The Therapeutic Potential of Orange Juice in Cardiac Remodeling: A Metabolomics Approach
Internal Medicine Department, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu 18618-687, Brazil; seiji.fujimori@unesp.br (A.S.S.F.); bertha.polegato@unesp.br (B.F.P.); marina.okoshi@unesp.br (M.P.O.)
Abstract
Cardiovascular diseases are a leading cause of death worldwide, and the process of cardiac remodeling lies at the core of most of these diseases. Sustained cardiac remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure, and ultimately death. Therefore, in order to attenuate cardiac remodeling and reduce mortality, different therapies have been used, but it is important to identify adjuvant factors that can help to modulate this process. One of these factors is the inclusion of affordable foods in the diet with potential cardioprotective properties. Orange juice intake has been associated with several beneficial metabolic changes, which may influence cardiac remodeling induced by cardiovascular diseases. Current opinion highlights how the metabolites and metabolic pathways modulated by orange juice consumption could potentially attenuate cardiac remodeling. It was observed that orange juice intake significantly modulates phospholipids, energy metabolism, endocannabinoid signaling, amino acids, and gut microbiota diversity, improving insulin resistance, dyslipidemia, and metabolic syndrome. Specifically, modulation of phosphatidylethanolamine (PE) metabolism and activation of PPARα and PPARγ receptors, associated with improved energy metabolism, mitochondrial function, and oxidative stress, showed protective effects on the heart. Furthermore, orange juice intake positively impacted gut microbiota diversity and led to an increase in beneficial bacterial populations, correlated with improved metabolic syndrome. These findings suggest that orange juice may act as a metabolic modulator, with potential therapeutic implications for cardiac remodeling associated with cardiovascular diseases.
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Keywords: orange juice, energy metabolism, gut microbiota, cardiac remodeling, cardiovascular diseases
Article notes
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Received 2024 Dec 10; Revised 2025 Feb 13; Accepted 2025 Feb 17; Collection date 2025 Mar.
1. Introduction
Cardiovascular disease (CVD) is a leading cause of mortality globally, responsible for a significant number of deaths and disabilities. In 2021, CVD accounted for 20.5 million deaths, comprising approximately one-third of all global deaths [1]. CVD can be prevented by addressing behavioral risk factors, such as diet. The process of cardiac remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload, which typically occurs in several CVDs, is associated with cellular and molecular alterations in cardiomyocytes and the interstitial matrix, which leads to anatomic and functional remodeling of the heart. The alterations include myocyte hypertrophy, interstitial fibrosis, increased oxidative stress, inflammation and apoptosis, and changed energy metabolism. Although initially adaptive, the sustained cardiac hypertrophic remodeling results in progressive myocyte dysfunction, heart failure, and ultimately death [2].
Despite treatment, CVDs have a high mortality and disability rates. Therefore, it is important to identify adjuvant factors that can modulate cardiac remodeling [3]. One of these is the inclusion of affordable foods with potential cardioprotective properties in the diet [4,5,6,7,8]. In accordance, the effects of orange juice and its compounds have been evaluated in clinical and experimental studies. Orange juice consumption can improve energy metabolism, antioxidant capacity, anti-inflammatory properties, insulin resistance, metabolic syndrome, and cardiac function, and it can reduce blood pressure and plasma lipides [6,7,9,10,11,12,13,14,15]. Moreover, orange juice positively modulated composition and metabolic activity of the intestinal microbiota [10,16].
In patients with a high cardiovascular risk and in cardiac injury models, such as doxorubicin-induced cardiotoxicity and myocardial infarction, orange juice consumption has been shown to improve endothelial function and left ventricular function, attenuate cardiac oxidative stress and inflammation, and modulate energy metabolism by providing more substrates for energy production [4,5,6,7,8].
The mechanisms by which orange juice leads to these changes are not yet fully understood. Orange juice contains a collection of bioactive compounds, antioxidants, and anti-inflammatory agents, including flavonoids (hesperidin and naringenin), carotenoids (xanthophylls, cryptoxanthins, carotenes), and vitamin C, in addition to other beneficial phytochemicals that have a significant protective effect against certain diseases [17].
Studies using a metabolomics approach have suggested some metabolites and metabolic pathways that may be involved in the beneficial effects of orange juice [6,16,18,19,20]. However, only a few studies evaluated the effects of orange juice consumption on metabolomic analysis in situations of high cardiovascular risk. Current opinion highlights that metabolites and metabolic pathways modulated by orange juice consumption can potentially attenuate cardiac remodeling. Nonetheless, further studies are needed to evaluate the metabolome in CVDs to confirm modulation of metabolic pathways by orange juice.
3. Metabolic Pathways Modulated by Orange Juice Intake and Potential Attenuation of Cardiac Remodeling
Studies on orange juice intake and metabolomic evaluation have shown that the altered metabolites and metabolic pathways are related to phospholipids, energy metabolism, endocannabinoid signaling, amino acids, and microbiota diversity and metabolism.
3.1. Phospholipids and Alterations in Energy Metabolism
The metabolomic studies presented above showed that orange juice intake modulates phospholipids and different metabolites related to energy metabolism. In the study by Fujimori et al. [20], orange juice intake induced the presence of PE and CPA. Both compounds are phospholipids. PE and CPA can modulate the expression and activity of peroxisome proliferator-activated receptors (PPARs) and their target genes [44,45]. Indeed, the activity of PPARs can be influenced by a variety of natural compounds, including polyunsaturated fatty acids, eicosanoids, and oxidized lipid components. PPARs detect fatty acid-derived signaling molecules, which suggests their function as general lipid or nutrient sensors [46,47] (Figure 1).
In the study by Tian et al. [44], Eicosapentaenoic acid-enriched phosphatidylethanolamine (EPA-PE) was shown to bind to PPARα/PPARγ and exert agonistic activity regarding the transcription of PPARα and PPARγ. EPA-PE treatment induced Pparα mRNA expression and its target genes, which encode enzymes of fatty acid β-oxidation, including Carnitine Palmitoyltransferase I (CPT1) in hepatocytes. EPA-PE significantly increased PPARα protein levels in the liver of healthy mice and increased PPARα and CPT1 protein levels in the liver of rodents with insulin resistance, which alleviated hepatic steatosis and lipid accumulation. These results indicate that EPA-PE activates hepatic fatty acid β-oxidation. In models with doxorubicin-induced cardiotoxicity, orange juice intake also increased CPT-1 expression in the liver (Figure 1).
Consistent with these results, orange juice intake in healthy volunteers decreased medium- and long-chain acylcarnitines and increased short-chain acylcarnitine blood levels, which affects both mitochondrial and peroxisomal fatty acid β-oxidation [19]. Acylcarnitines are formed by the binding of an acyl group (derived from fatty acids or related compounds) to carnitine via the carnitine acyltransferase I on the outer mitochondrial membrane. After CPT1-induced production of acylcarnitines, the inner mitochondrial membrane transporter carnitine-acylcarnitine translocase transports acylcarnitines into the mitochondrial matrix. Finally, the enzyme CPT2 reconverts acylcarnitines back into free carnitine and acyl-CoAs, which can then be oxidized [23].
β-oxidation is the primary process by which fatty acids are oxidized through the sequential removal of two-carbon units from the acyl chain to generate acyl coenzyme A (acyl-CoA). Long-chain acylcarnitines (C14 to C20) are essential for the transport and β-oxidation of fatty acids in mitochondria and peroxisomes [23]. Therefore, an increase in long-chain acylcarnitines in plasma or tissue generally occurs when fatty acid entry or metabolism within organelles is abnormal, potentially leading to cellular toxicity, oxidative stress, and reduced energy production [48]. A decrease in long-chain acylcarnitines indicates that fatty acids are physiologically entering the mitochondria for oxidation.
In rodents with doxorubicin-induced cardiotoxicity, orange juice intake improved the activity of 3-hydroxyacyl-CoA dehydrogenase, which is a key enzyme in fatty acid β-oxidation [7]. This enzyme is regulated by the mitochondrial concentration of acyl-CoA, which increases by both the entry of fatty acids into the mitochondria, and the availability of nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD). The availability of NAD+ and FAD depends on mitochondrial oxidative phosphorylation, ATP concentration, and oxygen levels [23]. Ribeiro et al. [7] showed that ATP synthase activity was also increased by orange juice intake. Thus, it is possible that orange juice improves fatty acid β-oxidation in the heart.
The improvement of liver β-oxidation of fatty acids can modulate serum lipid profile and reduce dyslipidemia, which has also been observed with orange juice intake [8,11]. Mitochondrial β-oxidation of fatty acids reduces hepatic and serum triglyceride (TG) levels by increasing the use of fatty acids as an energy source [44,49], decreases total cholesterol (TC) and low-density lipoproteins (LDL) by limiting hepatic cholesterol synthesis [44,50,51], and increases high-density lipoproteins (HDL) by removing cholesterol excess [52], thereby reducing the risk of cardiovascular disease (Figure 1).
The improvement of β-oxidation of fatty acids also plays a positive role in insulin resistance and metabolic syndrome. Altered β-oxidation increases reactive oxygen species production and mitochondrial dysfunction, as well as the accumulation of lipid intermediates, which can interfere with insulin signaling and activate pro-inflammatory pathways, leading to insulin resistance and metabolic syndrome [53]. Studies have shown that orange juice intake improves insulin resistance and prevents the development of metabolic syndrome [9,10,11], which are cardiovascular risk factors.
Homeostasis of β-oxidation of fatty acids in myocardium is crucial since the heart primarily uses fatty acids as an energy source. In conditions of cardiac injury, such as ischemia or myocardial hypertrophy, we observed reduced β-oxidation of fatty acids and increased glucose utilization as an energy source. Glucose oxidation requires less oxygen per ATP produced, making it theoretically more efficient under stress conditions [54]. However, restoring or improving β-oxidation may be beneficial, attenuating cardiac remodeling progression.
A decrease in β-oxidation during cardiac injury can lead to the accumulation of lipid intermediates, such as ceramides and diacylglycerols, which trigger lipotoxicity, oxidative stress, and apoptosis—frequent features in cardiac remodeling [54]. Restoring β-oxidation provides sustainable energy, especially in chronic injury states where energy demand may be high. However, the balance between metabolic pathways needs to be carefully adjusted to avoid disadvantages associated with increased oxygen consumption. An improvement in β-oxidation should be considered in specific contexts and accompanied by appropriate clinical support.
EPA-PE also modulates the expression of PPARγ [44,55]. PPARγ governs the expression of genes involved in lipid and glucose metabolism, including lipogenesis, fatty acid transport, glycolysis, and gluconeogenesis, which play a critical role in glycemic control [47,56]. PPARγ is the primary regulatory factor controlling the insulin signaling pathway and overall insulin sensitivity [56]. Treatment with EPA-PE promoted the expression of PPARγ in adipose tissue. Additionally, EPA-PE reduced adipocyte size, lipid droplets, insulin levels, and fasting blood glucose levels in rodents with insulin resistance. Consistent with these results, serum TG and TC levels were significantly reduced by EPA-PE administration [44]. Other studies have shown that PPARγ activation regulates CPT1, decreases circulating blood lipids, and inhibits liver steatosis [57,58]. Thus, PPARγ can regulate adipose tissue remodeling and attenuate insulin resistance and dyslipidemia (Figure 1).
PPARα and PPARγ also modulate inflammation. They are crucial for activation of immune system cells and release of anti-inflammatory cytokines and chemokines [47]. Additionally, they suppress the expression of inflammatory genes [46,47,56]. Cabral et al. [8] showed that orange juice intake increased myocardial PPARγ expression in a doxorubicin-induced cardiotoxicity model. Thus, PPARγ activation may be involved in orange juice-induced improvement in insulin resistance and dyslipidemia while reducing inflammation and preventing metabolic syndrome (Figure 1).
PPARγ also modulates mitochondrial function and structure. Mitochondria are highly abundant in cardiomyocytes, reflecting the heart’s highly oxidative nature and its dependence on these organelles to generate ATP from fatty acid and glucose oxidation, essential for muscle contraction. Thus, mitochondria play a crucial role in regulating cardiac function in both health and disease. PPARγ increases the expression of components of the respiratory chain complex and mitochondrial biogenesis-related genes [59]. Cabral et al. [8] observed that orange juice decreased serum aspartate aminotransferase (AST) concentration in doxorubicin-treated animals (Figure 1). Since mitochondria contain a large amount of AST, the decrease in AST may be a marker of decreased mitochondrial injury [15,60,61].
In summary, the increase in PE induced by orange juice intake may be associated with the activation of PPARα and PPARγ, which regulate energy metabolism, mitochondrial function, oxidative stress, and inflammatory activation. Myocardial modulation of energy metabolism, mitochondrial function, oxidative stress, and inflammation is related to cardiac remodeling, which can lead to cardiac dysfunction (Figure 1).
PE is the second most abundant phospholipid, representing approximately 37% of total phospholipids, in cardiomyocytes [62]. It participates in the respiratory complex IV [22] and in stabilization of the sarcolemmal membranes during ischemia [63]. PE deficiency impairs oxidative phosphorylation and mitochondrial ultrastructure and was associated with NLRP3 inflammasome activation and cardiac remodeling [64,65].
Other phospholipids and fatty acid-derived metabolites found in the plasma of animals that consumed orange juice, such as CPA, 9-HODE, 13-HODE, 12,13-DiHOME, 9,10-DiHOME, and 12-HETE, are also possible PPAR ligands and may modulate the aforementioned processes [46,66,67,68,69] (Figure 1). Studies have shown that these metabolites exhibit antioxidant and anti-inflammatory effects and play a role in glucose and fatty acid metabolism [18,43,70,71,72].
Another metabolite altered by orange juice intake is glycerophosphocholine (GPC), which was decreased in hypertensive subjects [11]. This compound is a precursor of several important metabolites. GPC cleavage forms choline and glycerol-3-phosphate. Choline is further metabolized to phosphatidylcholine, a key player lipid in membrane-mediated cell signaling [73]. Choline is used in acetylcholine synthesis. Kawamura et al. [74] showed that oral ingestion of GPC acutely increased plasma free choline levels by 50%, leading to a concomitant increase in growth hormone concentration and hepatic fat oxidation in young adult male subjects. Glycerol-3-phosphate is a precursor for lipids with central roles in signaling, such as lysophosphatidic acid, phosphatidic acid, CPA, and diacylglycerol. The latter is a precursor for various phospholipids synthesis, including PE [73] (Figure 1).
Other GPC metabolites include lysophosphocholines and platelet-activating factors, lipids that modulate systemic oxidative stress and inflammation [75,76]. GPC degradation under stress and tissue inflammation releases metabolites with antioxidant and anti-inflammatory action, leading to a decrease in its concentration [6,77]. GPC administration preserved mitochondrial complex I function, suppressed activity of intracellular superoxide-generating enzymes, and reduced biochemical signs of oxidative stress and inflammatory activation in a liver ischemia–reperfusion model [78].
3.2. Endocannabinoid Signaling
Endocannabinoids are lipid mediators that act as messengers in intercellular communication. They occur naturally in the body and mimic the activity of Δ9-tetrahydrocannabinol, the primary psychoactive ingredient of cannabis. The endocannabinoid system (ECS) is a widespread cell signaling system composed of a large group of these lipid mediators, their primary receptors, and the associated enzymes responsible for their synthesis and degradation. The most well-studied endogenous ligands are the endocannabinoids N-arachidonoylethanolamine/anandamide and 2-arachidonoylglycerol, and the two main metabotropic receptors that respond to them are named cannabinoid receptor type-1 (CB1) and type-2 (CB2). Together, these components of the ECS work harmoniously to maintain homeostasis [79,80].
Endocannabinoids influence cardiovascular pathology primarily through CB1 and CB2 receptors. CB1 activation exacerbates atherosclerosis by promoting inflammation, lipid accumulation, and inducing bradycardia by inhibiting norepinephrine. Conversely, CB2 activation exerts protective effects, reducing inflammatory cytokines, downregulating monocyte adhesion factors, and inhibiting NLRP3 inflammasome activation. Additionally, CB2 agonism enhances endothelial function and prevents oxidative stress. It also favors reverse cholesterol transport and stabilizes atherosclerotic plaques by reducing MMP-9 levels and collagen degradation, ultimately mitigating atherogenesis [79,81].
Some compounds modulated by orange juice intake participate in endocannabinoid signaling. PE, in addition to the effects previously mentioned, participates in endocannabinoid signaling [82]. The compound N-docosahexaenoyl phenylalanine, which is an N-acyl amide, is similar to endocannabinoids in structure and metabolism and can regulate cannabinoid physiology or operate in parallel via overlapping signaling pathways [25]. N-acyl amides are considered “orphan lipids”, since no specific receptor has been discovered for them. However, there is evidence of their ability to bind to different endocannabinoid receptors, exerting a cannabimimetic effect [83]. Activation of these receptors plays a central role in the regulation of cardiac function in both health and disease [84,85] (Figure 1).
An important relationship has been suggested between the endocannabinoid system and PPARs, especially PPARα and PPARγ. PPARs are activated by a large number of endogenous and exogenous lipid molecules, and also by endocannabinoids and endocannabinoid-like compounds. Furthermore, PPARs are indirectly modulated by receptors and enzymes that regulate the activity and metabolism of endocannabinoids, and vice versa, the expression of these receptors and enzymes may be regulated by PPARs. There is fascinating evidence that perturbation of the symbiotic gut microbial community may greatly impact on host health, either directly or indirectly, by regulating PPAR activity through endogenous, endocannabinoid-like modulators [80] (Figure 1).
3.4. Amino Acids
Valine, leucine, and isoleucine (branched-chain amino acids—BCAAs) were found to be decreased after orange juice intake in subjects with cardiovascular risk and pre- or stage 1 hypertension [6]. Numerous gut bacteria possess metabolic pathways allowing for BCAA biosynthesis. Additionally, colonic bacteria can utilize the amino acids leucine, valine, and isoleucine to generate a complex mixture of metabolic end products, including SCFAs and branched-chain fatty acids (isovalerate, isobutyrate, and isovalerate) [10,91]. Thus, the composition and metabolic performance of the intestinal microbiota contribute to BCAA availability to the host and are, at least partially, responsible for their effect on host metabolism [91] (Figure 1).
At the cellular level, BCAAs serve as direct building blocks or nitrogen donors for proteosynthesis, as an energy/anaplerotic substrate while being degraded down to the final glucogenic (propionyl-CoA and succinyl-CoA) and ketogenic (acetyl-CoA and acetoacetate) products and oxidized, or as nutritional signals via rapamycin complex (mTORC) activation [91]. BCAAs, particularly leucine, activates the mammalian target of mTORC1, the key intersection of amino acid and insulin signaling pathways, but chronic activation can inhibit the insulin receptor pathway and reduce insulin sensitivity, promoting the development of insulin resistance, obesity, and type 2 diabetes [92,93].
Additionally, mTORC1 stimulates lipogenesis, increasing fat storage in the liver and adipose tissue, which worsens dyslipidemia and hepatic steatosis [94]. mTORC1 also influences mitochondrial biogenesis and energy metabolism, but its chronic activation can lead to excessive production of reactive oxygen species and activate inflammatory factors, promoting chronic states of oxidative stress and inflammation, which are common in cardiovascular diseases [94,95]. In fact, high concentrations of BCAAs are associated with several cardiometabolic risk factors, such as insulin resistance [96], obesity, atherogenic dyslipidemia, elevated blood pressure [97,98], and an increased incidence of CVD events [99]. Thus, the decrease in these amino acids after orange juice intake may be beneficial to the heart and important in the process of cardiac remodeling.
4. Conclusions
Orange juice intake has shown promising effects on modulating key metabolic pathways, including phospholipid metabolism, energy regulation, endocannabinoid signaling, amino acid levels, and gut microbiota composition. The changes contribute to improved insulin sensitivity, lipid metabolism, and reduced inflammation, all of which play crucial roles in preventing or alleviating cardiac remodeling. The findings suggest that orange juice can act as a metabolic modulator, with potential therapeutic implications for CVDs. Nonetheless, further studies are needed to evaluate the metabolome in CVDs to confirm modulation of metabolic pathways by orange juice.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflicts of interest.
Funding Statement
This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) process number: 307.703/2022-3.
Footnotes
Footnote Group
References
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Associated Data
Data Availability Statement
Not applicable.