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Oleanolic Acid — Food Sources, Structure, Health Benefits, and Toxicity

Article author photo Arpi Gasparyan by Arpi Gasparyan | Last updated on Հուլիսի 19, 2024
Medically reviewed by Victoria Mazmanyan Article author photo Victoria Mazmanyan

Oleanolic Acid  Food Sources
 

Introduction

Oleanolic acid (OA) is a biologically active pentacyclic triterpenoid isolated from over 1600 plant species. Its main sources are the plants of the Oleaceae family, including olives (Olea europaea), from which the name oleanolic acid originates.

Its main function in plants is to prevent water loss and act as a first defense barrier against pathogens and herbivores.

Oleanolic acid may be found in its free form or as an aglycone, a precursor for triterpenoid saponins. It may also be found alone or in combination with ursolic acid, its isomer with similar properties (1).

Oleanolic acid and its derivatives are studied for their antioxidant, anti-inflammatory, anticancer, antidiabetic, antimicrobial, antiviral, hepatoprotective, renoprotective, cardioprotective, neuroprotective, antihypertensive, and lipid-lowering properties.

Structure

Oleanolic acid (C30H48O3) is a pentacyclic triterpenoid and a hydroxy monocarboxylic acid consisting of 5 rings (2, 3).

Oleanolic Acid structure

Oleanolic acid occurs either in its free form (as the free acid) or as an aglycone precursor for many triterpenoid saponins. Additionally, oleanolic acid can rearrange to its isomer form - ursolic acid or be oxidized to amyrin and taraxasterol (2).

Food Sources & Bioavailability of Oleanolic Acid

Aerial parts of plants are covered with a cuticle, a hydrophobic protective layer required for plant survival. According to current research, plant triterpenoids are concentrated in the cuticular waxes; thus, oleanolic acid levels are much higher in the fruit's skin and peel than in its pulp (4, 5).

Oleanolic acid can be found in a wide variety of dietary and medicinal herbs. Olives and their products (e.g., olive oil) are the main dietary sources of oleanolic acid. In the Mediterranean diet, which commonly includes olive products, the total daily intake of oleanolic acid is around 25mg (4).

The table below shows the main sources of oleanolic acid and their levels in each food per 100g serving, calculated for fresh or dry weights (4, 5, 6).

FoodOleanolic acid (mg/100g)
Olives, skin309.4-435.6 mg (fresh weight)
Olives, pulp2.7-2.9 mg (fresh weight)
Bilberries, whole fruit167.9-202.9 mg (dry weight)
Pears16.43-306.6 mg (fresh weight)
Persimmon, peel36.77 mg (dry weight)
Persimmon, flesh1.72 mg (dry weight)
Jujube18.2 mg (fresh weight)
Grapes, peel17.62 mg (dry weight)
Chinese hawthorn14.7 mg (fresh weight)
English lavender4.5 mg (dry weight)
Apples, skin2.8 mg (dry matter)
Apples, pomace1.6 mg (dry matter)
Pomegranate, peel2.7 ± 0.1 mg (dry weight)
Quince, skin0.25mg (dry weight)
Mandarin, peel0.1 mg (dry weight)
Lemon, peel0.03 mg (dry weight)

Dried fruits are consumed with their skin; thus, they are considered a better source of oleanolic acid. Analysis of various dried fruits and berries showed that the greatest oleanolic acid content was found in raisins, particularly green raisins (5).

The table below demonstrates the analyzed dried fruits and berries, the mean presence of skin in fruits, and oleanolic acid content (5).

Dried food with skinOleanolic acid (mg/100g)
Green raisins79mg
Sultana raisins66mg
Kyoho raisins38.5mg
Cranberries17.8mg
Blueberries13.9mg
Cherries1.72mg

Health Benefits of Oleanolic Acid

Oleanolic acid affects human health in a variety of ways; it is known for its antioxidant, anti-inflammatory, anticancer, antidiabetic, antimicrobial, antiviral, liver- and kidney-protective, cardioprotective, neuroprotective, antihypertensive, and lipid-lowering effects. 

In this section, we’ll discuss most of these effects in detail. 

Antioxidant & Anti-inflammatory Effects

Oleanolic acid is known for its free radical-scavenging properties by directly acting with reactive oxygen species and antioxidant activities by increasing Nrf2 in the cell nucleus and increasing the activity of antioxidant enzymes such as catalase, thioredoxin peroxidase, glutathione peroxidase, and superoxide dismutase and decreasing malonaldehyde (byproduct of lipid peroxidation) levels, and increasing the biosynthesis of glutathione (1, 7). 

Inflammation is one of the primary contributors to many diseases, such as insulin resistance, cancer, asthma, and gut and liver disorders. In human umbilical vein endothelial cells (HUVEC, isolated to study endothelial cells function in various conditions), oleanolic acid has been shown to inhibit the release of oligosaccharide (LPS) mediated HMGB1 protein, which is known to lead to an increase in

Additionally, oleanolic acid has been reported to down-regulate the release of two key biomarkers of inflammation - nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) (7).

Liver Health

Oleanolic acid is well-studied for its hepatoprotective (liver-protective properties) and is an over-the-counter medication in China taken during liver problems. 

According to studies, oleanolic acid reduces the risk of chemical-induced (such as ethanol, medications, carbon tetrachloride, mushrooms, and various other toxins) toxic liver disease, ischemia-reperfusion injury, immune-mediated liver damage, chronic liver diseases (such as non-alcoholic fatty liver disease or NAFLD or MASLD) causing fibrosis and cirrhosis and restores overall liver function and improves liver function tests and histology (7, 8, 9). 

Oleanolic acid increases the accumulation of Nrf2, a key transcriptional regulator of antioxidant enzymes, thus inducing Nrf2-dependent genes involved in liver protection. However, animal studies have shown that oleanolic acid protects the liver also through Nrf2-independent mechanisms, such as modulating the farnesoid X receptor, which regulates bile acid synthesis and its excretion from the liver (1, 8).

Obesity

Oleanolic acid may inhibit the expression of adipokines (cell-signaling molecules produced by fat tissue) and down-regulate the expression of the regulatory proteins for fat synthesis—PPARγ and C/EBPα. Additionally, oleanolic acid has been shown to reduce fat synthesis and accelerate its utilization by altering liver cell factors, such as PPARα, CPT1A, SREBP-1, ACC, and UCP1. 

Oleanolic acid could reduce resistin synthesis, a fat cell-specific secreted factor linked to fat cell (adipocyte) differentiation.

Animal studies have shown that oleanolic acid may also improve blood lipid levels by decreasing LDL or “bad” cholesterol, total cholesterol, and triglyceride levels and increasing HDL or “good” cholesterol levels (10).

Diabetes

Oleanolic acid has been used as a therapeutic agent in diabetic animals to improve insulin resistance, activate insulin response, inhibit glucose synthesis from non-carbohydrates, and promote glucose utilization. Oleanolic acid may also protect pancreatic β-cells and decrease the risk of diabetes complications (7, 11).

Animal studies have shown that oleanolic acid may reduce the expression of pro-inflammatory and inflammatory molecules, improve mitochondrial function, and activate M3 muscarinic receptors and G protein-coupled bile acid receptors. In animal models, treatment with oleanolic acid in insulin-resistant cells may improve insulin sensitivity by inhibiting IRS-1 (an essential factor in insulin-signaling pathways) and GLUT-4 (a major glucose transporter in muscles, fat tissues, and liver) proteins (7, 10, 11, 12). 

Oleanolic acid has also been demonstrated to inhibit glucose synthesis from non-carbs and attenuate insulin resistance in the liver (7).

Cardiovascular Health & High Blood Pressure

Oleanolic acid shows cardioprotective effects mainly by decreasing inflammation, attenuating oxidative stress, and reducing ROS (reactive oxygen species) levels, which are known to cause lipid peroxidation, dysfunction, and damage to heart muscle cells (10, 13, 14).

Furthermore, studies have reported that oleanolic acid may decrease the effects of ischemia-reperfusion injury under hyperglycemic conditions (14).

Oleanolic acid could also inhibit heart muscle cell injury and decrease cardiac fibrosis by reducing ET-1 and NF-κB activation, inhibiting PTP1B (protein tyrosine phosphatase 1B) effects, and inhibiting vascular remodeling or changes by decreasing the levels of Akt and mTOR (10, 15).

Additionally, oleanolic acid may suppress platelet aggregation, thus decreasing the risk of cardiovascular thrombosis (10).

Studies have shown that oleanolic acid may reduce ischemic stroke damage by increasing antioxidant α-tocopherol (α-TOC) and glutathionelevels and decreasing the leakage of lactate dehydrogenase, a damage marker.

Oleanolic acid also affects atherosclerosis. In addition to reducing oxidative stress, it reduces endothelial dysfunction and lipid deposition in human umbilical vein endothelial cells (HUVEC) by reducing the levels of the LOX-1 receptor and reactive oxygen species (ROS) and enhancing the level of Nrf2/HO-1 (10).

Animal studies have found that oleanolic acid may protect against diabetic cardiomyopathy by activating Nrf2/HO-1 and insulin-modulating glycogen synthase/glycogen phosphorylase signaling pathways (16).

Limited evidence notes the anti-hypertensive (blood pressure lowering) effects of oleanolic acid and its derivatives. For example, steroid-induced hypertension in rats showed that oleanolic acid significantly prevented an increase in systolic blood pressure, possibly due to increased diuresis and kidney protection (7).

Cancer

Many in vitro and in vivo studies have reported the anti-cancer and anti-tumor potential of oleanolic acid and its derivatives, decreasing the risk of breast, lung, cervix, bladder, liver, colon, prostate, pancreatic, stomach, gallbladder cancers, osteosarcoma, melanoma leukemia and other hematological malignancies, and malignant glioma (4, 7, 17). 

Some of the oleanolic acid’s antitumor activity is suggested to be through the up-regulation of the tumor protein (p53) and caspases, COX-2- and TRAIL-mediated activation of apoptosis (programmed cell death), cell cycle arrest, inhibition of signaling pathways, down-regulation of proangiogenic vascular endothelial growth factor A (VEGFA) and basic fibroblast growth factor (FGF), and the induction of miR-122 overexpression, a tumor-suppressor protein (4, 7).

Interestingly, oleanolic acid has the potential to be employed in clinical practice as an adjuvant anticancer treatment option: it has direct anticancer activities, can act synergistically with chemotherapeutic medications, increases medication concentrations within the cells, and increases radiosensitivity and the efficacy of radiotherapy (4, 17).

Gastrointestinal Health

Oleanolic acid and its derivatives were assessed for their gastroprotective (stomach-protective) and ulcer-healing properties in rats. A single oral dose administration of oleanolic acid was evaluated in pylorus ligature, aspirin- and ethanol-induced stomach ulcers. In the ethanol-induced gastric lesions, oleanolic acid at 100mg/kg and 200mg/kg doses showed the activity of omeprazole at 20mg/kg. The greatest gastroprotective activity showed the semisynthetic acetylated and methoxylated derivatives of oleanolic acid (18).

According to a study, oleanolic acid affects the composition of gut microbiota and leads to a reduction in the Actinobacteria abundance. Moreover, oleanolic acid promoted the growth of several potentially beneficial taxa while reducing the propagation of pathogenic bacteria, such as HelicobacterClostridium, and Streptococcus. The study showed that oleanolic acid also improved the intestinal immune system by regulating several pathways required to maintain the normal proliferation and regeneration of the epithelial cells (19).

Skin Health

Several studies note the potential beneficial effects of oral and topical oleanolic acid on skin health. For example, a study evaluated the inhibitory effect of oleanolic acid on atopic dermatitis-like lesions. The results noted that oleanolic acid has anti-atopic effects, relieves the symptoms, and regulates the inflammatory mediators. It suppressed the expression of Th2-type cytokines and chemokines derived from the mice skin keratinocytes by blocking the activation of NF-κB, Akt, and STAT-1 pathways (20).

Particulate matter (PM10) components bind to aryl hydrocarbon receptors and promote CYP1A1 (cytochrome P450 1A1) expression in keratinocytes. The activation of aryl hydrocarbon receptors in skin cells is linked to cell differentiation and inflammation, causing skin lesions. 

According to study results, oleanolic acid inhibits PM10-induced CYP1A1 and decreases proinflammatory cytokines TNF-α, IL-6, and MMP-1 levels. Additionally, oleanolic acid may reduce autophagosome accumulation. Thus, oleanolic acid may protect the skin from PM10 exposure and reduce skin inflammation and wrinkles (21).

Other Health Benefits

  • Neuroprotective effects: Oleanolic acid beneficially affected rodent models with focal brain hypoxia and damage, Parkinson’s disease, Alzheimer's disease, neurodegeneration, cognitive dysfunction, and cerebral ischemia-reperfusion injury.
  • Renoprotective effects: Oleanolic acid may attenuate kidney fibrosis, decrease the risk of diabetic nephropathy and kidney ischemia-reperfusion injury, and prevent cisplatin-induced nephrotoxicity (6).
  • Lung-protective effects: Oleanolic acid may decrease macrophage infiltration in lung tissue, regulate the inflammatory response, and decrease lung injury and oxidative stress risk; thus, it may be useful for treating acute lung injury and ARDS (acute respiratory distress syndrome) (22).
  • Anti-osteoporotic effects: In rodents, oleanolic acid increased bone mineral density, improved calcium balance, modulated vitamin D metabolism, and osteoblast and osteoclast activities, inhibited osteoclastogenesis, and reduced cartilage damage in osteoarthritis (6, 23, 24).
  • Anti-allergic effects: may show antiallergic and anti-inflammatory effects during allergic conjunctivitis and allergic asthma.
  • Anti-protozoal, anti-parasitic, anti-malaria, anti-viral activities (6, 25).

Side Effects & Toxicity

Oleanolic acid is generally safe and non-toxic. However, high doses may cause gut discomfort, nausea, diarrhea, liver injury, low blood pressure, and decreased blood glucose levels. 

Due to its blood pressure-lowering effect, oleanolic acid could enhance the effect of antihypertensive medications, such as ACE inhibitors and calcium channel blockers (6).

Repeated oral administration of oleanolic acid has been reported to cause cholestatic liver injury in mice (6).

Summary

Oleanolic acid (OA) is a biologically active pentacyclic triterpenoid isolated from over 1600 plant species.

Oleanolic acid is found in a wide variety of dietary and medicinal herbs, such as olives, olive oil, dried fruits such as raisins, apples, jujube, pears, blueberries, and more. Oleanolic acid levels are much higher in the fruit's skin and peel than in its pulp.

Oleanolic acid and its derivatives are studied for their antioxidant, anti-inflammatory, antimicrobial, antiviral, hepatoprotective, renoprotective, cardioprotective, neuroprotective, antihypertensive, and lipid-lowering properties.

For example, oleanolic acid possesses hepatoprotective effects and reduces the risk of toxic liver disease, fibrosis, and cirrhosis caused by chronic liver diseases. It may also improve liver function tests. Oleanolic acid may improve insulin resistance and activate insulin response in diabetic animal models.

Animal studies have shown that oleanolic acid may improve blood lipid levels by decreasing LDL or “bad” cholesterol, total cholesterol, and triglyceride levels and increasing HDL or “good” cholesterol levels.

Many in vitro and in vivo studies have reported the anti-cancer and anti-tumor potential of oleanolic acid and its derivatives, decreasing the risk of breast, lung, cervix, bladder, liver, colon, prostate, pancreatic, stomach, gallbladder cancers, osteosarcoma, melanoma leukemia and other hematological malignancies, and malignant glioma.

References

  1. https://www.sciencedirect.com/science/article/abs/pii/S0031942212000027
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Oleanolic-Acid 
  3. https://www.sciencedirect.com/science/article/abs/pii/S0031942222003132 
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372655/ 
  5. https://www.jstage.jst.go.jp/article/fstr/19/1/19_113/_pdf/-char/en 
  6. https://www.wjgnet.com/2307-8960/full/v8/i10/1767.htm
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150249/
  8. https://link.springer.com/article/10.1007/s00210-024-02959 
  9. https://onlinelibrary.wiley.com/doi/10.1111/liv.13940 
  10. https://www.mdpi.com/1420-3049/29/4/758 
  11. https://japsonline.com/admin/php/uploads/3412_pdf.pdf 
  12. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.697483/full 
  13. https://pubmed.ncbi.nlm.nih.gov/38059443/ 
  14. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047322 
  15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359497/ 
  16. https://pubmed.ncbi.nlm.nih.gov/28673009/ 
  17. https://aacrjournals.org/mct/article/18/1/62/92469
  18. https://www.tandfonline.com/doi/full/10.1080/14756360701633187 
  19. https://pubmed.ncbi.nlm.nih.gov/34227118/ 
  20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584529/ 
  21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921861/ 
  22. https://tgkdc.dergisi.org/text.php?lang=en&id=3318 
  23. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01435/full 
  24. https://pubs.rsc.org/en/content/articlelanding/2023/fo/d3fo01902k 
  25. https://wjarr.com/sites/default/files/WJARR-2022-1469.pdf 
Article author photo Arpi Gasparyan
Մասնագիտությունը՝ General Medicine at YSMU
Թարմացվել է՝ Հուլիսի 19, 2024
Medically reviewed by Victoria Mazmanyan
Ցանկացած դիետա սկսելուց առաջ անհապաղ խորհդակցեք Ձեր բժիշկի հետ: