Managing Hypercholesterolaemia

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appleAn Apple a Day, Pomegranate, and Bergamot Citrus for a Cholesterol and Whole-Health Solution

“An apple a day keeps the doctor away,” is a phrase that many have heard since youth, likely spoken by a carer who was trying to get some fruit into a picky eater. Science has also proven the benefits of this wisdom.[i] Pomegranate has a similar reputation, particularly with respect to cardiovascular health. And a fast up-and-comer is the bergamot citrus, with cholesterol-lowering benefits at the top of its list of virtues. But does the data actually support the purported benefits of these fruits? A look at the clinical studies suggest it does, at least where cardiovascular health is concerned.

An Apple a Day…

Many of us have not taken much time to consider the nutritional value of apples beyond their fibre content. At a glance, the nutritional information isn’t too compelling: Aside from a modest amount of vitamin C, very low levels of vitamins and minerals are found in this fruit. However, what is not listed in the basic nutritional summary is possibly the primary contributor to the apple’s famed reputation: polyphenols.

Green tea is a source of one of the most recognised polyphenols, epigallocatechin gallate (EGCG). EGCG is well known for its cancer-preventative, antioxidant, and detoxifying effects,[ii],[iii] which are each effects that apple polyphenols may also deliver.[iv],[v] Polyphenols found at high levels in the seeds and skin of grapes, such as the famous resveratrol, are also known for their antioxidant and cardioprotective benefits. Silybin (found in milk thistle) and curcumin (found in turmeric) are additional polyphenols with a wide array of health benefits; however, many of these are challenged by limited bioavailability.[vi]

Apples are a source of flavonoids (a type of polyphenol), such as quercetin and rutin, both known for their anti-allergic and antioxidative effects.[vii],[viii],[ix],[x] Clinically, apple polyphenol extracts have been shown to have anti-allergic effects and reduce symptoms of atopic dermatitis.[xi] Procyanidins (also known as condensed tannins) are another type of flavonoid found at high levels in apples and their extracts.[xii],[xiii] The procyanidins found in apples include epicatechin oligomers, similar to the compounds found in green tea. Studies suggest these polyphenols are well absorbed and influence levels in the bloodstream more than 23 hours after consumption, peaking around two to two and a half hours after consumption.7,[xiv] The total polyphenol content of an unripe apple is 10 to 100 times that of a ripe one,[xv] likely due to the importance of polyphenols in protecting the developing fruit from ultraviolet radiation and pathogens.[xvi]

Epidemiological evidence suggests apple consumption is associated with a decreased risk of lung cancer, chronic obstructive pulmonary disease, asthma, and type 2 diabetes; reduced bronchial hypersensitivity and improved lung function; and a decreased risk of cardiovascular disease, coronary mortality, and thrombotic stroke in women; as well as possibly contributing to a reduced risk of death from coronary heart disease in elderly men.[xvii] In vitro studies suggest extracts from apples have a high antioxidant potential (with only 0.4% coming from vitamin C),[xviii] which may contribute to their ability to reduce lipoprotein oxidation and tumor cellular proliferation.[xix],[xx] Some of these benefits may be due to the pro-oxidant effects of apples as well,[xxi] which induce cellular antioxidant transcription via activation of a protein in the body known as nuclear factor E2-related factor (Nrf2). Nrf2 turns on the transcription of antioxidant elements, detoxification enzymes, and proteins required for glutathione synthesis and recycling.[xxii],[xxiii]

Recent studies have sought further understanding of how apple extracts may benefit cardiovascular health. Animal models have shown that apple polyphenols can significantly reduce hepatic and serum cholesterol by dose-dependently increasing expression of hepatic cholesterol 7 alpha-hydroxylase, the enzyme which performs the rate-limiting step of bile acid synthesis; suppressing plasma activity of cholesteryl ester transport protein, a protein that facilitates the transport of cholesteryl esters and triglycerides between lipoproteins; and increasing faecal excretion of steroids, cholesterol, and exogenous cholesterol oxidation products (which can be found in processed foods).[xxiv],[xxv],[xxvi] In animals, an anti-obesity effect of apple polyphenols has also been demonstrated, with supplementation reducing the increase of white adipose tissue due to high-fat diet feeding.[xxvii]

Clinically, improvements in cholesterol balance with supplementation of apple polyphenols have also been observed. In one of these randomised, double-blind, placebo-controlled trials (RDBPCT), healthy male and female subjects with slightly elevated cholesterol levels (between 200 to 260 mg/dL at baseline) were given an apple polyphenol product at a dosage of 300, 600, or 1,500 mg/day for a period of four weeks.[xxviii] It was found that the apple polyphenols had a dose-dependent effect of reducing total cholesterol, also decreasing low-density lipoprotein (LDL) cholesterol significantly at the highest dosage. A second RDBPCT looked at the impact of apple polyphenols on healthy individuals with a higher body mass index (BMI) of 23 to 30 kg/m2. In this study, apple polyphenols taken at a dosage of 600 mg/day for 12 weeks significantly reduced both total and LDL cholesterol compared to baseline, with a significant reduction seen at four weeks compared to placebo.[xxix] Decreases in visceral fat and body weight were also seen in the group receiving the apple polyphenols, compared to baseline and placebo.

Pomegranate: The Punic Apple

With its consumption dating back to early Greek and Roman civilizations, the pomegranate fruit has long had a substantial reputation as a health food. Its Latin name, Punica granatum, has its origins in the region as well, with “Punica” being the feminised Roman name for Carthage, the city from which the best of the pomegranate fruits (also known as the Punic apple) came from, and “granatum” referring to the seediness or grainy texture.[xxx]

Much like the apple, the pomegranate contains numerous polyphenols, including ellagic acid, ellagitannins, and quercetin.[xxxi] The peel contains the highest level of these polyphenols and is pressed with the arils (the fleshy cup of fruit including the seed) in the process of making juice. The ellagitannin found at the highest level in pomegranate juice, punicalagin, is responsible for 50% of the antioxidant activity of the juice.[xxxii] As a large molecule with a molecular weight, punicalagin is first metabolised into ellagic acid and then converted to urolithins by the microflora of the gastrointestinal tract. Both ellagic acid and urolithins enter the bloodstream, with urolithins existing longer than ellagic acid in circulation, persisting between 12 and 56 hours.[xxxiii],[xxxiv],[xxxv],[xxxvi] Interindividual variability of the microflora in the gut has been shown to be a factor in levels of the different urolithins found in the bloodstream after pomegranate consumption, as well as the variable effects that have been shown in clinical studies.[xxxvii]

Clearly, the early Greeks and Romans knew what they were doing, as scientific studies have shown many potential health benefits of pomegranate consumption, including protection from cellular oncogenic changes and proliferation,[xxxviii],[xxxix] reduction of the progression of chronic inflammatory diseases (including autoimmune and neurodegenerative diseases),[xl] and improvements of metabolic dysfunction and its complications in adults as well as children.[xli],[xlii],[xliii],[xliv]

Consumption of a pomegranate extract with a high fraction of punicalagin has been shown to improve numerous markers of cardiovascular and metabolic health. In patients who had experienced a myocardial infarction, 300 mg of a pomegranate extract containing 30% punicalagins was given twice daily in addition to other indicated medications, with comparisons made to a placebo group who received only the indicated medications.[xlv] After four weeks, significantly greater improvements in triglycerides, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol was seen in the group receiving the pomegranate extract compared to the placebo group. Additionally, a significantly greater reduction in oxidised LDL cholesterol, homocysteine, and high-sensitivity C-reactive protein (hs-CRP) was seen in the group receiving the pomegranate extract. In the subset of these patients additionally having type 2 diabetes, significant improvements in blood glucose and HbA1c levels were also seen.[xlvi] Other clinical studies have shown similar findings, with significant improvements in total, LDL, and oxidized LDL cholesterol after consumption of pomegranate from six weeks to three years.[xlvii],[xlviii],[xlix]  

In addition to its positive impact on cholesterol and blood sugar, consumption of the juice of pomegranate and/or its extracts has been shown in clinical studies to inhibit angiotensin-converting enzyme activity and reduce systolic and diastolic blood pressures,[l],[li],[lii],[liii] also decreasing carotid intima–media thickness (CIMT), a marker of coronary heart disease risk, by up to 30% in patients with atherosclerosis.49

Bergamot Citrus

At first glance, the bergamot orange (or bergamot citrus) may leave you wondering what the fruit actually is. With a green or yellow color similar to that of a lime, a knobbled surface similar to the grooves and ridges of the human brain, and a shape like a pear, the bergamot orange has probably compelled many curiosity seekers to purchase it just to find out how this strange-looking fruit actually tastes. Likely a hybrid of the bitter orange and lemon,[liv] bergamot citrus has been used for its essential oil, which has been cultivated in Italy since the 15th century and used as a fragrance for perfumes and cosmetics for many years. Bergamot citrus is also the ingredient that gives Earl Grey tea its characteristic smell and taste. Recent research has shown the fragrance has an effect of improving mood and reducing cortisol and fatigue,[lv],[lvi] which has even prompted hospitals to research if it may be beneficial to use preoperatively as a nonpharmacological anxiolytic.[lvii]

Beyond its action as an aromatherapy, bergamot citrus has also been studied for its benefits on cardiovascular health, primarily for encouraging a healthy balance of lipids.[lviii] Bergamot citrus peel and juice are also a source of polyphenols, primarily flavonoids, including hesperetin, neoeriocitrin, naringin, and neohesperetin.[lix],[lx],[lxi] Conjugates of these compounds also found in the fruit have been shown to be structural analogs to statins, with computational models showing they likely act as inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase).[lxii] Animal models have shown a significant increase in faecal bile acids and steroid excretion with consumption of bergamot polyphenols (BPs) as well.[lxiii] BPs also have significant antioxidant and anti-inflammatory effects and have been shown in animal models to improve insulin resistance and hepatic steatosis.[lxiv],[lxv]

Human studies have also shown that treatment with BPs improves dyslipidaemia and hyperglycaemia. In a RDBPCT of individuals with metabolic syndrome (including a group with isolated hypercholesterolemia, a group with mixed hyperlipidemia, and a group with mixed hyperlipidemia and hyperglycaemia), treatment with 500 or 1,000 mg of BPs for 30 days led to dose-dependent reductions in total and LDL cholesterol and an increase in HDL cholesterol.64 In individuals having elevated triglyceride or blood glucose levels, a dose-dependent reduction was also seen. An improvement in flow-mediated vasodilation was also observed in the groups taking BPs.

Lower doses of bergamot extract have also been shown to significantly improve lipid profiles. When taken daily for 6 months by individuals with moderate hypercholesterolaemia, supplementation with 400 mg of bergamot extract, providing 150 mg of BPs, led to significant reductions in total and LDL cholesterol (up to 12% and 20%, respectively) and triglycerides (up to 17%), and a significant increase in HDL cholesterol (up to 8%).[lxvi] A significant increase in large LDL particles and decreases in small, more atherogenic LDL particles was also seen. Additionally, CIMT was shown to significantly decrease by up to 25%.

The use of BPs has also been studied as an adjunctive therapy to statins, as the side effects of statins may limit their use. In one open-label, parallel group, placebo-controlled study, patients were, for 30 days, randomised to treatment with placebo, 10 or 20 mg of rosuvastatin per day, 1,000 mg of BPs per day, or 1,000 mg of BPs plus 10 mg of rosuvastatin per day.

Caution should be used when using extracts of citrus, including the bergamot orange, as citrus products often contain furocoumarins. Furocoumarins occur naturally in citrus and are the compounds likely responsible for the well-known cytochrome P450 enzyme–inhibiting effects of grapefruit juice.[lxviii] Furocoumarins can also be phototoxic, even when ingested orally.[lxix] Unless removed as a part of processing, both bergamot juice and extracts may contain these potentially problematic compounds at clinically relevant levels.58 It is therefore important to choose bergamot citrus products that do not contain furocoumarins.

Clearly, consumption of the apple, pomegranate, and bergamot citrus can benefit health in many ways. As the availability of these fruits—particularly in pesticide-free forms—may be limited seasonally, regionally, and for other reasons, supplemental extracts are often the next best thing.


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