Hypolipemic and hypoglycaemic activity of bergamot polyphenols: From animal models to human studies
Graphical abstract
Introduction
Hyperlipidemia or hypercholesterolemia is an important risk factor for the development of atherosclerosis and coronary artery disease [1], [2]. Main pathogenic blood parameters are increased concentrations of cholesterol bound to Low-density Lipoprotein (cLDL), total blood cholesterol (totChol) and triglycerides (TG). Conditions of insulin resistance such as impaired glucose tolerance or "prediabetes" are also characterized by a high risk of cardiovascular diseases (CVD) [3]. Majority of therapeutic protocols rely on drugs that belong to statin family. Statins inhibit the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which catalyzes the rate-limiting step in mevalonate biosynthesis, a key intermediate in cholesterol metabolism. This is associated to a decrease in totChol and a switch from cLDL to High-density Lipoprotein (cHDL) fraction. Despite the significant clinical benefits provided by statins [1], many patients, in particular those with metabolic syndrome, do not achieve their recommended low-density and high-density lipoprotein (LDL, HDL) cholesterol target goals with statins [3]. Moreover, the use of statins is forbidden in more than 40% of patients eligible for this therapeutic approach, mostly for the occurrence of side effects including myalgia, myopathy or liver disease and rhabdomyolysis in more severe cases [4], [5].
This limits the use of statins and suggests the need of alternative therapeutic approaches.
Experimental and epidemiological evidence suggest that dietary polyphenols, in particular flavonoids, may play a role in ameliorating atherosclerosis and pleiotropic anti-oxidative and anti-inflammatory effects have been proposed as an underlying mechanism [6], [7], [8]. Yet these compounds when analysed separately show rather weak cholesterol-lowering effects in animal experiments [9]. In contrast, some natural compositions of plant polyphenols seem to possess a good hypolipemic activity both in animal models and in human studies, suggesting that synergistic effects of individual compounds may play a central role in the beneficial effects [6], [8], [9]. This observation provides the rationale for the identification of optimally synergizing elements and their plant sources with the best ability to prevent hyperlipidemia and cardiovascular complications.
Bergamot (Citrus bergamia) is an endemic plant of the Calabrian region in Southern Italy with a unique profile of flavonoid and flavonoid glycosides present in its juice and albedo, such as neoeriocitrin, neohesperidin, naringin, rutin, neodesmin, rhoifolin and poncirin. Bergamot differs from other Citrus fruits not only because of the composition of its flavonoids, but also because of their particularly high content [10], [11]. Among them naringin, present also in grapefruit, have already been reported to be active in animal models of atherosclerosis [12], while neoeriocitrin and rutin have been shown to inhibit LDL oxidation [13]. Importantly, bergamot juice (BJ) is rich in neohesperidosides of hesperetin and naringenin, such as melitidine and brutieridine. These flavonoids possess 3-hydroxy-3-methylglutaryl moiety with a structural similarity to the natural substrate of HMG-CoA reductase and are likely to exhibit statin-like proprieties [14]. Experimental evidence obtained in animal models of diet-induced hypercholesterolemia and renal damage [15], [16] as well as in the rat model of mechanical stress-induced vascular injury [17] supports the hypolipemic and vasoprotective effects of bergamot constituents. However, the therapeutic potential of bergamot has never been investigated in human studies, even though the traditional use of BJ in the Calabrian region suggested since long time its potential beneficial use in counteracting atherosclerosis.
The present study has been carried out to verify, in a rat model of diet-induced hyperlipemia, the effect of bergamot-derived polyphenolic fraction (BPF) on totChol, cLDL, cHDL, TG and blood glucose. This effect was also investigated by giving orally BPF for 30 consecutive days in 237 patients suffering from isolated or mixed hyperlipemia either associated or not with hyperglycaemia. In patients we have also studied the possible contribution of HMG-CoA reductase inhibition by BPF to its hypolipemic activity and this effect was also compared with changes of reactive vasodilation to verify the potential beneficial effect of BPF in modulating the imbalanced endothelial reactivity.
Section snippets
Plant material
C. bergamia Risso & Poiteau fruits were collected from plantations located between Reggio Calabria and Bianco, in 90 km long costal area in South Italy.
Preparation of BPF
BJ was obtained from peeled-off fruits by industrial pressing and squeezing. The juice was oil fraction-depleted by stripping, clarified by ultra-filtration and loaded on suitable polystyrene resin columns absorbing polyphenol compounds of MW between 300 and 600 Da (Mitsubishi). Polyphenol fractions were eluted by a mild KOH solution. Next the
Results
To assess the nutraceutical proprieties of bergamot flavonoids we concentrated bergamot juice in a form of powder, highly enriched in polyphenols. This was achieved by a standardized procedure of partial purification of bergamot polyphenol fraction (BPF) on a polystyrene resin column. The BPF preparation used in all studies contained 26–28% of 5 main flavonoids. 6–6.15 g of BPF correspond to 1000 ml bergamot juice in terms of flavonoid content. The content of 5 main flavonoids in a standardized
Discussion
Based on the data presented in this study, the BPF treatment leads to a significant reduction of coronary artery disease risk and other cardiovascular complications according to the headlines of National Cholesterol Education Programme (NCEP—ATP III) in a rat model of diet-induced hyperlipemia. This effect was also confirmed in human studies carried out in patients with pure or mixed hyperlipemia either or not associated with hyperglycaemia (metabolic syndrome).
Scientific evidence obtained with
Acknowledgments
We thank Domenico Malara, Malara s.r.l., Reggio Calabria, Italy and Franco Nava, Piacenza, Italy for developing BPF purification procedure. We are grateful to Artur Janda, Jagellonian University, Cracow, Poland, for help with the statistical analysis and Capua s.r.l, Reggio Calabria, Italy, for technical support.
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