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Research Article, J Food Nutr Disor Vol: 5 Issue: 5

Selected Edible Plant-Derived Therapies for Controlling Dyslipidemia

Michael Anthony Nammour1, Nicole Danielle Nammour2, Marlene F Daher3, Mohamad Mroueh4, Joey C Daher5 and Costantine F Daher5*
1Medical School, Louisiana State University Health Sciences, Shreveport, USA
2Biology Department, University of Mississipi, Mississipi, USA
3Green Clinic, Ruston, Louisiana, USA
4School of Pharmacy, Lebanese American University, Byblos, Lebanon
5Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Byblos, Lebanon
Corresponding author : Dr. Costantine F. Daher
Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, P.O. Box 36, Byblos, Lebanon
E-mail: [email protected]
Received: May 11, 2016 Accepted: July 01, 2016 Published: July 07, 2016
Citation: Nammour MA, Nammour ND, Daher MF, Mroueh M, Daher JC, et al. (2016) Selected Edible Plant-Derived Therapies for Controlling Dyslipidemia. J Food Nutr Disor 5:5. doi:10.4172/2324-9323.1000205

Abstract

Selected Edible Plant-Derived Therapies for Controlling Dyslipidemia

Dyslipidemia is a well-known major modifiable risk factor for cardiovascular disease (CD), the number one killer in the United States. One of the major challenges in controlling dyslipidemia is the high annual cost invested in the commonly used therapeutic drugs. Among the many lipid lowering agents available for the treatment of dyslipidemia, statins remain the most widely used. However, the use of statins as well as other therapeutic drugs is associated with various serious adverse effects. Quite often, patients cannot tolerate such side effects. Therefore, it became essential for them to look for a safe but effective alternative approach to manage dyslipidemia. Over the last decades, the interest in herbal medicinal products and supplements as an alternative remedy for the treatment of various metabolic diseases has increased tremendously worldwide. Although therapies involving many plant-derived agents have shown promising potential in term of efficacy in treating dyslipidemia, the issue of safety remains a major obstacle. For the greatest majority of natural product, there is still an inadequate knowledge about their mode of action, contraindications, potential side effects, and interactions with other drugs and other functional foods. The present review examines several plant-derived therapies for managing dyslipidemia and highlights some important challenges when it comes to safety concerns.

Keywords: Alternative medicine; Cholesterol; Dyslipidemia; Herbal therapy; Triglyceride

Keywords

Alternative medicine; Cholesterol; Dyslipidemia; Herbal therapy; Triglyceride

Introduction

Dyslipidemia is characterized by elevated levels, above 90th percentile of general population, of total cholesterol (TC), triglycerides (TG), low-density lipoproteins cholesterol (LDL-C), and lowered levels under 10th percentile of general population of high-density lipoproteins cholesterol (HDL-C) [1,2]. Dyslipidemia, more specifically, high-serum LDL-C and low-serum HDL-C are well known major modifiable risk factors for cardiovascular disease (CD). CD has been recognized as the number one killer in the United States for decades, and in 2010 the Centers for Disease Control and Prevention estimated that $444 billion was spent on CD alone [3]. This annual cost is expected to increase as life expectancy continues to increase, thus making cost-effective primary prevention of CD of paramount importance [3]. In 2011, CD accounted for 1 out of every 3 deaths, and with the recent decline in cigarette smoking, dyslipidemia has become the number one modifiable risk factor for vascular disease [3]. Dyslipidemia can either be classified as primary (inherited) or secondary [4]. Secondary hyperlipidemia may arise from diet, type 2 diabetes mellitus, excessive alcohol consumption, cholestatic liver disease, nephrotic syndrome, chronic renal failure, hypothyroidism, cigarette smoking, obesity, and drugs [5]. Other than CD, dyslipidemia is significantly associated with common comorbid diseases such as diabetes, insulin resistance, and obesity [6]. TC and LDL-C reduction through dietary modifications and medications that affect lipid metabolism has been proven to reduce the occurrence of atherosclerosis and cardiovascular events in both animals and humans [7,8].
The pathophysiology of dyslipidemia on CD involves oxidative stress causing vascular damage, protein oxidation, lipid peroxidase production, and nuclear DNA damage [9]. Oxidized LDL is a chemically modified form of LDL that inhibits the production of vasodilators such as nitric oxide [10]. Oxidized LDL can enter macrophages via unregulated scavenger receptors and form isoprostanes [2]. As oxidized LDL accumulates macrophages become large foam cells that induce endothelial expression and secretion of cytokines, growth factors, and cell surface adhesion molecules, which in combination with T lymphocytes and smooth muscle cells form the fatty streak. The fatty streak eventually progresses into an atheromatous plaque inside the arterial lumen that obstructs blood flow. This mechanism highlights the relationship between increased LDL levels and the incidence of CD [8,11].
The traditional management of dyslipidemia includes lifestyle modification and pharmacotherapy based on identifying groups that are considered high, moderate, or low risk for major cardiovascular events [3]. The guidelines for dyslipidemia management have been developed internationally by many independent organizations in order to improve patient care and reduce costs related to CD [3]. The 2009 Canadian Cardiovascular Society Dyslipidemia guidelines have been widely used however many developments have occurred since then [12]. The principle changes from the 2009 Guidelines include: the introduction of the concept of cardiovascular age, recommending more frequent monitoring of patients with Framingham Risk Scores > 5%, using Apolipoprotein (Apo) B or non-HDL-C as alternate lipid markers, addition of chronic kidney disease as a high-risk feature, reduced age for treatment in diabetes, specific recommendations about health behaviors, new recommendation about statin adverse effects, and use of Grading of Recommendations Assessment, Development and Evaluation (GRADE) recommendations and process [12]. The total CD Framingham Risk Score, modified for family history of premature coronary artery disease, is currently recommended for baseline risk assessment with LDL-C remaining as the primary target of therapy. Though, more emphasis has been placed on non-HDL-C and Apo B as alternate targets [12]. It is important to realize that overall cardiovascular risk is dependent on the phenotype of the patient, with LDLC being only one factor [12].
There are many lipid lowering agents available for the treatment of dyslipidemia. Statins, the most widely used, are known to reduce TC synthesis and increase LDL-C uptake via inhibition of 3-hydroxy- 3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) [13]. Other benefits include decreases in TGs, slight increases in HDL-C, improvement of endothelial function, stabilization of platelets, decreasing inflammation and oxidation of lipoproteins, and improvement of blood flow [14]. However, statin use is associated with serious adverse effects such as liver dysfunction and myopathy [14]. Fibrates, another commonly used medication for dyslipidemia, can decrease TG by reducing the production of VLDL cholesterol, and increasing lipoprotein lipase (LPL) activity through activation of Peroxisome proliferator-activated receptor-α (PPARα) [15]. Some adverse effects of fibrates include increased risk of pancreatitis, bile stones, and myopathy [15]. Bile acid sequestrants can interrupt the enterohepatic circulation of bile acids by binding to negatively charged bile acids and bile salts in the small intestine resulting in increased conversion of cholesterol into bile [15]. Adverse effects of bile acid sequestrants include TG elevation and GI symptoms such as constipation [15]. Nicotinic acid (niacin) can reduce TG by lowering VLDL cholesterol production through binding to G protein-coupled receptor 109A and inhibition of hormone-sensitive lipase activity [15]. Niacin can also decrease TC, LDL-C and increase HDL-C however niacin is associated with side effects such as flushing, hyperglycemia, hepatotoxicity and gout [15,16]. Ezetimibe is an intestinal cholesterol absorption inhibitor that can reduce LDL-C levels, and is most commonly used with statins as this further reduces LDL-C levels [15]. Omega-3 fatty acids reduce the production of VLDL cholesterol and can lower TG levels however its most commonly reported side effect is an increase in the susceptibility to bleeding when consumed with anti-coagulant drugs [15]. There are many other new drugs being studied to combat dyslipidemia including Microsomal triglyceride transfer protein (MTP) inhibitors, acyl-coenzyme A: cholesterol acyltransferase 2 (ACAT2) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, PPARα agonists among others [2]. Although there are many available pharmacologic agents, most have adverse effects [17]. Patients may not be able to tolerate these side effects, which illustrate the need for a safe but effective alternative approach to managing dyslipidemia.
The use of complementary and alternative medicine for treating chronic diseases dates back to the ancient times. This approach has gained popularity in the last few decades due to the high cost and concerns about the adverse effects of prescribed drugs. Dyslipidemia is one of the very common chronic diseases that secured a substantial portion from the complementary and herbal medicine. Many plants were proven to have positive impact on dyslipidemia. In the present manuscript, the objective is to cover selected commonly edible plants with reported hypolipidemic effects.
Curcuma longa
Curcumin, a bright yellow chemical, is a major curcuminoid of Curcuma longa L. (turmeric) which is a member of the ginger family (Zingiberaceae). The exact origin of the plant is not known, but it is thought to originate from Southeast Asia and is cultivated extensively in Bangladesh, Indonesia China, Malaysia, Thailand, and the Philippines. It is a dairy hepatanoid used as herbal supplement, food coloring, food flavoring as well as an additive to cosmetics. Curcumin has many reported pharmacologic activities including anti-diabetic [18] anti-inflammatory [19] antioxidant [20] and cancer preventative [20,21]. Tai et al. reported that curcumin suppression of proprotein convertase subtilisin/kexin type 9 (PCSK9) expressions is associated with increase in cell-surface LDL receptor (LDLR) and LDLR activity in hepatic cells and it acts in a molecular mechanism that is distinct from statins [22]. Curcumin treatment was also reported to partially recover the metabolism disorders induced by high fat diet. The following metabolic pathways were involved: TCA cycle, glycolysis, and gluconeogenesis, synthesis of ketones and cholesterol, ketogenesis of branched chain amino acids, choline metabolism, and fatty acid metabolism [23]. Additionally, curcumin was proposed to act as a scavenger of free radicals and/or influence signal transduction (AKT, AMPK) pathways, and modulate the activity of specific transcription factors that regulates the expression of genes involved in free radical scavenging and lipid homeostasis (HMG-CoA reductase, and carnitine palmitoyltransferase). At the cellular level it leads to adaptive cellular stress response by affecting the lipid metabolic enzymes [24].
Studies have shown that supplementation of 1 gm/day for 30 days of curcumin led to significant reduction in serum TG levels but did not have a significant influence on other lipid parameters as well as body mass index (BMI) and body fat [25]. However, when curcumin was given at 1gm/day for 8 weeks to subjects with metabolic syndrome, it was shown to be more effective than placebo in reducing TC, LDL-C, TG, lipoprotein (a) and elevating HDL-C concentration [26]. Interestingly, the lipid reducing effect of curcumin was significantly enhanced after fermentation. Hyperlipidemic mice treated with 500 mg/kg, 200 mg/kg, and 100 mg/kg of fermented curcumin showed a significant reduction in serum TC by 38.7%, 34.5%, and 32.7% and serum TG by 38.3%, 28.6% and 30.1% respectively [27]. Similarly, hyperlipidemic rats treated for 30 days with 200 mg/kg of curcumin exhibited a significant decrease in serum TC, TG, LDL-C and homocysteine levels as well as an increase in HDL-C level [28]. The effect of curcumin on high fat fed hamsters was also investigated and proved to significantly decrease the level of free fatty acids, TC, TG, and leptin [9]. Um et al. studied the potential mechanism of curcumin consumption on high cholesterol diet-induced atherosclerosis in rabbits [29]. Curcumin decreased TC, TG, LDL-C, and oxidized LDL-C by 30.7%, 41.3%, 30.4%, and 66.9% respectively but did not significantly affect HDL-C. It also decreased cholesterol-induced CD36 expression, circulating inflammatory cytokines, and soluble adhesive molecule levels. In addition, curcumin decreased mRNA and protein expression of intracellular adhesion molecule-1 and vascular adhesion molecule-1. Curcumin also inhibited cholesterol induced upregulation of matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9. This study results demonstrate the anti-atherosclerotic effects of curcumin [29]. Recent studies have shown that rabbits fed on high-cholesterol diet for 6 week concurrently with curcuminoids (50 mg/kg) extracts showed major improvement in their lipid profile. This has been translated in a significant increase in HDL-C and decrease in TC, LDL-C, TG, lipoprotein (a), serum oxidized LDL, homocysteine, MMP-9 and CETP [30](Table 1).
Table 1: Selected edible plants for the treatment of dyslipidemia.
Trigonella foenum-graecum
Trigonella foenum-graecum L., commonly known as fenugreek, is one of the oldest medicinal plants belonging to the pea family (Fabaceae) that grows in Southwestern Europe, Western Asia, India, North Africa, and USA [31]. In many parts of the world, it is commonly eaten as a spice prepared from the dried seed of the plant and used as an antioxidant as well as glucose and cholesterollowering product [31]. These properties have been studied recently by Belguith-Hadriche et al. who showed significant hypocholesterolemic effects and anti-oxidant activity in cholesterol fed rats [32]. Similarly, it has been shown that fenugreek (200 mg/kg) given to hyperlipidemic rats normalized the activities of anti-oxidative enzymes (superoxide dismutase and catalase), reduced TC (26.2%), TG (36.6%), plasma lipid peroxidation (33.9%), hepatic 4-hydroxynonenal activity (27%) and isoprostanes (28%), thereby confirming the anti-dyslipidemic and anti-oxidant properties [33]. Therefore fenugreek may play a role in improving free radicals that can cause dyslipidemia and atherosclerosis. Studies on dyslipidemic hamsters also showed that fenugreek significantly decreased plasma TG, TC, and free fatty acids by 33%, 22% and 14% respectively. In addition, there was a 39% increase in the HDL-C/TC ratio [34].
Previous studies suggested that the hypolipidemic effect of fenugreek is due to inhibition of fat accumulation and upregulation of LDLR [35]. The effect of fenugreek treatment was comparable to Orlistat, a standard anti-obesity drug, and offered significant protection against monosodium glutamate (MSG) induced dyslipidemia and oxidative stress [36]. Similar studies have shown that fenugreek exhibits a preventative effect on fat accumulation and dyslipidemia secondary to impairing lipid digestion and absorption in addition to improvement in glucose and lipid metabolism [37]. When given to high fat fed diet induced obese rats fenugreek inhibited fat accumulation and ameliorated dyslipidemia by causing significant decreases in serum lipids including TGs, TC, LDL-C, and VLDL [38].
Defatted fenugreek seeds have been suggested to raise the levels of HDL-C [39] and a dose of 25 or 50 grams per day for 20 days lowered significantly TG and TC [40]. Sharma et al. treated 15 non obese, asymptomatic, hyperlipidemic adults with 100 g/day of defatted fenugreek powder for 3 weeks. Both TG and LDL-C were lowered from baseline at the end of the treatment period, however, a slight decrease in HDL-C was observed at the end of the trial [41]. In another study, Sharma et al. gave 25 grams of fenugreek seeds per day for 24 weeks to 60 patients with type 2 diabetes mellitus (DM) and noted normal lipid profiles at the end of the treatment period [41,42]. Sowmya et al. treated 20 hypercholesterolemic adults with 12.5-18 grams of powdered, germinated fenugreek. One month posttreatment, a significant reduction in TC and LDL-C was observed but no significant change in the levels of TG, VLDL, and HDL-C was observed [43]. Bordia et al. looked at the effects of 2.5 grams of fenugreek given twice a day for 3 months to 40 subjects with coronary artery disease and type 2 DM. Significant decreases in TC and TG were observed but no change in HDL-C was noted [44]. Studies on Wistar rats, maintained on basal or high cholesterol diet, showed that dietary intervention with fenugreek seed powder (10%) or more importantly fenugreek seed powder (10%) with garlic powder (2%) offers significant cardioprotective effects against isoproterenolinduced myocardial infarction [45]. The effects of aqueous extract of Trigonella foenum-graecum seeds (0.5 and 1.0 g/kg b. w.; administered from day 43 to 70) on fat deposition and dyslipidemia in monosodium glutamate (MSG)-obese rats was recently investigated. Data have shown that extract treatment reduced significantly fat deposition and dyslipidemia (LDL-C and VLDL-C) possibly via improving glucose and lipid metabolism, enhancing insulin sensitivity and down regulating lipogenic enzymes [46].
Few transient side effects of fenugreek were noted including gas and diarrhea for the first few days, however, these symptoms subsided after the first few days [41,47,48]. Also, some patients reported dizziness [49]. Monitoring the blood glucose when supplementation starts is necessary since fenugreek affects the blood glucose levels [39,47]. One should also note that because fenugreek preparation may have derivatives of coumarin, a risk of bleeding or change in prothrombin time (PT or INR) should be considered [50]. Because fenugreek can cross react with chickpeas, caution is warranted in those with history of allergies to chickpeas [51].
Cinnamon
Cinnamon is a spice extracted from the inner bark of several trees from the genus Cinnamomun, mainly C. verum (J. Presi) and it is indigenous to Sri Lanka and Southwest India. Cinnamon is commonly used for fragrance and baking. The smell and flavor are both caused by the oily part of the plant, which is very high in cinnamaldehyde. This compound is responsible for the health benefits of the spice. Cinnamon is full of antioxidants, which protect the body from free radicals. These antioxidants are polyphenols and phenolic acid similar to those found in berries, dark chocolate and red wine [52].
Studies have shown that cinnamon fed rats (200 or 400 mg/kg) had significant decreases in TC, TG, LDL-C and significant increase in HDL-C after 8 weeks of treatment [53]. Similar work revealed that cinnamon (200 mg/kg) given for 6 weeks, causes significant decreases in TC and TG. The potential mechanism suggested for the hypolipidemic effects was speculated to be related to the high content of polyphenols which inhibit the intestinal absorption of cholesterol with subsequent decrease in serum cholesterol level [54]. Long term treatment (8 weeks) of rats with cinnamon bark methanolic extract and regular training had an improved effect on lipid profile by significantly increasing HDL-C levels and decreasing serum TC and LDL-C. Cinnamon had an additive effect when added to regular training [55]. Cinnamon powder administered to hyperlipidemic albino rats at doses of 0.5 g/kg and 0.75 g/kg lowered total lipids by 45% and 49%, TG by 38% and 53%, TC by 53% and 64%, and LDL-C by 50% and 59% respectively. In addition HDL-C showed an increase by 42% and 48% respectively. When cinnamon was given at a dose of 0.25 g/kg no significant effect was noted [56]. The effect of cinnamon, barley flour and their combination was also investigated. Results showed that, when used separately, both improved lipid profile, but the most effective treatment was the combination of cinnamon and barley [57]. Studies on type 2 diabetes patients showed that the intake of 3 glasses of black tea along with 3 g cinnamon for 8 weeks can result in significant benefits in TC, LDL-C, and HDL-C levels compared with controls [58](Table 2).
Table 2: Adverse effects, contraindications, overdose and drug interactions of selected plants used in the treatment of dyslipidemia.
Nigella sativa
Nigella sativa L. (black caraway or black seed) often called black cumin is an annual flowering plant in the family Ranunculaceae native to South and Southwest Asia. It has been used widely in Asian, Far Eastern, and Middle Eastern countries as a spice, food preservative, and for its beneficial health effects [59]. These effects result from the diverse and rich chemical composition including amino acids, proteins, carbohydrates, fibers, oils, minerals, alkaloids, saponins, and others [60]. The potential role of N. sativa includes amelioration of oxidative stress through free radical scavenging activity, reduction of blood glucose, and improving dyslipidemia [61]. The lowering effect on cholesterol by black cumin was attributed to the inhibition of cholesterol absorption, decreased hepatic cholesterol synthesis, and up-regulation of LDL receptors. In the same study N. sativa was well tolerated with no severe adverse effects [62]. Asgary et al. looked into different preparations of N. sativa and all preparations produced significant decreases in serum level of TC, TG, LDL-C however the effect on HDL-C was not significant [62]. Ibrahim et al. found that N. sativa significantly improved lipid profile in menopausal women by decreasing TC, TG, and LDL-C while increasing HDL-C compared to placebo over 2 month treatment [63]. Qidwai et al. reviewed articles published on N. sativa, a total of 12 trials (6 human, 6 animal studies) with the majority of trials were done in animals and humans with diabetic or metabolic syndrome. Decreases in weight, total lipids, TG, and LDL-C were noted; however the increase in HDL-C was questionable [64]. Studies on obese women (25-50 years old; BMI 30- 35) with a low calorie diet showed that a daily dose of 3 g of N. sativa divided into one gram before each meal caused a significant decrease in TG (-14% vs. 1.4%) and VLDL (-14% vs. 7%) when compared to placebo [65]. Muneera et al. compared N. sativa to simvastatin in treating hyperlipidemic rats for 6 weeks. Both N. sativa and simvastatin treated groups showed similar significant improvement in lipid profiles. However, ALT levels were significantly elevated in the group treated with simvastatin as compared to the N. sativa group. Therefore, N. sativa showed a protective role in terms of hepatic dysfunction as compared to simvastatin with similar hypolipidemic effects. These results suggest that N. sativa may be considered as a relatively safe and effective cholesterol-lowering agent [66].
Zingiber officinale
Zingiber officinale (Roscoe), commonly known as ginger is a flowering plant in the family of Zingiberacaea to which turmeric belongs. It is indigenous to southeastern Asia and cultivated in many countries including US, India, China and tropical regions. It is a widely used spice and part of folk medicine around the world. A mixture of zingerone, shogaols and gingerols causes the characteristic odor and flavor [67]. Shalaby et al. studied the effect of ginger on dyslipidemia and found that 400mg/kg of ginger given to high fat fed rats caused a significant decrease in lipid profile. In the same study, it was concluded that the possible potential mechanism of action was related to shogaols that inhibit the intestinal absorption of cholesterol with subsequent decreases in serum cholesterol level [54]. Alizadeh- Navaei et al. studied the effect of ginger on volunteer hyperlipidemic patients. In this study, 45 patients in the treatment group received 3 grams of ginger per day divided into 3 doses while the 40 patients in placebo group received a lactose capsule at the same dose and rate for 45 days. Significant reductions in TG, TC, LDL-C, and VLDL were noted in the ginger treated group [68]. Similar studies on hypercholesterolemic rat revealed that ginger given at 3 different doses (aqueous infusion: 100 mg/kg, 200 mg/kg, and 300 mg/kg) for 2 or 4 weeks induced significant decreases in all lipid profile parameters [69]. In comparison to a standard anti-hypercholesterolemic drug (atorvastatin), ginger was even more effective in reducing hypercholesterolemia, especially at the 200 and 300 mg/kg doses [69]. Recent studies on rabbits fed a high-cholesterol diet for 6 week concurrently with ginger (200 mg/kg) revealed a significant increase in HDL-C and a significant decrease in TC, LDL-C, TG, lipoprotein(a), serum oxidized LDL, homocysteine, MMP-9 and CETP [30]. Type 2 diabetes patients receiving 3 glasses of black tea with 3 g ginger for 8 weeks showed significant improvement in their TC, LDL-C, and HDL-C levels compared with controls [58].
Crocus sativus
Saffron is a spice derived from the flower of Crocus sativus L., commonly known as “saffron crocus” and is native to Greece and southwest Asia. The deep orange aromatic powder is used to color and flavor food. The active agent in C. sativus is derived from the stigma [70]. Previous studies on diabetic rat showed that saffron (40 mg/kg and 80 mg/kg) administered to animals for 28 days caused a significant dose dependent decrease in the serum level of total lipids, TG, TC, and LDL-C in addition to a significant increase in HDL-C [66]. Similar studies on hyperlipidemic rats evaluated the hypolipidemic and antioxidant potential of oral administration of saffron (25, 50, and 100 mg/kg) or its active ingredient crocin (4.84, 9.69, and 19.38 mg/kg) for five consecutive days [71]. Both saffron and crocin decreased the levels of TG, TC, aspartate transaminase (AST) and alanine transaminase (ALT). Also, both were able to quench free radicals and protect against oxidation. Saffron, however, was found to be superior to crocin alone. This suggests the presence of other potential active constituents of saffron apart from crocin causing the synergistic effect [71]. Treatment of Type 2 diabetes patients with 3 glasses of black tea with 1 g saffron for 8 weeks caused significant improvement in their TC, LDL-C, and HDL-C levels compared with controls [58].
Hydrastis canadensis
Hydrastis canadensis L. (goldenseal) contains berberine as a major naturally occurring molecule. The plant is indigenous to US and cultivated in many countries around the world. This compound is also found naturally in a number of plants, including members of Coptis and Berberis genera. Berberine is a quaternary ammonium salt highly concentrated in the roots, rhyzomes and stem barks of these plants [72]. Several recent studies looked into the mechanism of the lipid lowering effect of berberine and concluded that this effect is related to activating an AMP-activated protein kinase signaling pathways and increasing LDLR expression in liver [73-75]. Other mechanisms of berberine action were studied after it was noted that berberine was poorly absorbed in the gut epithelium [76]. The level of berberine used in vitro to achieve results were much higher than the levels used in vivo, therefore, suggesting that the accumulated berberine in the gut contributed to the hypolipidemic effect through modulating the gastrointestinal physiology [77]. The speculation was that berberine had an effect on modulating the turnover of bile acids and farnesoid X receptor signaling pathway [77].
The action of berberine on the excretion of cholesterol in high fat diet induced hyperlipidemic hamsters was investigated. Berberine was shown to significantly promote the excretion of cholesterol from the liver into the bile leading to large decreases in TG, TC, and LDL cholesterol levels [78]. Wang et al. studied the effect of 50 mg/ kg, 100 mg/kg, and 150 mg/kg of berberine treatment in rats. The TC and non HDL cholesterol were reduced by 29-33% and 31- 41% respectively, with no significant difference observed between the different doses. The study also concluded that the decrease in cholesterol level was partly attributed to an inhibition of intestinal absorption, hampering intraluminal cholesterol micellarization and reducing enterocyte cholesterol uptake and secretion [79]. Xial et al. showed that pretreatment with berberine reduced the expression of hepatic PCSK9, decreased TC, TG, LDL cholesterol and increased HDL cholesterol in mice [80]. Other similar studies showed that berberine could decrease serum TC and LDL cholesterol in rats fed high fat diet. It was also concluded that berberine upregulates LDLR and apoE, and downregulates HMG-CoA reductase gene expression in the liver [81].
Berberine has a low bioavailability and is metabolized by the liver. A small percentage of patients experience side effects such as nausea, vomiting, constipation, and hypertension. Berberine should be avoided by pregnant women because of its potential adverse effects on the fetus [72]. Berberine inhibits the activity of several CYP450 enzymes in vitro and in vivo, as well as regulates the gene expression of CYP450. Therefore, pharmacokinetic interactions must be considered when using berberine in conjunction with other drugs metabolized by CYP450 [82].
Glycyrrhiza glabra
Licorice (Glycyrrhiza glabra L .) also known as “sweet root”, grows in some parts of Southeast Europe and Western Asia. Glycyrrhizic acid (GA) is a triterpenoid saponin and is the main bioactive agent of the root of G. glabra [83]. It has been reported that GA is a potent inhibitor of 11 beta-hydroxylase; therefore it will have an effect on the treatment of various metabolic disorders including dyslipidemia [84]. The effect of 100 mg/kg of GA given to high fat diet induced obese rats for 28 days was investigated. Results showed a significant decrease in free fatty acids, TC, LDL cholesterol, and tissue lipid deposition, as well as a significant increase in HDL cholesterol [83]. In traditional medicine, Fibrates and Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor (PPAR) agonists that induce increase in LPL activity [85]. Both Fibrates and TZDs can cause side effects such as gallstones with Fibrates [86] and peripheral edema with TZDs [87]. It was postulated that GA causes up-regulation of LPL expression via the activation of PPAR class nuclear receptors [88]. These side effects make GA a more attractive alternative since it has activity as a PPAR agonist [89,90].
Salvia officinalis
Sage (Salvia officinalis L.) is an evergreen shrub, member of the family Laminaceae, and is native to the Mediterranean region and naturalized in all Europe. Sage tea is known for its antidiabetic antiseptic, antiphlogistic, and antihydrotic properties [91,92]. It also has an anti-inflammatory effect on the oral cavity and gingivitis [93]. The active components are polyphenol including rosmarinic acid [94]. Studies have shown that sage tea drinking in 6 healthy females aged 40-50 achieved improvement in the lipid profile including decreased TC and LDL cholesterol as well as increased HDL cholesterol. No hepatotoxic or adverse effects have been reported [95]. In a randomized placebo controlled parallel group study conducted on 40 hyperlipidemic type 2 diabetic patients given 500 mg capsule of S. officinalis leaf extract 3 times per day for 3 months the fasting glucose, HbA1c, TC, TG and LDL cholesterol were all decreased in the treatment group by 32.2%, 22.7%, 16.9%, 56.4%, and 35.6% respectively. HDL cholesterol was increased by 27.6% and no adverse effects were noted [96]. In a similar study, 67 hyperlipidemic patients received one 500 mg capsule of sage leaf extract every 8 hours for 2 months. Significant decreases were observed in TC, TG, LDL cholesterol, and VLDL as well as increased HDL cholesterol without any significant change of SGOT, SGPT or creatinine. Also, no significant side effects were noted suggesting that sage may be effective and safe in the treatment of dyslipidemia [97].
Lima et al. evaluated the biosafety and bioactivity of common sage tea in vivo. Results revealed that sage treated group contained interesting bioactivities that improved the liver antioxidant potential [98]. In another animal study, sage tea drinking increased carbon tetrachloride (CCl4) induced liver injury. Since CCl4 toxicity results from its bioactivation by CYP450, the expression level of this protein was measured and was found to be increased. The study concluded that sage tea did not have a toxic effect on its own, however, herb-drug interactions are possible and may affect the efficacy and safety if used with drugs that are metabolized by Phase I enzymes [99]. However, a more recent study, rosmarinic acid extract from S. officinalis was shown to be effective in suppressing lipid oxidation [100].
Camelia sinensis
Green tea is made from Camelia sinensis (L. Kuntze) leaves that has not undergone the same withering oxidation applied when processing sinensis into oolong or black tea [101]. The plant grows in China, India, Sri Lanka, Japan, Indonesia, Turkey and Pakistan. Green tea is well known to contain many biologically active compounds of which catechins (epigallocatechin, epigallocatechin gallate, epicatechin, epicatechin gallate) constitute the bulk of the flavonoids [102]. Studies hypercholesterolemic rats have shown that an 8 week period of green tea ethanolic extract intake was effective in reducing TC, LDL cholesterol, and TG by 15.4%, 21.5%, and 12.9% respectively [102]. Recently, it has been shown that supplementation of rat drinks with catechins and epigallocatechin gallate (1.1 mg/ ml) for 56 days was effective against hypercholesterolemia, obesity and hyperglycemia [103]. Several studies investigated the role of epigallocatechin gallate, the major catechin in green tea, in dyslipidemia. Epigallocatechin gallate was found to lower TC, LDL cholesterol and TG [104]. When it is given for 60 days at a dose of 50 mg/kg to high fat fed rats it resulted in a decrease in adipose tissue TG [105]. Drinking epigallocatechin gallate also decreased both TC and LDL-C [103].
The effect of 500 mg/kg of green tea extract given to obese rats for 5 days a week for 12 weeks was also investigated. The obese treated rats showed a significant decrease in hyperlipidemia, fat synthesis, body weight, and fat deposition compared to the control group. AMPK was also induced in adipose tissue in treated animals. The study concluded that the metabolic changes in the green tea treated group are caused by the induced AMPK activation and amelioration of white adipose tissue dysfunction caused by obesity [106]. Recently, epigallocatechin gallate present in green tea was found to be a potent inhibitor of human 11 beta-hydroxysteroid dehydrogenase, a microsomal enzyme that catalyses the conversion of glucocorticoid receptor, and therefore has potential for treatment of various metabolic disorders including dyslipidemia [107].
Portulaca oleracea
Portulaca oleracea L., also known as pigweed, common purslane, and moss rose, is an annual succulent in the family Portulacaceae. It is common in Europe, Middle East, Asia, and Mexico and maybe eaten as a leaf vegetable with a salty and sour taste [108]. The World Health Organization indicated purslane as one of the most widely used medicinal plant [109]. The therapeutic value is related to the presence of many biologically active compounds including flavonoids, alkaloids, coumarins and high content of omega-3 fatty acids with considerable benefits in heart health and immune system [109]. Assessed of lipid profiles before and after 45 days of taking 50- 60 grams of purslane leaves or Lovastatin 20mg daily showed that the serum levels of TC, LDL cholesterol, and TG decreased significantly in both study groups. However purslane had a more significant decrease in serum TG when compared to Lovastatin [110]. It was also shown that the intake of 1 gram of P. oleracea seeds for 1 month may decrease levels of TC, LDL cholesterol and TG in dyslipidemic adolescents. This positive effect on serum lipid profile was attributed to the polyphenolic and antioxidant compounds [111]. Similar reductions in TG and TC was observed of P. oleracea in rats fed cholesterol enriched diet and found [112].
Basella alba
Basella alba L. is an edible vine in the family Basellaceae. It is found in tropical Asia and Africa where it is widely used as a leaf vegetable. It is known as vine spinach, red vine spinach among other names. Basella alba has been used for its health benefits since ancient times because of its analgesic, antifungal, and antinuclear activities [113]. It is also used in treating ulcers, hypertension, anemia, digestive disorders, and cancer [113]. In vitro studies revealed that B. alba leaf methanolic extract is capable of significantly (74%) inhibiting HMGCoA reductase activity which is important for cholesterol synthesis in the liver. The mechanism by which it acts remains unknown and in vivo studies are needed to investigate its role in the management of dyslipidemia [114].
Recent studies conducted on rabbits with induced hypercholesterolemia showed that treatment with B. alba methanolic extract significantly reduced the levels of TC, LDL-C and TG, and increased HDL-C and antioxidant enzymes (SOD and GPx) levels. Unlike B. alba treated group, liver enzymes (AST and ALT) and creatine kinase were elevated in hypercholesterolemic and statin-treated groups indicating liver and muscle injuries. In addition, B. alba extract suppressed significantly aortic plaque formation and reduced the intima:media ratio similar to the simvastatin-treated group. This is the first in vivo study on B. alba that suggests its potential as an alternative therapeutic agent for hypercholesterolemia and atherosclerosis [115].
Fermentum Rubrum
Fermentum Rubrum, commonly known as red yeast rice (RYR), is a fermented product of red yeast Monascus purpureus on rice [116]. RYR and lifestyle modifications were shown to decrease LDL cholesterol without increasing creatine phosphokinase (CPK) or pain levels, thus making it a valuable alternative treatment for those patients with hypercholesterolemia that cannot tolerate statin therapy. In the same study, the supplemented dose of RYR was found to contain a naturally-occurring lovastatin (monacolin) with an equivalent daily dose of 6 mg. Since such a small dose cannot be solely behind the observed decrease in LDL cholesterol, it was thought that other active ingredients, beside monacolin, may be found in RYR [117]. This supports previous reports noting that RYR contains various compounds that may be contributing to the hypolipidemic effect including isoflavanoids, sterols and monounsaturated fats (pat). In another study, RYR along with lifestyle modification and fish oil intake were proven to be as good as simvastatin taken for 12 weeks when levels of LDL were monitored [118]. In a Chinese Meta-analysis study, the beneficial effect of RYR on blood lipid profile was also shown. Briefly, a daily capsule of 1-2 grams of RYR significantly lowered TC, LDL cholesterol, and TG by 10-44%, 7-25%, and 7-44% respectively [116]. In a randomized, double blind, placebo-controlled study the effect of 600 mg dose of RYR given twice daily was investigated in 79 hyperlipidemic patients for 8 weeks. Data showed significant decreases in TC, TG, LDL cholesterol, and Apo B by 21.5%, 15.8%, 27.7% and 26% respectively. However, no significant changes in HDL cholesterol and Apo A-I were noted. In addition, RYR was well tolerated [119]. RYR was also compared to fluvastin when given to patients with dyslipidemia secondary to nephrotic syndrome. 72 patients were assigned randomly into three groups. First group included 20 subjects that received RYR dose of 600 mg, twice a day for a month, then 600 mg once for 1 month. The second group (30 subjects) received 20 mg fluvastin daily. The third group was the control group with no therapy given. Results showed that cholesterol and proteinuria were significantly decreased from baseline at 3, 6 months and 1 year in both treated groups with no clinical evidence of neuropathy or myopathy. No change was noted in the control group [120].
Even though RYR is a natural supplement, some side effects were noted in some studies. In fact, two studies reported myopathy as an adverse effect [121,122]. In a case study, acute hepatitis was reported in a patient who took over-the-counter lipid-lowering product that contained red yeast rice. In the same patient, the liver function tests returned to normal after the supplement was discontinued [123,124]. The FDA warned in 2007 about the use of use of some RYR products sold on the internet because of the possible side effects of myopathy causing secondary renal impairment [125]. The lack of uniformity in the preparation of red yeast rice should be therefore considered by patients and physicians before taking this supplement.
Tree Nuts
Nuts are high in their fat content, despite that fact, the FDA allow a CHD risk reduction claim for nuts and nut products that contain 1.5 oz (about 42 nuts) [126]. The FDA relied on the data from cohort studies about the effectiveness of nuts in lowering cholesterol [127,128] as well as their effect in reducing CHD noted in two cohort studies [129,130]. The decreased concern about the fat content of nuts is due to the fact that nuts contain monounsaturated fatty acids (MUF) and polyunsaturated fatty acids (PUF). In fact, the AHA [131] and National Cholesterol Education Program Adult Treatment Panel III [131] liberalized the guidelines of intake of MUF. Nuts are also rich in antioxidants and have well demonstrated cardio protective properties [132-136].
Prunus dulcis (Mill.), the almond tree, produces almond nut. Almonds are considered rich in phenolic compounds that are mainly concentrated in the almond skin [89] These compounds have been correlated to the antioxidant protection against LDL-C oxidation in vitro and in vivo [127,137,138]. The antioxidant activity of almonds was demonstrated by their effects on two biomarkers of lipid peroxidation, serum MDA (malondialdehyde) and urinary isoprostanes. In the same study almonds reduced the oxidation of LDL-C in addition to decreasing TC, which contributes to the cardio protective mechanism [139]. The intake of 10 g/day of almonds before breakfast was also shown to cause a significant increase in HDL-C at 6 weeks (12-14%) and 12 weeks (14-16%) [140]. In addition, there was a significant decrease in serum TC, TG, LDL-C, VLDL-C, TC/HDL-C and LDL-C/HDL-C.
Semecarpus anacardium L.f., native to India and commonly known as Ballataka or Bhilwa, is a nut tree that is closely related to cashews. Jaya et al. investigated the hypolipidemic effects of S. anacardium given at 300 mg/kg for 21 days in male diabetic rats. This study revealed that the level of TC, LDL-C, VLDL, TG, and free fatty acids were all decreased in comparison with the control group. It was also found that HDL-C was increased in the treatment group. Therefore, this study noted a hypolipidemic effect of S. anacardium in male diabetic rats [141].
Pistacia vera L., also known as pistachio, is a member of the cashew family and with an origin in Central Asia and the Middle East. The effect of pistachio nut consumption on lipemia in healthy men and women was previously investigated. Data have shown that a 3 week period of pistachio nut consumption can result in a significant improvement in total TC and HDL-C as well as in oxidative stress in healthy man and women when compared with the control group [142].
Pinus eldarica (Medw.) is an Afghan pine tree from the family Pinaceae. The nuts, resins, buds and needles have been used in the treatment of bronchial asthma and skin conditions [143,144]. Pine nut oil has several compounds with antioxidant properties among these compounds beta carophyllene, alpha pinene, and beta pinene [145]. High concentrations of polyphenols and fatty acids are found in P. eldarica [146]. Huseini et al. studied the effect of P. eldarica given at 100 mg/kg/day or 200 mg/kg/day to 40 male hypercholesterolemic rabbits. The results showed decreased fasting TC, LDL-C and aortic atherosclerotic involvement compared to the control group [145].
Juglans regia L. species is the Persian or English walnut tree that produces the commonly edible walnut. Early studies have shown that walnut supplementation can have an antiatherogenic property by beneficially altering lipid distribution among various lipoprotein subclasses even when the total plasma lipids are unchanged [147]. Studies on diabetic subjects revealed that although the consumption of a walnut-enriched diet significantly reduced serum TC and LDL-C from baseline, the improvement did not reach statistical significance compared with the consumption of an ad libitum diet without walnuts. Also, serum TG and HDL-C did not improve after consumption of a walnut-enriched diet [148]. Studies on healthy Caucasian men and postmenopausal women ≥ 50years old showed that the consumption of 43 g/day of walnuts for 8weeks significantly reduced non-HDL-C and Apo B, a finding that probably explain partly the relationship between regular walnut consumption and reduced CHD risk [149]. More recent work has shown that acute and chronic walnut intake (42.5-85 grams per day) lowered TC, LDL-C, blood pressure and improved endothelial function, decreased oxidative stress and markers of inflammation, and increased cholesterol efflux which is important in removing cholesterol from peripheral tissue [150].
Sabaté et al. pooled data from 25 nut consumption studies conducted on normolipidemic and hypercholesterolemic men and women who were not taking lipid-lowering medications. Data analyses revealed that the effects of nut consumption on blood lipid levels were dose related, and more interestingly different types of nuts had similar effects. The lipid-lowering effect of nuts was found to be highest among subjects with high baseline LDL-C and with low BMI and among those consuming Western diets [151]. Recent well controlled meta-analysis study has shown that tree nut intake, regardless of type, can lower TC, LDL-C, Apo B, and TG. The doseresponse between nut intake and TC and LDL-C was nonlinear and a stronger effect was observed for doses ≥ 60 g nuts/day. The major determinant of the hypolidemic effect seems to be nut dose rather than nut type, knowing that for Apo B a stronger effect was observed in subjects with type 2 diabetes rather than in healthy subjects [152]. Similarly, a cross-sectional well designed survey conducted on 9660 randomly selected Iranian adults aged ≥ 19 years showed that frequent consumption of nuts (walnuts, almonds, pistachios and hazelnuts), particularly ≥ 4 times per week, may decrease the occurrence of dyslipidemia and have cardioprotective effects [153]. Also, frequent (≥ 1 time/day) seeds and nuts consumption in the same population, resulted an inverse association with all classes of obesity among women [154]. Along the same line, a cross-sectional study conducted on 7210 men and women (mean age, 67 y) recruited into the PREDIMED study revealed that there is an inverse association between nut consumption and the prevalence of general obesity, central obesity, metabolic syndromes, and diabetes in subjects at high cardiovascular risk [154].

Conclusion

Dyslipidemia is a major risk factor of cardiovascular disease, hence increasing morbidity and mortality around the world. Cost and side effects of medication therapy can be a hindrance and a rate limiting factor of patient’s compliance. The advantages of plant derived hypolipidemic agents include affordability, availability, namely in poor and underprivileged countries where the cost of traditional medicine can be prohibitive. The cost can vary in different countries, but it is the side effect of commonly used medicine [17,83,84] that has been a major negative factor in patient’s willingness to continue treatment. Plant-derived natural hypolipidemic agents become a good alternative in these patients who suffer from the side effects or cannot afford expensive therapy. In addition, the synergistic effects of these plant-derived agents when added with commonly used medicine or when used together, allow physicians to use them as an adjunct, and therefore, ensuring lesser side effects and better compliance [154]. The disadvantage of these plant-derived agents is the lack of large, multicenter, randomized, clinical trials to investigate efficacy and side effects. In addition, although side effects with these agents are rare, one needs to be aware of their interaction when used in combination with other products. In addition, broader trials studying combination therapy will further improve our understanding on supply, efficacy, and cost. Finally, more studies that further discuss the specific mechanism of action of these plants, would also improve understanding on potential side effects and interactions.

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