1	1	0	High	Yes	No	No	No	No	No	No	0.55
5,6-Dimethylundecane	C13H28	184.36	13	0	8	0	0	Low	No	No	No	No	Yes	No	No	0.55
1,2-Diphenyl-1-butanone	C16H16O	224.3	17	12	4	1	0	High	Yes	No	No	No	No	Yes	No	0.55
Isopropylbenzene (2-phenylpropane)	C9H12	120.19	9	6	1	0	0	Low	Yes	No	No	No	No	No	No	0.55
3,5-Dimethyloctane	C10H22	142.28	10	0	5	0	0	Low	Yes	No	No	No	No	No	No	0.55
2-Phenyl-3-buten-1-ol	C10H12O	148.2	11	6	3	1	1	High	Yes	No	No	No	No	No	No	0.55
2,4,4-Trimethylhexane	C9H20	128.26	9	0	3	0	0	Low	Yes	No	No	No	No	No	No	0.55
Benzoylcarboxaldehyde (Phenylglyoxal)	C8H6O2	134.13	10	6	2	2	0	High	Yes	No	Yes	No	No	No	No	0.55
Endo-tricyclo [5.2.1.0(2.6)] decane	C10H16	136.23	10	0	0	0	0	Low	Yes	No	No	Yes	Yes	No	No	0.55
2,4-Dimethyl-3-hexanone	C8H16O	128.21	9	0	3	1	0	High	Yes	No	No	No	No	No	No	0.55
Cyclopentacycloheptene (Azulene)	C10H8	128.17	10	10	0	0	0	Low	Yes	No	Yes	No	No	No	No	0.55
2,3-Heptanedione (Acetyl valeryl)	C7H12O2	128.17	9	0	4	2	0	High	Yes	No	No	No	No	No	No	0.55
1,6-Methano[10] annulene	C11H10	142.2	11	10	0	0	0	Low	Yes	No	Yes	No	No	No	No	0.55
1-Naphthaleneacetic acid, methyl ester	C13H12O2	200.23	15	10	3	2	0	High	Yes	No	Yes	No	No	No	No	0.55
Methyl tridecanoate	C14H28O2	228.37	16	0	12	2	0	High	Yes	No	Yes	No	No	No	No	0.55
Cis 9-Octadecanoic acid	C18H34O2	282.46	20	0	15	2	1	High	No	No	Yes	No	Yes	No	No	0.85
9-Octadecenoic acid	C18H34O2	282.46	20	0	15	2	1	High	No	No	Yes	No	Yes	No	No	0.85
Methyl cis-9-octadecenoate	C19H36O2	296.49	21	0	16	2	0	High	No	No	Yes	No	No	No	No	0.55
Oleic acid amide (Adogen 73)	C18H35NO	281.48	20	0	15	1	1	High	Yes	No	Yes	No	Yes	No	No	0.55
Tetradecahydrobenzo[a] cyclodecene	C14H26	194.36	14	0	0	0	0	Low	No	No	No	No	Yes	No	No	0.55
Lycopene	C40H56	536.87	40	0	16	0	0	Low	No	Yes	No	No	No	No	No	0.17

The initial mean body weights of the animals before the treatment and their final mean body weights after the treatment is as shown in table 2. There were no significant (p > .05) differences in the initial mean body weights of the animals across all the groups before the treatment. By contrast, there were significant (p < .05) differences in the final mean body weights of the animals across the groups after high-fat diet, and treatment with lycopene, and various tomato products. Group B indicated significantly (p < .05) higher final mean body weight (192.6 ± 2.73 g), when compared with group A (181.2 ± 0.75 g). However, the final mean body weight of group C (182.2 ± 1.33 g), group D (183.0 ± 1.02 g), and group E (182.2 ± 0.74 g), were significantly (p < .05) lower when compared with that of group B and group A. Group D apparently had the lowest final mean body weight, when compared to all other groups. Meanwhile, there was no significant (p > .05) difference in the final mean body weights between group C, group D, and group E. Furthermore, the mean final body weight was significantly higher when compared with the initial body weight in groups B (p = .001), D (p = .024) and E (p = .009) respectively. In contrast, no significant differences were observed between the initial and final body weights of groups A and C respectively.

Table 2.

the Initial and Final Body Weights of the Rats Before and After 6-Weks of Exposure to High-fat Diet.

Experimental Groups	Initial Body Weights (g)	Final Body Weight (g)
A	180.6 ± 0.80	181.2 ± 0.75
B	180.4 ± 1.02	192.6 ± 2.73* ^a
C	180.2 ± 1.32	182.2 ± 1.33^a^, ^b
D	180.0 ± 0.63	183.0 ± 1.02 * ^a^, ^b
E	180.4 ± 1.02	182.2 ± 0.74 * ^a^, ^b

Data are expressed as means ± SD for n = 5 animals per group. *Significant difference between initial and final body weight.

significantly (p < .05) different compared with group A.

significantly (p < .05) different compared with group B.

Figure 1 shows the effects of hyperlipidemic diet (group B) and treatment with pure lycopene (group C), raw tomato juice (group D) and tomato puree (group E) on the total cholesterol levels of the Wistar rats. Data indicated that the hyperlipidemic diet induced significantly (p < .001) higher TC level (8.34 ± 0.61 mmol/L) in group B compared, with the control (4.14 ± 0.14 mmol/L). The TC levels of the treatment groups; C (2.82 ± 0.12 mmol/L), D (2.40 ± 0.14 mmol/L), and E (2.64 ± 0.14 mmol/L) indicated significant decreases (p < .001) when compared with the control and hyperlipidemic groups respectively. Among the treatment groups, the lycopene group (C) showed the highest mean TC, followed by group E and group D. However, no significant differences were found when the treatment groups were compared with each other.

Figure 1.

The Mean Total Cholesterol Concentration Among Different Study Groups.

The mean triglyceride levels of the five study groups are compared and shown in Figure 2. Analysis of variance indicated that the experimental group fed with hyperlipidemic diet (group B) had significantly higher triglyceride level (2.88 ± 0.08 mmol/L) compared with the control (2.10 ± 0.15 mmol/L). The treatment groups C (1.76 ± 0.16), D (1.66 ± 0.10 mmol/L) and E (1.72 ± 0.15 mmol/L) indicated significantly lower triglyceride levels compared with the control group A (p < .01) and group B (p < .001) respectively. Regarding the treatment groups, the lycopene group (C) showed the highest mean TC, followed by group E and group D. However, the mean triglyceride levels did not differ among the treatment groups.

Figure 2.

The Mean Triglycerides Concentration Among Different Study Groups.

Figure 3 shows comparison of the mean HDL concentrations of the different study groups A to E. The group D treated with raw tomato had significantly (p < .001) higher HDL level (2.46 ± 0.10 mmol/L) compared with the control (1.24 ± 0.14 mmol/L), group B (1.22 ± 0.08 mmol/L), group C (1.24 ± 0.10), and group E (1.46 ± 0.05 mmol/L). Similarly, group E rats treated with tomato puree indicated significantly higher HDL compared with group A (p = .004), group B (p = .002) and group C (p = .004).

Figure 3.

The Mean High Density Lipoprotein Concentration among Different Study Groups.

The effects of hyperlipidemic diet (group B), lycopene (group C), raw tomato (group D), and tomato paste (group E) on the serum low-density lipoprotein of the albino rats are as shown in Figure 4. Group B significantly (p = .016) had a higher mean concentration of LDL (2.30 ± 0.14 mmol), when compared with group A (2.08 ± 0.26 mmol/l). The mean LDL of group C (1.71 ± 0.07 mmol/l), group D (1.40 ± 0.14 mmol/l), and group E (1.66 ± 0.10 mmol/l), were significantly (p < .001) lower when compared with those of group B and group A. Interestingly, group D had significantly (p < .01) lower mean values of LDL when compared with the other treatment groups C and D. Meanwhile, there was no significant (p > .05) difference in the mean values of LDL between group C and E.

Figure 4.

The Mean Low-Density Lipoprotein Among Different Study Groups.

The mean TC/HDL ratio of the study groups are as shown in Figure 5. Data indicated that group B had significantly (p < .001) higher TC/HDL ratio (6.88 ± 1.01) compared with control group (3.39 ± 0.55), groups C (2.29 ± 0.26), D (0.97 ± 0.04) and E (1.80 ± 0.09) respectively. Group A also indicated significantly higher mean TC/HDL ratio compared with groups C (p = .004), D (p < .001) and E (p < .001) respectively. Regarding the treatment groups, the raw tomato group (D) indicated a significantly lower mean TC/HDL ratio compared with group D (p = .001) and group E (p = .022).

Figure 5.

the Mean Total Cholesterol High Density Lipoprotein Ratio among Different Study Groups.

Figure 6 shows the protein-protein interaction of the various proteins involved in the lipid reduction potential of tomato extract. A total of three hundred twenty-six (326) genes related to lipid metabolism were retrieved from NCBI and OMIM. These genes were compared with the genes predicted with SwissTargetPrediction using the Compounds identified. PPARA was identified as the common gene in both targets using Venn diagram (Venny 2.1.0). Figure 7 shows the hub genes involved in tomato extract lipid metabolism. The top 6 genes were PPARA, PPARGC1A, NCOA1, RXRA, NCOR1 and NCOR2 with PPARA as the major target proteins.

Figure 6.

Protein-Protein Interaction Network Showing Proteins Involved In Lipid Reduction Action Of Tomato Extract.

Figure 7.

Hub Putative Genes Involved in Lipid Reduction Action of Tomato Extract.

Table 3 shows the functional enrichment approach to find Gene ontology terms for lipid control mechanism of tomato. The gene ontology and pathway enrichment analysis showed that the hub genes regulate four (4) different cellular components which are the chromatin (GO:0000785), nucleoplasm (GO:0005654), transcriptional regulator complex (GO:0005667) and the transcriptional repressor complex (GO:0017053). The molecular function of the hub genes showed they are involved in: Transcription factor binding (GO:0008134), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), nuclear receptor binding (GO:0016922), transcription regulator activity (GO:0140110), Transcription coregulator activity (GO:0003712), DNA binding (GO:0003677), chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), Transcription coregulator binding (GO:0001221) enzyme binding (GO:0019899), nuclear steroid receptor activity (GO:0003707), and Sequence-specific DNA binding (GO:0043565). The enrichment analysis showed 15 biological processes. Among these are Regulation of cellular ketone metabolic process (GO:0010565), Regulation of fatty acid metabolic process (GO:0019217), Positive regulation of fatty acid oxidation (GO:0046321), Regulation of lipid metabolic process (GO:0019216), Gluconeogenesis (GO:0006094), Negative regulation of cellular biosynthetic process (GO:0031327), Regulation of ATP metabolic process (GO:1903578), Positive regulation of fatty acid beta-oxidation (GO:0032000), Fatty acid metabolic process (GO:0006631), Negative regulation of metabolic process (GO:0009892), Negative regulation of glycolytic process (GO:0045820), Positive regulation of gluconeogenesis (GO:0045722), Negative regulation of phosphate metabolic process (GO:0045936), Regulation of cellular carbohydrate metabolic process (GO:0010675), Negative regulation of nitrogen compound metabolic process (GO:0051172). A total of 3 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified to be regulated by the hub genes. The major pathways involved in this activity were PPAR signalling pathway, Adipocytokine signalling pathway and Thyroid hormone signalling pathway.

Table 3

Functional Enrichment Approach to Find Gene Ontology Entries for Lipid Control Mechanism of Tomato.

Category	GO ID	Term	Gene Count	FDR	Genes
Cellular components	GO:0000785	Chromatin	7	0.0027	NCOR1, JUN, NCOR2, NCOA1, PPARA, RXRA
	GO:0005654	Nucleoplasm	10	0.0027	PER2, PPARGC1A, NCOR1, FABP1JUN, NCOR2, NCOA1, PPARA, LPIN1RXRA
	GO:0005667	Transcription regulator complex	5	0.0027	NCOR1, JUN, NCOR2, NCOA1, RXRA
	GO:0017053	Transcription repressor complex	3	0.0042	NCOR1, JUN, NCOR2,
Molecular function	GO:0008134	Transcription factor binding	8	4.95E-07	PER2, PPARGC1A, NCOR1, JUN, NCOR2NCOA1, PPARA, RXRA
	GO:0061629	RNA polymerase II-specific DNA-binding transcription factor binding	7	4.95E-07	PPARGC1A, NCOR1, JUN, NCOR2NCOA1, PPARA, RXRA
	GO:0016922	Nuclear receptor binding	5	1.14E-05	PPARGC1A, NCOR1, NCOR2, NCOA1, RXRA
	GO:0140110	Transcription regulator activity	9	3.85E-05	PER2, PPARGC1A, NCOR1, JUN, NCOR2, NCOA1, PPARA, LPIN1, RXRA
	GO:0003712	Transcription coregulator activity	6	0.00012	PER2, PPARGC1A, NCOR1, NCOR2, NCOA1LPIN1
	GO:0003677	DNA binding	8	0.0055	PER2, PPARGC1A, NCOR1, JUN, NCOR2NCOA1, PPARA, RXRA
	GO:0003682	Chromatin binding	5	0.0057	PPARGC1A, FABP1, JUN, NCOR2NCOA1
	GO:0003713	Transcription coactivator activity	4	0.0084	PER2, PPARGC1A, NCOA1, LPIN1
	GO:0001221	Transcription coregulator binding	3	0.016	PER2, PPARA, RXRA
	GO:0019899	Enzyme binding	7	0.016	PPARGC1A, NCOR1, JUN, NCOR2NCOA1, PPARA, RXRA
	GO:0003707	Nuclear steroid receptor activity	2	0.0405	PPARA, RXRA
	GO:0043565	Sequence-specific DNA binding	6	0.0445	PER2, PPARGC1A, NCOR1, JUN, PPARA, RXRA
Biological process	GO:0010565	Regulation of cellular ketone metabolic process	5	0.00011	PPARGC1A, NCOR1, FABP1, NCOR2, PPARA,
	GO:0019217	Regulation of fatty acid metabolic process	4	0.00098	PPARGC1A, NCOR1, FABP1, PPARA
	GO:0046321	Positive regulation of fatty acid oxidation	3	0.00098	PPARGC1A, FABP1, PPARA
	GO:0019216	Regulation of lipid metabolic process	5	0.0017	PPARGC1A, NCOR1, FABP1, PPARA, LPIN1
	GO:0006094	Gluconeogenesis	3	0.0027	PER2, PPARGC1A, PPARA
	GO:0031327	Negative regulation of cellular biosynthetic process	7	0.0057	PER2, NCOR1, JUN, NCOR2, PPARA, LPIN1RXRA
	GO:1903578	Regulation of ATP metabolic process	3	0.0058	PPARGC1A, NCOR1, PPARA
	GO:0032000	Positive regulation of fatty acid beta-oxidation	2	0.0096	FABP1, PPARA
	GO:0006631	Fatty acid metabolic process	4	0.0097	PER2, PPARGC1A, PPARA, LPIN1
	GO:0009892	Negative regulation of metabolic process	8	0.0115	PER2, NCOR1, FABP1, JUN, NCOR2
	GO:0045820	Negative regulation of glycolytic process	2	0.0115	PPARA, LPIN1, RXRA
	GO:0045722	Positive regulation of gluconeogenesis	2	0.0121	NCOR1, PPARA
	GO:0045936	Negative regulation of phosphate metabolic process	4	0.0155	PPARGC1A, PPARA
	GO:0010675	Regulation of cellular carbohydrate metabolic process	3	0.0157	NCOR1, JUN, PPARA, LPIN1
	GO:0051172	Negative regulation of nitrogen compound metabolic process	7	0.0157	PPARGC1A, NCOR1, PPARA
KEGG Pathway	hsa03320	PPAR signaling pathway	3	0.0024	FABP1, PPARA, RXRA
	hsa04920	Adipocytokine signaling pathway	3	0.0024	PPARGC1A, PPARA, RXRA
	hsa04919	Thyroid hormone signaling pathway	3	0.0042	NCOR1, NCOA1, RXRA

Abbreviations: FDR, false discovery rate.

Figure 8 shows the interaction of the compound-target-pathway of the compounds, hub genes and pathways that are involved in tomato metabolism. The result showed that the compounds that played role were 2-Ethylhexane (3-methylheptane), Ethylcyclohexane, 3,5-Dimethyloctane, 2,4,4-Trimethylhexane, Endo-tricyclo [5.2.1.0(2.6)] decane, Cyclopentacycloheptene (Azulene), 1,6-Methano[10] annulene, Methyl tridecanoate, Cis 9-Octadecanoic acid, 9-Octadecenoic acid, Methyl cis-9-octadecenoate, Oleic acid amide (Adogen 73) and Tetradecahydrobenzo[a] cyclodecene.

Figure 8.

Interaction Of The Compound-Target-Pathway Of The Compounds, Hub Gens And Pathways That Are Involved In Tomato Metabolism.

The compound-target-pathway analysis of top 10 activities showed 9-Octadecenoic acid, Cis 9-Octadecanoic acid, Methyl cis-9-octadecenoate, 2,4,4-Trimethylhexane, Endo-tricyclo [5.2.1.0(2.6)] decane and 3,5-Dimethyloctane as the most active compounds in tomato with respect to lipid metabolism (in respective order) while PPARA was the most important target (hub gene). PPAR signalling pathway followed by Adipocytokine signalling pathway were the most involved pathway (Figure 9).

Figure 9.

Top 10 Most Active Compound-hub-Gene-Pathway Analysis.

Discussion

Cardiovascular disorders are major issue of public health concern. Therefore, the main goal of public health programs is to minimize the risk of cardiovascular illnesses, especially by lowering blood cholesterol and promoting healthier lifestyles. Examining the potential of dietary antioxidants—like lycopene, which is found naturally in tomatoes and tomato-based products—comes to mind when doing this. Consuming tomatoes and tomato-derived products is linked to a lower risk of cardiovascular diseases, according to mounting empirical data.^13,23,33 Thus, the purpose of this investigation was to ascertain how pure lycopene, raw tomatoes, and tomato puree affected the lipid profile of albino rats, considering the early atherosclerosis events brought on by a high-fat diet in vivo.

Obesity is well recognized as a primary cause of elevated risk of conditions like dyslipidemia, insulin resistance, hypertension, and atherosclerosis, as well as an independent risk factor for cardiovascular illnesses.^34,35 Obesity frequently results in adipose tissue inflammation, which can be lessened by lowering body fat percentage.³⁶ After six weeks of exposure to a high-fat diet, the weight of the albino rats was significantly suppressed by the administration of lycopene, raw tomato (RT), and tomato puree (TP), preventing overweight. It's interesting to note that, in contrast to the RT and TP groups, the rats in the pure lycopene group saw a greater influence on sustaining their body weights, as evidenced by the fact that the animals’ mean final weight did not vary from their initial body weight. Tomato juice intake dramatically lowered body weight, body fat, waist circumference, and BMI, according to a prior study.³⁷ Adipokine expression and secretion have also been shown to be mediated by lycopene.^38,39 In line with this, dietary-based interventions have demonstrated that adipokine consumption can change adipokines to a more anti-inflammatory profile.^40,41

When group B animals were fed a high-fat diet exclusively, their serum levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), and cholesterol to HDL ratio levels were significantly higher than those of group A animals fed a regular diet alone. This indicates that a six-week addition of 1% cholesterol to the rats’ diet can change the concentration of blood lipids by raising the levels of TC, TG, LDL, and TC/HDL ratio. These outcomes agree with the findings of earlier research conducted by Vaskonen et al and Gorinstein et al^42,43 After a 6-week period, the albino rats were given lycopene, raw tomatoes, and tomato puree, which prevented the hyperlipidemic effects of a high-fat/high-cholesterol diet by lowering the rats’ TC, triglyceride, LDL, and TC/HDL ratios, but increasing the HDL. This is consistent with other research that found that consumed lycopene, whether in tomato paste, juice, or pure form, decreased serum cholesterol levels.^44-46

According to reports, lycopene's hypolipidemic effects are mostly caused by prevention of hepatic lipid production.^47-49 This may be partly because the lycopene compounds block the function of macrophage 3-hydroxy-3-methyl glutaryl coenzyme A reductase, an important enzyme involved in the manufacture of cholesterols. Moreover, lycopene may modify lipid metabolism processes including lipogenesis by inducing the AMP-activated protein kinase (AMPK) signaling pathway. Ripe tomatoes contain compounds called esculeoside A and esculeogenin A, which have been demonstrated to have inhibitory effects on the buildup of cholesterol ester in human monocyte-derived macrophages.^50,51

Furthermore, the TC, TG and LDL levels of the corresponding groups treated with raw tomato juice, tomato puree, and pure lycopene did not differ statistically significantly; nonetheless, the raw tomato group appeared to have a more positive effects than the lycopene and tomato puree groups. In addition, the raw tomato group presented significantly higher HDL and lower TC/HDL levels compared with the other groups. It is unclear why the raw tomato group showed a more pronounced hypolipidemic effects. However, because lycopene works well with other bioactive substances like phenolic compounds (chlorogenic acid, caffeic acid, rutin, and naringenin), folates, and antioxidant vitamins (E and C), it is believed that raw tomato extract has a higher antilipidemic activity than pure lycopene.⁵² Furthermore, it's thought that longer processing periods and thermal processing are often linked to higher losses of bioactive components in tomato.⁴² Similar to this, some tomato components—such as the pulp, seeds, and skin—are eliminated as byproducts of industrial processing. This implies that the final product as seen in tomato puree can lose certain important functional components.⁵³ However, our findings did not support earlier research showing that tomato puree or paste had a greater lowering effect on lipids than raw tomatoes.²⁸

The in silico simulation of the lipid profile reduction of tomato extract showed PPARA protein as the primary target protein in altering lipid metabolism in humans. and PPAR signaling pathway, Adipocytokine signaling pathway and Thyroid hormone signaling pathway as the major pathway involved in the process. This makes the protein and the associated pathways target for lipid reduction therapy. The peroxisome proliferator-activated receptor alpha (PPARA) is ligand-activated transcription factors that belong to the superfamily of nuclear hormone receptors (which include PPARβ/δ, and PPARγ) and play an important role in nutrient homeostasis^54,55 and function as key regulator of lipid metabolism. It is activated by oleylethanolamide, a naturally occurring lipid that regulates satiety.⁵⁶ PPARA lowers plasma TG in part by reducing very low-density lipoprotein (VLDL) production by inducing genes involved in fatty acid oxidation and the concomitant reduction in lipid availability for VLDL production.^57‐59 Comparison of human and murine PPARA shows 85% identity at the nucleotide level and 91% identity at the amino acid level levelling a comparative result.⁵⁸

This study is potentially prone to a number of limitations. It has provided information on the effect of tomato products on lipid metabolism of Wistar rats as well as the in silico simulation on humans. However, the application to humans needs clinical validation via randomised clinical trial. Due to differences in metabolism, body size, and other physiological factors, the precise doses used in rat studies may not always translate to humans. As a result, without additional research, the selected dose ranges may not be applicable to dietary recommendations for humans or therapeutic use. By conducting studies that explore a wider range of doses and determining the minimal effective dose as well as the safety threshold, a clearer picture of how these tomato-based products could be used in clinical settings will be provided. More so, the present study did not add antioxidation assay.

Conclusion

The results of this study indicated that tomato products and pure lycopene were effective in lowering serum levels of TC, TG, LDL and TC/HDL ratio in albino rats fed with high-fat/high-cholesterol diet. They also increased the HDL level and helped the rats lose weight. Interestingly, the raw tomato group appeared to have a more pronounced hypolipidemic effects than the lycopene and tomato puree groups. The in silico simulation in humans showed PPARA protein as target gene in lipid metabolism control which had affinity with compounds contained in the tomato extract. The tomato-based products therefore, may present a viable way to lower the chance of developing cardiovascular diseases. Thus, an increase in consumption of tomatoes and their products in the diet is recommended because of their positive effects on the tested parameters. In other words, the findings indicate that not just lycopene, but whole tomato products (like raw tomato powder and puree) can have a beneficial effect on lipid profiles. This suggests that whole foods might offer a broader range of health benefits due to the synergistic effects of various bioactive compounds in tomatoes, beyond lycopene alone. Encouraging the consumption of whole tomatoes or tomato-based foods, rather than relying solely on supplements, aligns with public health strategies that advocate for the consumption of whole, minimally processed foods for disease prevention.

Footnotes

ORCID iD

Henshaw Uchechi Okoroiwu

Ethical Considerations

Ethical approval for this study was obtained from Experiments and Ethics Committee of the College of Health Sciences, Ebonyi State University, Abakaliki, Nigeria (EBSU/REC/BMS/2210/04/003).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets used in this study are present in the article. The gene sets utilized are available in NCBI and OMIM which are publicly available.

Statement of Human and Animal Rights

All procedures in this study were conducted in accordance with the Ethics Committee of the College of Health Sciences, Ebonyi State University, Abakaliki, Nigeria approved protocol.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

References

Rao

Agarwal

. Role of antioxidant lycopene in cancer and heart disease. J Am Coll Nutr. 2000;19(5):563-569.

Basuny

Gaafar

Arafat

. Tomato lycopene is a natural antioxidant and can alleviate hypercholesterolemia. Afr J Biotechnol. 2009;8(23):6627-6633.

Grundy

Brewer

Jr. Cleeman

Smith

Jr. Lenfant

. Definition of metabolic syndrome: report of the national heart, lung, and blood institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109(3):433-438.

Kaur

. A comprehensive review on metabolic syndrome. Cardiol Res Pract. 2014:943162. https://doi.org/10.1155/2014/943162

Nguyen

El-Serag

. The epidemiology of obesity. Gastroenterol Clin North Am. 2010;39(1):1-7. https://doi.org/10.1016/j.gtc.2009.12.014

Hruby

. The epidemiology of obesity: a big picture. Pharmacoeconomics. 2015;33(7):673-689.

Swinburn

Sacks

Hall

, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378(9793):804-814. https://doi.org/10.1016/S0140-6736(11)60813-1

Hasani-Ranjbar

Nayebi

Larijani

Abdollahi

. A systematic review of the efficacy and safety of herbal medicines used in the treatment of obesity. World J Gastroenterol. 2009;15(25):3073-3085.

Fladseth

Wilsgaard

Lindekleiv

, et al. Outcomes after coronary angiography for unstable angina compared to stable angina, myocardial infarction and an asymptomatic general population. Int J Cardiol Heart Vasc. 2022;42:101099.

10.

Davis

Fish

Perkins-Veazie

. A rapid spectrophotometric method for analyzing lycopene content in tomato and tomato products. Postharvest Biol Technol. 2003;28(3):425-430.

11.

Jeong

Choi

Kim

, et al. Effect of change in total cholesterol levels on cardiovascular disease among young adults. J Am Heart Assoc. 2018;7(12):1-15.

12.

Aviram

Fuhrman

. Polyphenolic flavonoids inhibit macrophage-mediated oxidation of LDL and attenuate atherogenesis. Atherosclerosis. 1998;137:S45-S50.

13.

Przybylska

Tokarczyk

. Lycopene in the prevention of cardiovascular diseases. Int J Mol Sci. 2022;23(4):1-23.

14.

Martí

Roselló

Cebolla-Cornejo

. Tomato as a source of carotenoids and polyphenols targeted to cancer prevention. Cancers (Basel). 2016;8(6):58. https://doi.org/10.3390/cancers8060058

15.

Ference

Ginsberg

Graham

, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: 1. Evidence from genetic, epidemiologic, and clinical studies. Eur Heart J. 2017;38(32):2459-2472.

16.

Sesso

Liu

Gaziano

Buring

. Dietary lycopene, tomato-based food products and cardiovascular disease in women. J Nutr. 2003;133(7):2336-2341. https://doi.org/10.1093/jn/133.7.2336

17.

Zhang

Zhu

. Effect of lycopene on blood lipids: a systematic review and meta-analysis of randomized controlled trials. J Clin Lipidol. 2020;14(3):375-386.

18.

Martí

Leiva-Brondo

Lahoz

Campillo

Cebolla-Cornejo

Roselló

. Polyphenol and l-ascorbic acid content in tomato as influenced by high lycopene genotypes and organic farming at different environments. Food Chem. 2018;239:148-156.

19.

Okoroiwu

Okafor

Uko

Atangwho

. Some hematological parameters of Wistar rats treated with Chromolaena odorata leave extracts. J Biol Res Bollett Soc Ital Biol Sper. 2017;90(1):51-55. https://doi.org/10.4081/jbr.2017.6210

20.

Okoroiwu

Atangwho

Uko

Maryann

. Haemostatic property of chromolaena odorata leaf extracts: in vitro and in vivo evaluation in Wistar rats. J Biol Res Bollett Soc Ital Biol Sper. 2016;89(2):56-60. https://doi.org/10.4081/jbr.2016.6211

21.

Matulka

Hood

Griffiths

. Safety evaluation of a natural tomato oleoresin extract derived from food-processing tomatoes. Regul Toxicol Pharmacol. 2004;39(3):390-402.

22.

Rao

. Carotenoids and human health. Pharmacol Res. 2007;55(3):207-216. https://doi.org/10.1016/j.phrs.2007.01.012

23.

Gärtner

Stahl

Sies

. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr. 1997;66(1):116-122. https://doi.org/10.1093/ajcn/66.1.116

24.

Zhang

Duan

Liang

. Optimization of lycopene extraction from tomato peels by response surface methodology. Food Sci Nutr. 2020;8(2):953-960. https://doi.org/10.1002/fsn3.1371

25.

George

Kaur

Khurdiya

Kapoor

. Antioxidants in tomato (lycopersium esculentum) as a function of genotype. Food Chem. 2011;84(1):45-51. https://doi.org/10.1016/S0308-8146(03)00165-1

26.

Nara

Miyoshi

Honma

Koga

. Antioxidative activity of water extracts from roasted products. J Agric Food Chem. 2010;54(22):8745-8750. https://doi.org/10.1021/jf061386j

27.

Atessahi

Yilmaz

Karahan

. Effects of lycopene against cisplatin-induced nephrotoxicity in rats: an experimental study. Toxicology. 2005;212(2-3):116-123. https://doi.org/10.1016/j.tox.2005.04.016

28.

Khayat Nouri

Namvaran Abbas Abad

. Comparative study of tomato and tomato paste supplementation on the level of serum lipids and lipoproteins levels in rats fed with high cholesterol. Iran Red Crescent Med J. 2013;15(4):287-291.

29.

Bose

Agrawal

. Effect of long-term supplementation of tomatoes (cooked) on levels of antioxidant enzymes, lipid peroxidation rate, lipid profile, and glycated haemoglobin in type 2 diabetes mellitus. West Indian Med J. 2006;55(4):274-278.

30.

Randox Laboratories Ltd. Effective cardiac risk assessment with the Randox lipid profile and hsCRP test. SelectScience. Retrieved from : https://www.selectscience.net.

31.

Asanga

Joseph

Umoh

, et al. New perspectives on the therapeutic potentials of bioactive compounds from Curcuma longa: targeting COX-1 & 2, PDE-4B, and antioxidant enzymes to counteract oxidative stress and inflammation. Nat Prod Commun. 2024;19(5):1-21. https://doi.org/10.1177/1934578X241255508

32.

Percie du Sert

Hurst

Ahluwalia

, et al. The ARRIVE guideline 2.0. Updated guideline for reporting animal research. BMC Vet Res. 2020;16:242.

33.

Riso

Visioli

Grande

, et al. Effect of a tomato-based drink on markers of inflammation, immunomodulation, and oxidative stress. J Agric Food Chem. 2006;54(7):2563-2566.

34.

Barroso

Marins

Alves

Gonçalves

ACS

Barroso

Rocha

GDS

. Association of central obesity with the incidence of cardiovascular diseases and risk factors. Int J Cardiovasc Sci. 2017;30(5):416-424.

35.

Akil

Ahmad

. Relationships between obesity and cardiovascular diseases in four southern states and Colorado. J Health Care Poor Underserved. 2011;22(4 Suppl):61-72.

36.

Gregor

Hotamisligil

. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-445.

37.

Chang

Huang

Yang

Chao

. Tomato juice supplementation in young women reduces inflammatory adipokine levels independently of body fat reduction. Nutrition. 2015;31(5):691-696.

38.

Gouranton

Thabuis

Riollet

, et al. Lycopene inhibits proinflammatory cytokine and chemokine expression in adipose tissue. J Nutr Biochem. 2011;22(7):642-648.

39.

Luvizotto

RDAM

Nascimento

Imaizumi

, et al. Lycopene supplementation modulates plasma concentrations and epididymal adipose tissue mRNA of leptin, resistin and IL-6 in diet-induced obese rats. Br J Nutr. 2013;110(10):1803-1809.

40.

Wang

Zhao

, et al. The effect of tomato on weight, body mass index, blood pressure and inflammatory factors: a systematic review and dose-response meta-analysis of randomized controlled trials. J King Saud Univ Sci. 2020;32(2):1619-1627.

41.

Kirichenko

Markina

Bogatyreva

Tolstik

Varaeva

Starodubova

. The role of adipokines in inflammatory mechanisms of obesity. Int J Mol Sci. 2022;23(23):14982. doi: https://doi.org/10.3390/ijms232314982

42.

Vaskonen

Mervaala

Krogerus

Karppanen

. Supplementation of plant sterols and minerals benefits obese zucker rats fed an atherogenic diet. J Nutr. 2002;132(2):231-237.

43.

Gorinstein

Bartnikowska

Kulasek

Zemser

Trakhtenberg

. Dietary persimmon improves lipid metabolism in rats fed diets containing cholesterol. J Nutr. 1998;128(11):2023-2027.

44.

Ferro

Mazza

Angotti

, et al. Effect of a novel functional tomato sauce (OsteoCol) from vine-ripened tomatoes on serum lipids in individuals with common hypercholesterolemia: tomato sauce and hypercholesterolemia. J Transl Med. 2021;19:1.

45.

Nouri

Abad

ANA

. Comparative study of tomato and tomato paste supplementation on the level of serum lipids and lipoproteins levels in rats fed with high cholesterol. Iran Red Crescent Med J. 2013;15(4):287-291.

46.

El-Nashar

Abduljawad

. Impact effect of lycopene and tomato-based products network on cardio-protective biomarkers in vivo. Funct Foods Health Dis. 2012;2(5):151-165.

47.

Abdel-Rahman

Abdelrazek

HMA

Zeidan

Mohamed

Abdelazim

. Lycopene: hepatoprotective and antioxidant effects toward bisphenol A-induced toxicity in female wistar rats. Oxid Med Cell Longev. 2018;2018:95167524.

48.

Wang

Geng

Zou

, et al. Lycopene prevents lipid accumulation in hepatocytes by stimulating PPARα and improving mitochondrial function. J Funct Foods. 2020;67:103857.

49.

Zhao

Wang

, et al. Lycopene prevents DEHP-induced liver lipid metabolism disorder by inhibiting the HIF-1α-induced PPARα/PPARγ/FXR/LXR system. J Agric Food Chem. 2020;68(41):11468-11479.

50.

Manabe

Murakami

El-Aasr

, et al. Content variations of the tomato saponin esculeoside A in various processed tomatoes. J Nat Med. 2011;65(1):176-179.

51.

Fujiwara

Kiyota

Hori

, et al. Esculeogenin A, new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT. Arterioscler Thromb Vasc Biol. 2007;27(11):2400-2406.

52.

Navarro-González

Pérez-Sánchez

Martín-Pozuelo

García-Alonso

Periago

. The inhibitory effects of bioactive compounds of tomato juice binding to hepatic HMGCR: in vivo study and molecular modelling. PLoS One. 2014;9(1):e83968.

53.

Pehrsson

. Are processed tomato products as nutritious as fresh tomatoes? Scoping review on the effects of industrial processing on nutrients and bioactive compounds in tomatoes. Adv Nutr. 2022;13(1):138-151.

54.

Kersten

Desvergne

Wahli

. Roles of PPARs in health and disease. Nature. 2000;405(6785):421-424. doi: https://doi.org/10.1038/35013000

55.

Evans

Barish

Wang

. PPARs and the complex journey to obesity. Nat Med. 2004;10(4):355-361. doi: https://doi.org/10.1038/nm1025

56.

Rakhshandehroo

Knoch

Müller

Kersten

. Peroxisome proliferator-activated receptor alpha target genes. PPAR Res. 2010;2010:612089. https://doi.org/10.1155/2010/612089

57.

Kersten

. Peroxisome proliferator activated receptors and lipoprotein metabolism. PPAR Res. 2008;2008:132960. doi: https://doi.org/10.1155/2008/132960

58.

Uniprot. Q07869 · PPARA_HUMAN. Available at: https://www.uniprot.org/uniprotkb/Q07869/entry. Accessed July 13, 2024.

59.

Uchiyama

Ordonez

GPM

Pham

, et al. PPARɑ variant V227A reduces plasma triglycerides through enhanced lipoprotein lipolysis. J Lipid Res. 2025;66(5):100806.