As a kid in a traditional Italian family, I was raised on olive oil. And I now consume generous quantities of extra-virgin olive oil (EVOO) just about every day. For one thing, I love its taste. I am so hooked on EVOO that I shudder when a friend serves me a wonderful meal with a great salad, but sets out bottles of commercial salad dressing instead of dressing it with EVOO. I am particularly bothered by bottled dressings with big labels saying MADE WITH REAL ITALIAN OLIVE OIL and showing ladies in colorful dresses carrying baskets of olives while the very fine print on the back of the bottle lists the amount of olive oil as only 15%, and it’s not even extra-virgin oil. I have always known that olive oil is good for me. But for most of my life I could not respond intelligently if somebody asked me “why?” I thought here, as a break from heavy stuff in molecular biology, I would addresses that question and review some of the research on olive oil. I particularly focus on EVOO.
Olive oil and the Mediterranean Diet
There is a two-part generic argument often heard for olive oil. The first part is that a Mediterranean Diet contributes significantly to health and longevity. The second part is that olive oil is an essential component of a Mediterranean diet and therefore must be one of the key “good for you” components. There seems to be good research evidence for the first-part argument as outlined in my August 2009 blog post Recent research on the Mediterranean diet. The second part of the argument by itself does not meet the “beyond a reasonable doubt” test needed to convict somebody in a court trial. What if something else in the Mediterranean Diet is providing most of the benefits, like the tomatoes? The rest of this blog entry will establish the value of EVOO beyond a reasonable doubt.
Olive oil and heart disease risk
A good place to start is with a carefully controlled and fairly-large international 2006 study that directly relates phenolic content of olive oils to familiar lipid levels like HDL and triglycerides: The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial “BACKGROUND: Virgin olive oils are richer in phenolic content than refined olive oil. — OBJECTIVE: To evaluate whether the phenolic content of olive oil further benefits plasma lipid levels and lipid oxidative damage compared with monounsaturated acid content. DESIGN: Randomized, crossover, controlled trial. SETTING: 6 research centers from 5 European countries. PARTICIPANTS: 200 healthy male volunteers. MEASUREMENTS: Glucose levels, plasma lipid levels, oxidative damage to lipid levels, and endogenous and exogenous antioxidants at baseline and before and after each intervention. INTERVENTION: In a crossover study, participants were randomly assigned to 3 sequences of daily administration of 25 mL of 3 olive oils. Olive oils had low (2.7 mg/kg of olive oil), medium (164 mg/kg), or high (366 mg/kg) phenolic content but were otherwise similar. Intervention periods were 3 weeks preceded by 2-week washout periods. RESULTS: A linear increase in high-density lipoprotein (HDL) cholesterol levels was observed for low-, medium-, and high-polyphenol olive oil: mean change, 0.025 mmol/L (95% CI, 0.003 to 0.05 mmol/L), 0.032 mmol/L (CI, 0.005 to 0.05 mmol/L), and 0.045 mmol/L (CI, 0.02 to 0.06 mmol/L), respectively. Total cholesterol-HDL cholesterol ratio decreased linearly with the phenolic content of the olive oil. Triglyceride levels decreased by an average of 0.05 mmol/L for all olive oils. Oxidative stress markers decreased linearly with increasing phenolic content. Mean changes for oxidized low-density lipoprotein levels were 1.21 U/L (CI, -0.8 to 3.6 U/L), -1.48 U/L (-3.6 to 0.6 U/L), and -3.21 U/L (-5.1 to -0.8 U/L) for the low-, medium-, and high-polyphenol olive oil, respectively. LIMITATIONS: The olive oil may have interacted with other dietary components, participants’ dietary intake was self-reported, and the intervention periods were short. CONCLUSIONS: Olive oil is more than a monounsaturated fat. Its phenolic content can also provide benefits for plasma lipid levels and oxidative damage. International Standard Randomised Controlled Trial number: ISRCTN09220811”. So, in only three weeks cholesterol and triglyceride scores improved in the olive oil takers and the scores increased most markedly in those taking the olive oil with the most phenolic content, i.e., the extra-virgin olive oil. And the result is not just because the olive oil is a “good fat.”
The 2007 publication Changes in the phenolic content of low density lipoprotein after olive oil consumption in men. A randomized crossover controlled trial reports on a trial cohort of 30 men, and my impression is that this cohort may have been part of the larger cohort of the first study mentioned above. The writeup has a somewhat different focus, however, focusing on the antioxidant properties of virgin olive oil. “Olive oil decreases the risk of CVD (cardiovascular disease). This effect may be due to the fatty acid profile of the oil, but it may also be due to its antioxidant content which differs depending on the type of olive oil. In this study, the concentrations of oleic acid and antioxidants (phenolic compounds and vitamin E) in plasma and LDL were compared after consumption of three similar olive oils, but with differences in their phenolic content. Thirty healthy volunteers participated in a placebo-controlled, double-blind, crossover, randomized supplementation trial. Virgin, common, and refined olive oils were administered during three periods of 3 weeks separated by a 2-week washout period. Participants were requested to ingest a daily dose of 25 ml raw olive oil, distributed over the three meals of the day, during intervention periods. All three olive oils caused an increase in plasma and LDL oleic acid (P < 0.05) content. Olive oils rich in phenolic compounds led to an increase in phenolic compounds in LDL (P < 0.005). The concentration of phenolic compounds in LDL was directly correlated with the phenolic concentration in the olive oils. The increase in the phenolic content of LDL could account for the increase of the resistance of LDL to oxidation, and the decrease of the in vivo oxidized LDL, observed in the frame of this trial. Our results support the hypothesis that a daily intake of virgin olive oil promotes protective LDL changes ahead of its oxidation.”
Coming back to the Mediterranean Diet, the 2005 review article The phenolic compounds of olive oil: structure, biological activity and beneficial effects on human health relates the phenolic content of olive oil to the diet’s salutary benefits. “The Mediterranean diet is rich in vegetables, cereals, fruit, fish, milk, wine and olive oil and has salutary biological functions. Epidemiological studies have shown a lower incidence of atherosclerosis, cardiovascular diseases and certain kinds of cancer in the Mediterranean area. Olive oil is the main source of fat, and the Mediterranean diet’s healthy effects can in particular be attributed not only to the high relationship between unsaturated and saturated fatty acids in olive oil but also to the antioxidant property of its phenolic compounds. The main phenolic compounds, hydroxytyrosol and oleuropein, which give extra-virgin olive oil its bitter, pungent taste, have powerful antioxidant activity both in vivo and in vitro.”
Again, the messages appear to be that it is the phenolic ingredients in olive oil that are important, that their antioxidant activities are important and that the most healthful olive oil is the one with the most concentration of the polyphenols, namely first-press extra-virgin olive oil (EVOO).
Further, though olive oil seems to be a simple substance the biochemical activities of olive oil polyphenols is not simple, as discussed in the 2008 paper Nutritional benefit of olive oil: the biological effects of hydroxytyrosol and its arylating quinone adducts. “A unique characteristic of olive oil is its enrichment in oleuropein, a member of the secoiridoid family, which hydrolyzes to the catechol hydroxytyrosol and functions as a hydrophilic phenolic antioxidant that is oxidized to its catechol quinone during redox cycling. Little effort has been spent on exploring the biological properties of the catechol hydroxytyrosol quinone, a strong arylating electrophile that forms Michael adducts with thiol nucleophiles in glutathione and proteins. This study compares the chemical and biological characteristics of hydroxytyrosol with those of the tocopherol family in which Michael adducts of arylating desmethyltocopherol quinones have been identified and correlated with biologic properties including cytotoxicity and induction of endoplasmic reticulum stress. It is noted that hydroxytyrosol and desmethyltocopherols share many similarities, suggesting that Michael adduct formation by an arylating quinone electrophile may contribute to the biological properties of both families, including the unique nutritional benefit of olive oil.”
The 2007 document The olive oil antioxidant hydroxytyrosol efficiently protects against the oxidative stress-induced impairment of the NObullet response of isolated rat aorta reports “Moreover, hydroxytyrosol was found to be a potent OH(*) scavenger, which can be attributed to its catechol moiety. Because of its amphiphilic characteristics (octanol-water partitioning coefficient = 1.1), hydroxytyrosol will readily cross membranes and provide protection in the cytosol and membranes, including the water-lipid interface. The present study provides a molecular basis for the contribution of hydroxytyrosol to the benefits of the Mediterranean diet.”
A number of other published studies confirm these messages like the 2004 publication Effects of differing phenolic content in dietary olive oils on lipids and LDL oxidation–a randomized controlled trial and the 2010 publication Biological activities of phenolic compounds present in virgin olive oil, the 2005 report International conference on the healthy effect of virgin olive oil, the 2009 report Chemistry and health of olive oil phenolics, and a number of others.
Olive oil and cancers
A number of studies relate the effects of the active polyphenols in olive oil to killing (induction of apoptosis in) cancer cells. For example the 2009 study Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells reports “Olive oil intake has been shown to induce significant levels of apoptosis in various cancer cells. These anti-cancer properties are thought to be mediated by phenolic compounds present in olive. These beneficial health effects of olive have been attributed, at least in part, to the presence of oleuropein and hydroxytyrosol. In this study, oleuropein and hydroxytyrosol, major phenolic compound of olive oil, was studied for its effects on growth in MCF-7 human breast cancer cells using assays for proliferation (MTT assay), cell viability (Guava ViaCount assay), cell apoptosis, cellcycle (flow cytometry). Oleuropein or hydroxytyrosol decreased cell viability, inhibited cell proliferation, and induced cell apoptosis in MCF-7 cells. Result of MTT assay showed that 200 mug/mL of oleuropein or 50 mug/mL of hydroxytyrosol remarkably reduced cell viability of MCF-7 cells. Oleuropein or hydroxytyrosol decrease of the number of MCF-7 cells by inhibiting the rate of cell proliferation and inducing cell apoptosis. Also hydroxytyrosol and oleuropein exhibited statistically significant block of G(1) to S phase transition manifested by the increase of cell number in G(0)/G(1) phase.”
The 2009 study Extra-virgin olive oil polyphenols inhibit HER2 (erbB-2)-induced malignant transformation in human breast epithelial cells: relationship between the chemical structures of extra-virgin olive oil secoiridoids and lignans and their inhibitory activities on the tyrosine kinase activity of HER2 reports “Extra-virgin olive oil (EVOO – the juice of the olive obtained solely by pressing and consumed without any further refining process) is unique among other vegetable oils because of the high level of naturally occurring phenolic compounds. We explored the ability of EVOO polyphenols to modulate HER2 tyrosine kinase receptor-induced in vitro transformed phenotype in human breast epithelial cells. — EVOO polyphenols induced strong tumoricidal effects by selectively triggering high levels of apoptotic cell death in HER2-positive MCF10A/HER2 cells but not in MCF10A/pBABE matched control cells. EVOO lignans and secoiridoids prevented HER2-induced in vitro transformed phenotype as they inhibited colony formation of MCF10A/HER2 cells in soft-agar. Our current findings not only molecularly support recent epidemiological evidence revealing that EVOO-related anti-breast cancer effects primarily affect the occurrence of breast tumors over-expressing the type I receptor tyrosine kinase HER2 but further suggest that the stereochemistry of EVOO-derived lignans and secoiridoids might provide an excellent and safe platform for the design of new HER2 targeted anti-breast cancer drugs.”
The 2008 paper Analyzing effects of extra-virgin olive oil polyphenols on breast cancer-associated fatty acid synthase protein expression using reverse-phase protein microarrays is another of several more relating EVOO to breast cancer. “These findings reveal for the first time that phenolic fractions, directly extracted from EVOO, may induce anti-cancer effects by suppressing the expression of the lipogenic enzyme FASN in HER2-overexpressing breast carcinoma cells, thus offering a previously unrecognized mechanism for EVOO-related cancer preventive effects.”
The 2008 document tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO) relates to the same theme. “Among the fractions mainly containing the single phenols hydroxytyrosol and tyrosol, the polyphenol acid elenolic acid, the lignans (+)-pinoresinol and 1-(+)-acetoxypinoresinol, and the secoiridoids deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (i.e. secoiridoids and lignans) were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation occurred regardless the molecular mechanism contributing to HER2 overexpression (i.e. naturally by gene amplification and ectopically driven by a viral promoter). Pre-treatment with the proteasome inhibitor MG132 prevented EVOO polyphenols-induced HER2 depletion. CONCLUSION: The ability of EVOO-derived polyphenols to inhibit HER2 activity by promoting the proteasomal degradation of the HER2 protein itself, together with the fact that humans have safely been ingesting secoiridoids and lignans as long as they have been consuming olives and OO, support the notion that the stereochemistry of these phytochemicals might provide an excellent and safe platform for the design of new HER2-targeting agents.”
It is interesting to me that the emphasis in the last-mentioned study and in several other studies seems to be not on promoting the use of EVOO as an anti-cancer health measure but rather on identifying biochemical pathways on which to base new drug developments. Perhaps this is because the point of departure of most of these studies is acknowledging the health benefits of a Mediterranean diet and consuming lots of olive oil. And, perhaps cynically, I wonder if it reflects research funding sources for whom finding a new blockbuster drug may be more important than public health.
A 2010 study publication Extra-virgin olive oil-enriched diet modulates DSS-colitis-associated colon carcinogenesis in mice reports “RESULTS: Disease activity index (DAI) was significantly higher on SFO (sunflower oil) vs. EVOO diet at the end of the experimental period. EVOO-fed mice showed less incidence and multiplicity of tumors than in those SFO-fed mice. beta-catenin immunostaining was limited to cell membranes in control groups, whereas translocation from the cell membrane to the cytoplasm and/or nucleus was showed in DSS-treated groups and its expression was higher in SFO-fed animals. Cytokine production was significantly enhanced in SFO-fed mice, while this increase was not significant in EVOO-fed mice. Conversely, cyclooxigenase-2 (COX-2) and inducible nitric oxidase synthase (iNOS) expression were significantly lower in the animal group fed with EVOO than in the SFO group. CONCLUSIONS: These results confirm that EVOO diet has protective/preventive effect in the UC-associated CRC. This beneficial effect was correlated with a better DAI, a minor number of dysplastic lesions, a lower beta-catenin immunoreactivity, a proinflammatory cytokine levels reduction, a non modification of p53 expression and, COX-2 and iNOS reduction in the colonic tissue.”
Olive oil and inflammation
A study in done back 2001 Protective effects upon experimental inflammation models of a polyphenol-supplemented virgin olive oil diet again demonstrated a dose-dependent effect of olive oil polyphenols in protecting rats from induced inflammation damage. “CONCLUSIONS: This study demonstrates that virgin olive oil with a higher content of polyphenolic compounds, similar to that of extra virgin olive oil, shows protective effects in both models of inflammation and improves the disease associated loss of weight. This supplementation also augmented the effects of drug therapy.”
Synergy of olive oil with other supplements
A 2006 study Intestinal anti-inflammatory activity of combined quercitrin and dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, in rats with DSS-induced colitis found synergy between administration of fish oil, quercetin and olive oil in a rat model of colitis. “In addition, a complete restoration of colonic glutathione content, which was depleted as a consequence of the colonic insult, was obtained in rats treated with QR plus FO diet; this content was even higher than that obtained when colitic rats were treated with FO diet alone. When compared with the control colitic group, the combined treatment was also associated with a lower colonic nitric oxide synthase and cyclooxygenase-2 expression as well as with a significant reduction in different colonic proinflammatory mediators assayed, i.e. leukotriene B(4), tumor necrosis factor alpha and interleukin 1beta, showing a significantly greater inhibitory effect of the latter in comparison with rats receiving FO diet without the flavonoids (quercetin). CONCLUSIONS: These results support the potential synergism between the administration of the flavonoid and the incorporation of olive oil and n-3 PUFA to the diet for the treatment of these intestinal inflammatory disorders.”
EVOO and gene expression
Finally, I want to mention that new studies are starting to look at the effects of EVOO on gene expression. For example, the 2010 publication Gene expression changes in mononuclear cells from patients with metabolic syndrome after acute intake of phenol-rich virgin olive oil. “BACKGROUND: Previous studies have shown that acute intake of high-phenol virgin olive oil reduces pro-inflammatory, pro-oxidant and pro-thrombotic markers compared with low phenols virgin olive oil, but it remains unclear if the effects attributed to its phenolic fraction are exerted at the transcriptional level in vivo. To achieve this goal, we aimed at identifying in humans those genes which undergo expression changes mediated by virgin olive oil phenolic compounds. RESULTS: Postprandial gene expression microarray analysis was performed on peripheral blood mononuclear cells at the postprandial period. Two virgin olive oil-based breakfasts with high (398 ppm) and low (70 ppm) content of phenolic compounds were administered to 20 patients with metabolic syndrome following a double-blinded random crossover design. To eliminate the potential effect that might exist in their usual dietary habits, all subjects followed a similar low-fat, carbohydrate rich diet during the study period. Microarray analysis identified 98 differentially expressed genes (79 underexpressed and 19 overexpressed) when comparing the intake of phenol-rich olive oil with the low-phenol olive oil. Many of those genes are linked to obesity, dyslipemia and type 2 diabetes mellitus. Among these, several genes are involved in inflammatory processes mediated by transcription factor NF-kappa B, activator protein-1 transcription factor complex AP-1, cytokines, mitogen-activated protein kinases MAPKs or arachidonic acid pathways. CONCLUSION: This study shows that intake of a breakfast based in virgin olive oil rich in phenol compounds is able to repress the in vivo expression of several pro-inflammatory genes, thereby switching the activity of peripheral blood mononuclear cells to a less deleterious inflammatory profile. These results provide at least a partial molecular basis for the reduced risk of cardiovascular disease observed in Mediterranean countries, where virgin olive oil represents the main source of dietary fat.”
I could continue this blog entry citing more and more studies but it should be clear by now that the old Italian folklore about the health value of olive oil is right-on and the pungent extra-virgin variety is by far the best. What I have to figure out now based on the final study quoted is how can I work extra virgin olive oil into my regular daily breakfast? I want to do that without adding carbs and confounding tastes like blueberries and EVOO. I will need to do some experimenting. Perhaps they will go together fine.
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