Accepted Manuscript

Medicinal plants in treatment of hypertriglyceridemia: A review based

on their mechanisms and effectiveness

Hamid Mollazadeh , Davood Mahdian , Hossein Hosseinzadeh

PII: S0944-7113(18)30305-2
DOI: https://doi.org/10.1016/j.phymed.2018.09.024
Reference: PHYMED 52620

To appear in: Phytomedicine

Received date: 24 March 2018

Revised date: 31 July 2018
Accepted date: 3 September 2018

Please cite this article as: Hamid Mollazadeh , Davood Mahdian , Hossein Hosseinzadeh , Medicinal
plants in treatment of hypertriglyceridemia: A review based on their mechanisms and effectiveness ,
Phytomedicine (2018), doi: https://doi.org/10.1016/j.phymed.2018.09.024

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 ACCEPTED MANUSCRIPT

Medicinal plants in treatment of hypertriglyceridemia:

A review based on their mechanisms and effectiveness

Hamid Mollazadeh a,b, Davood Mahdian c and Hossein Hosseinzadeh e,d*

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a
Department of Physiology and Pharmacology, School of Medicine, North Khorasan University
of Medical Sciences, Bojnurd, Iran.

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b
Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical
Sciences, Bojnurd, Iran

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c
Department of Pharmacology, School of Medicine, Sabzevar University of Medical Sciences,
Sabzevar, Iran
d
Department of Pharmacodynamic and Toxicology, School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran
e

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Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of
Medical Sciences, Mashhad, Iran.
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*
Corresponding author: Hossein Hosseinzadeh, Pharmaceutical Research Center,
Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Tel.: +985138819042, Fax: +985138823251, E-mail address: hosseinzadehh@mums.ac.ir
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Table of contents
Abstract
Introduction
 Pathophysiology
 Clinical Presentations
 Treatment Approaches

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Purposes and methodology

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Plants
 Allium sativum (Garlic)

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 Fagopyrum esculentum (Buckwheat)
 Crocus sativus
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Nigella sativa
Curcuma longa (Curcumin) US
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Cinnamomum verum (Cinnamon)
 Plant sterols and stanols
 Aloe vera
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 Anethum graveolens (Dill)

 Apium graveolens
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 Commiphora mukul (Guggul)

 Plantago ovata (Psyllium)
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 Red Yeast Rice

 Camellia sinensis (green tea)
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 Beta vulgaris
 Glycine max (Soy)

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Andrographis paniculata
 Berberis aristata and Berberis vulgaris
 Silybum marianum (Silymarin)
 Arachis hypogaea (Peanut)
 Asparagus officinalis
 Other plants
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Toxicity
Conclusion
Declaration of Conflicting Interests

References

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Abstract

Background: Hypertriglyceridemia (HTg) defines as high amounts of triglyceride (TG) in the

blood which can lead to serious complications over time. HTg is usually a part of metabolic
disorders such as diabetes mellitus, metabolic syndrome, and dyslipidemia. Different

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medications have been used to treat HTg but experimentally, many herbs have been

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recommended for treating HTg as an adjuvant therapy. In most cases, the recommendations are
based on animal studies and limited evidences exist about their mechanisms and clinical

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usefulness.
Purpose: This review focused on the herbs which have been shown TG lowering effect.
Method: The search was done in PubMed, Science Direct, Scopus, Web of Science and Google

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Scholar databases with keywords search of medicinal plant, plant extract, hypertriglyceridemia,
dyslipidemia, hyperlipidemia, lipoprotein lipase and apolipoprotein. Results: According to the
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results, which have been yielded in a 20-years period of 1997 to 2017, many plants showed
positive effects but Allium sativum, Nigella sativa, Curcuma longa, Anethum graveolens and
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Commiphora mukul had the best TG lowering effect with exact mechanisms of action than other
plants.
Conclusion: It seems that use of these plants as complementary therapeutics or extraction of their
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active ingredients along with currently available drugs will improve the management of HTg in
patients.
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Key words: Medicinal plants, Phytochemical, Hypertriglyceridemia, Mechanism, Metabolic

syndrome
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Abbreviations
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AMPK, adenosine monophosphate-activated protein kinase; BBE, Buckwheat bran extract CAD,
coronary artery diseases; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease;
EGCG, epigallocatechin gallate; FAS, fatty acid synthase; G6PD, glucose-6 phosphate
dehydrogenase; HDL, high density lipoprotein; HMGCoA, 3-hydroxy-3-methylglutaryl
coenzyme A; HTg, hypertriglyceridemia; ICAM-1, intercellular adhesion molecule 1; LDL, low
density lipoprotein; LDLR, LDL receptor; LPL, lipoprotein lipase; LXRα , liver X receptor
alpha; MTP, microsomal transfer protein; NCEP ATP III, National Cholesterol Education
Program Adult Treatment Panel; PPAR, peroxisome proliferator-activated receptors; PSA, plant
stanols esters; PSE, plant sterols esters; SAC, S-allyl cysteine; SEC, S-ethyl cysteine; SPC, S-
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propyl cysteine; SREBP-1, sterol regulatory element-binding transcription factor 1; TG,

triglyceride; VCAM-1, vascular cell adhesion molecule 1; VLDL, very low density lipoprotein;

Introduction
High amounts of triglyceride (TG) in the blood above a threshold value are defined as
hypertriglyceridemia (HTg). Based on National Cholesterol Education Program Adult Treatment
Panel (NCEP ATP III) guidelines, plasma TG level above than 150 mg/dL known as HTg. In this

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classification, people with plasma TG level between 151-199 mg/dL are considered at borderline

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stage (Table 1) (Pejic and Lee 2006). In another HTg classification performed by The Endocrine
Society, HTg defines as four steps that mentioned in Table 2 (Berglund, Brunzell et al. 2012).

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HTg prevalence was in relation to sex (men are at greater risk than women), smoking, high fat
diet, hypothyroidism, lack of mobility, diabetes and BMI (body mass index) greater than 25

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kg/m2 (Pejic and Lee 2006). One of the most life-threatening adverse effects of HTg is acute
pancreatitis and HTg is the main cause of 2-7% of acute pancreatitis. Also, patients with HTg are
squired with another lipid abnormalities including hypercholesterolemia and metabolic syndrome
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and these are risk factors for coronary artery disease (Pejic and Lee 2006; Aguilar-Salinas,
Tusie-Luna et al. 2014).
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Pathophysiology
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Genetic defects in TG metabolism lead to primary HTg, clinical disorders and excessive TG due
to environmental factors. On the contrary, when one or more factors including poor diet, alcohol
use, obesity, metabolic syndrome, and type 2 diabetes are reasons for inducing HTg, this sever
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type of HTg is called secondary HTg. Systemic circulating form of TG, in the bloodstream called
chylomicron. After TG picking up by adipose and muscle tissue, remnant chylomicrons have
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entered the liver and converted to very low density lipoprotein (VLDL). VLDL is acerbated with
TG. Then TG content of VLDL decreased and LDL is formed. This lipoprotein has large
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quantities of cholesterol and TG and considered as the main risk factor for arthrosclerosis.
Apolipoproteins are essential factors for lipid metabolism, their transfer, and action, thus any
defect in these proteins and another parts of lipid system tend to the creation of many
dyslipidemic disorders (Walden and Hegele 1994; Yuan, Al-Shali et al. 2007). Table 3
summarizes the primary dyslipidemias and it is notable that HTg is a clinical feature of each of
these dyslipidemias except Fredrickson type IIa (familial hypercholesterolemia). Patterns of
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lipoprotein fractions are the basis of Fredrickson or WHO ICD (World Health Organization
International Classification of Diseases) phenotypes classification (Hegele, Ban et al. 2009).

Clinical Presentations
Most often, HTg is usually asymptomatic and non-detectable until lipid profile is studied. TG
serum level above 500 mg/dl (and with higher danger above 1000 mg/dl) is a risk factor for acute

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pancreatitis. Xanthomas (skin lesions that were seen in many types of the clinical features),

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hepatomegaly, splenomegaly and lipemia retinalis are another clinical presentations of HTg
(Yuan, Al-Shali et al. 2007; Martínez, Díaz et al. 2008). Seldom, corneal arcus (an opaque color

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around the cornea) have been seen. Gastrointestinal upset, pain in chest or back with pancreatitis
are the main clinical presentations in chylomicronemia (as a lipoprotein contains high level of

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TG). Memory loss, dementia, and depression were seen in this situation. These clinical
presentations were seen at TG level above than 2000 mg/dl (Leaf 2008; Vipperla, Somerville et
al. 2017).
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Treatment Approaches
Pancreatitis and cardiovascular disease are two major HTg consequences. The relation between
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TG level and risk of coronary artery diseases (CAD) is not completely specified. It is a positive
relation between HTg and the risk of coronary heart disease (CHD) development especially in
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the presence of CHD risk factors (low serum HDL, high serum LDL, diabetes mellitus, obesity,
and smoking) (Austin, McKnight et al. 2000). Inasmuch as HTg is in parallel with
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hyperchlostrolemia, serum LDL level is a predictor of CAD and myocardial infarction, the
importance of treatment has been able to understand. The incidence of HTg is in combination
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with low serum level of HDL and increasing serum HDL level is necessary to decrease coronary
events. Even thought, HTg in combination with other CAD and CHD risk factors including
hypertension, hypercholesterolemia, low HDL and hypertension and HTg alone is a potent risk
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factor for CHD (Nordestgaard and Varbo 2014).

First step in the treatment of HTg is therapeutic lifestyle changes including treatment of obesity,
quite smoking, stop alcohol intake, physical activity including and dietary limitation of fat
specially saturated fat and carbohydrates and simple sugars (Pejic and Lee 2006). Serum TG
higher than 200 mg/dL needs to take medications. Briefly, HTg treatment needs fibrates and fish
oil as two primary medications for use separately or together. In accompaniment of HTg with
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hypercholesterolemia, statins (as 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase

inhibitors should be added to the drugs regimen with taking into account the exact complications
of drugs interaction especially myopathy. In cases with low HDL niacin can be added to the
treatment (Maki, Bays et al. 2012).

Purposes and methodology

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Nowadays, in addition to the different chemical drug classes, medicinal plants and herbal

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products have an important role in the prevention and treatment of diseases especially
dyslipidemia. More safety and popularity, being easy to earn and fewer side effects of herbal

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drugs are the main characteristics of their high consumption in medical science (Mollazadeh and
Hosseinzadeh 2016).

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The aim of this study was to evaluate and investigate the important medicinal plants with
lowering TG effects. We tried to show their mechanisms, types of extract and the protocol of use
in cellular, animal and clinical studies. For this purpose, we inquired various databases such as
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PubMed, Science Direct, Scopus, Web of Science and Google Scholar with keywords search of
medicinal plant, plant extract, hypertriglyceridemia, dyslipidemia, hyperlipidemia, lipoprotein
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lipase, apolipoprotein, etc. In this review, the best articles were selected and indicated the
lowering effects of plants on the hypertriglyceridemic condition in a 20-year period of 1997 to
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2017. Attempts have been done to make the best knowledge of their mechanisms and effects.

Plants
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Allium sativum (Garlic)

Garlic (Allium sativum, family Alliaceae) has a history of use for high TG, cholesterol and
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atherosclerosis prevention. Garlic can increase the risk of bleeding and is not for people on
blood-thinning medications on plasma lipoproteins and postprandial lipemia (Putri, Mangisah et
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al. 2017). In a study performed by Thompson et al. raw and boiled aqueous extracts of garlic
(500 mg/kg for 4 weeks) in normal rats significantly reduced plasma TG in treated animals by
either orally or intraperitoneally (i.p.) methods in a dose-dependently manner compared to
control animals. But the results of oral rout were more significant than i.p. method. TG lowering
effect of boiled extract was significantly lower than raw extract and it can be a reason of
destroying the active, volatile, and chemically unstable ingredient(s) in this extract (Thomson,
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Al-Qattan et al. 2006). This effect of garlic mediated via the inhibition of fatty acid synthase
(FAS) by active garlic components. S-ethyl cysteine (SEC), γ-glutamyl-S-methyl cysteine, allyl
cysteine, diallyl-disulfide, S-allyl cysteine (SAC) and S-propyl cysteine (SPC) are water-soluble
organosulfur compounds of garlic with potent inhibitory effect on FAS and mono oxygenase
activity. These compounds decrease [2-14C] acetate incorporation into fatty acid synthesis and
finally TG synthesis. This main mechanism of garlic was introduced for the first time by Lio and

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Yeh in cultured rat hepatocytes (Liu and Yeh 2001). Another TG lowering mechanism of garlic

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is its microsomal TG transfer protein (MTP) inhibition potency. MTP has an important role in
apoB-containing lipoproteins assembly and secretion by transferring TG to newly synthesized

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apoB. Also, MTP increases the synthesis of VLDL in the liver and chylomicrons in the intestine.
Many in vitro and in vivo studies had shown that reduced MTP activity and expression was

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accompanied with a decrease in the secretion rate of apoB-containing lipoprotein (van
Greevenbroek, Robertus-Teunissen et al. 1998; Wetterau, Gregg et al. 1998). MTP inhibitors e.g.
lomotapide uses in the treatment of many dyslipidemia such as familial hypercholesterolemia
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and HTg. In Lin study, fresh garlic extract inhibited MTP activity in the intestine but liver MTP
activity didn’t affect. A possible reason was the inactivation of active components of extract in
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the liver. In this study, fresh garlic extract reduced expression of intestinal MTP mRNA in rats
and MTP mRNA in HepG2 and Caco-2 cells (Lin, Wang et al. 2002). The results of Rajasree et
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al study showed that garlic with a dose of 1-4% in the diet of rats significantly reduced serum TG
level (Rajasree, Rajamohan et al. 1999). Lowering TG effect of garlic extract and its active
constituents was shown in many animal studies (Ali, Al-Qattan et al. 2000; Hassan 2012).
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Human studies about lowering TG effect of garlic was first performed at 1975 (Hosseini and
Hosseinzadeh 2015) and many studies from 1975 to date were done and this effect was
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confirmed today. Garlic has a potent lipid lowering effect by inhibition of many enzymes
mediating in cholesterol and TG synthetize including glucose-6 phosphate dehydrogenase
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(G6PD) and FAS. (Williams, Sutherland et al. 2005; Sobenin, Pryanishnikov et al. 2010; Ashraf,
Khan et al. 2011).

Fagopyrum esculentum (Buckwheat)

Buckwheat (family Polygonaceae), known as common buckwheat or Japanese buckwheat, is an
Asian plant with potent antihypertensive (Li, Matsui et al. 2002), antidiabetic (Kawa, Taylor et
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al. 2003), and antiobesity (Son, Kim et al. 2008) properties. TG lowering effect of Buckwheat
bran extract (BBE) was shown by Tomotake et al. BBE is able to increase the intestinal
elimination of bile acid and acid sterol (Tomotake, Yamamoto et al. 2006). Also, similar results
were shown in Wang study (Wang, Liu et al. 2009). BBE treated to diabetic mice with a dose of
1 mg per 20 g of mice body weight for 6 weeks. The results showed that serum TG and fatty
liver was significantly reduced in treated mice compared to control group. Also, mRNA gene

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expression of lipogenic enzymes (FAS, Acetyl CoA oxidase and Stearyl CoA Desaturase 1) was

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significantly reduced. In this study, BBE reduced sterol regulatory element-binding protein 1 and
carbohydrate responsive element binding protein, as two main transcription factors that have a

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role in lipogenesis gene expression. BBE didn’t influence the β-oxidation process (Hosaka,
Sasaga et al. 2014). Also, BBE decreased lipogenesis in hepatocytes. Glucose lowering effect of

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Buckwheat is related to its reducing TG effect which excess glucose converted to Acetyl-CoA.
Acetyl-CoA is a primary substance for TG synthetize (Postic, Dentin et al. 2004). Also, glucose
activates lipogenesis genes such as Acetyl-CoA Carboxylase and FAS and glucose lowering
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effect is another mechanism of BBE to reduce TG level (Andreolas, da Silva Xavier et al. 2002).
BBE is a potent antioxidant plant and it has a role in attenuation fatty liver and serum TG by
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decreasing oxidative stress and inflammation in the liver (Hijona, Hijona et al. 2010).
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Crocus sativus
Crocus sativus L., (family Iridaceae), is extensively used in traditional medicine in Iran and
many countries. Saffron, the dried stigma of C. sativus consists of crocin, crocetin, and safranal
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which are responsible for its many pharmacological activities such as antihyperlipidemic
activity. It was shown that the major TG lowering mechanisms of saffron enumerated as its
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antioxidant potency, peroxisome proliferator-activated receptors α (PPARα) activation and

increasing adiponectin serum level that secreted from adipose tissue and have roles in lipid
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metabolism especially TG (Razavi and Hosseinzadeh 2017). Active constituents of saffron

(crocin) modulates serum TG. Crocin with dose of 80 mg/kg after 12 weeks in rats received high
fat diet significantly reduced serum TG compared to control group (Mashmoul, Azlan et al.
2014). In streptozocin- induced diabetic rats, saffron with dose of 40 and 80 mg/kg significantly
has decreased serum TG after 4 weeks of treatment (Kermani, Mousavi et al. 2015).

Nigella sativa
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Nigella sativa L., (family Ranunculaceae), is used thousands of years for its various
pharmacological properties especially its beneficial effect in dyslipidemia. The most active
ingredient of N. sativa is thymoquinone (TQ, 30-48% in the black seeds and responsible for most
plant effects). N. sativa is a potent inhibitor of hepatic HMG-CoA reductase. It increases
arylesterase activity and has regulatory effects on genes that influence cholesterol metabolism. N.
sativa is a plant with antioxidant effect that influences its effects on lipid profile (Mollazadeh

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and Hosseinzadeh 2014; Razavi and Hosseinzadeh 2014; Amin and Hosseinzadeh 2016).

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Petroleum ether extract of N. sativa seeds is a potent extract for its TG lowering effect (Paarakh
2010).

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TQ with a dose of 10 mg/ml for 30 days reduced serum TG level in atherogenic suspension fed
rats (Ahmad and Beg 2013). In a similar study, N. sativa oil with a dose of 800 mg/kg orally for

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4 weeks caused a significant decrease in serum TG level in rats (El-Dakhakhny, Mady et al.
2000). N. sativa has a protective effect against metabolic syndrome. In a study performed by
Ibrahim et al. it was shown that use of N. sativa seeds powder (1 g/day) for 2 months in 30
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menopausal women had significant effects on metabolic syndrome parameters like serum TG
level (Ibrahim, Hamdan et al. 2014). In a similar study, N. sativa seeds powder (500 mg/day) for
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a period of 6 weeks significantly reduced serum TG in patients with metabolic syndrome (Shah,
Khan et al. 2012).
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Curcuma longa (Curcumin)

Curcuma longa L. (family Zingiberaceae), known as curcumin, extracted from the spice turmeric
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have been used in traditional and Ayurvedic medicine for centuries as immunomodulatore
(Mollazadeh, Cicero et al. 2017), hepatoprotective (Momtazi, Shahabipour et al. 2016),
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antitumor (Iranshahi, Sahebkar et al. 2010), antioxidant (Sahebkar 2013), anti-inflammatory

(Panahi, Sahebkar et al. 2012) and etc. Curcumin is an antiatherogenic agent by its potent
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cholesterol and TG lowering effect (Olszanecki, Jawień et al. 2005). Lowering TG effect of
curcumin was shown by DiSilvestro et al. in healthy subjects that consumed a low dose of
curcumin (80 mg/day) in a lipidated form for 4 weeks. After that, plasma level of TG was
significantly lower than before treatment (DiSilvestro, Joseph et al. 2012). Turmeric is a potent
inhibitor of LDL oxidation (Ramırez-Tortosa, Mesa et al. 1999) and hypolipidemic effect of it
was shown in diabetic rats, besides that, turmeric increased serum HDL level in animal studies
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(Babu and Srinivasan 1997; Arafa 2005). Curcumin is a potent inhibitor of intestinal cholesterol
absorption. So curcumin increases cholesterol-7á-hydroxylase activity that is the rate-limiting
enzyme in bile acid biosynthesis (Alwi, Santoso et al. 2008).
It was shown that short period of treatment with curcumin did not show any positive effect on
TG level (Asai and Miyazawa 2001). The most beneficial effect of curcumin is on TG liver
content than TG plasma level (Asai, Nakagawa et al. 1999).

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In an 18 weeks- period study performed on LDLR-/- mice with a diet of high-cholesterol,

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curcumin (0.02%w/w) suppressed hepatic TG accumulation by upregulation of PPARα
expression that is very important in fatty acid oxidation genes activation. The results of the study

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showed that curcumin increased liver X receptor alpha (LXRα) transcription in liver. LXRα
regulates cholesterol-7a-hydroxylase (a main enzyme in converting cholesterol to bile acid).

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LXRα also activates ATP-binding cassette, sub- family A1 (ABCA1) expression, which
mediates reverse cholesterol transport from peripheral tissues back to the liver for removal.
Increased LXRα activity was associated with suppressed hepatic TG accumulation (Shin, Ha et
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al. 2011). In another study, curcumin (0.05-g/100-g diet for 10 weeks) reduced plasma and
hepatic TG level in hamster fed with high fat diet regimen. Curcumin reduced hepatic FAS
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activity with an increase in hepatic fatty acid β-oxidation activity. Also, curcumin decreased
plasma level of leptin that has the main role in hepatic TG secretion, reduction in hepatic fatty
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acid oxidation and ketogenesis. Curcumin attenuated the leptin resistance and its level (Jang,
Choi et al. 2008). Curcumin shows hypolipidemic effects with various mechanisms (e.g.
HMGCoA reductase inhibition, amelioration of intercellular adhesion molecule 1 (ICAM-1) and
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vascular cell adhesion molecule 1 (VCAM-1) localization, increase Apo B levels and cholesteryl
ester transfer protein (CETP) activity, increase liver Apo A-I expression, decrease in HMGCo A
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reductase, and acyl coenzyme A: cholesterol acyltransferase and paraoxonase activity) but the
above mention mechanisms are related to its TG lowering effect (Jang, Choi et al. 2008; Shin,
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Ha et al. 2011).

Cinnamomum verum (Cinnamon)

Cinnamomum verum (formerly C. zeylanicum, family Lauraceae), is a medicinal plant with
various pharmacological characteristics (Mollazadeh and Hosseinzadeh 2016). Cinnamon shows
its TG lowering effect by inhibiting both hepatic HMG Co-A reductase and 5-lipoxygenase
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enzymes and enhancement of lipolytic action and hepatic antioxidant enzyme activity (Lee, Jeon
et al. 2003). In Khan et al study, cinnamon with doses of 1, 3, and 6 g per day caused a reduction
in TG in patients with metabolic syndrome after 40 days of treatment (Khan, Safdar et al. 2003).
In streptozotocin-induced diabetic rats fed with 5% cinnamon for 8 weeks, serum TG was
significantly decreased compared to control group (Shatwan, Ahmed et al. 2013).

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Plant sterols and stanols

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Plant sterols esters (PSE) and their saturated forms, plant stanols esters (PSA), are similar in their
chemical structures with cholesterol and absorb from intestinal tract instead of cholesterol. They

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have hypolipidemic activity and many clinical studies have confirmed this effect (Naumann, Plat
et al. 2008; Demonty, Ras et al. 2013). The lowering TG effect of PSA and PSE are related to

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some mechanisms including increased lipoprotein lipase (LPL) activity, changes in cholesteryl
ester transfer protein activity and some related regulatory genes (such as PPARα) as a
compensatory response (Plat, Brufau et al. 2009; Sialvera, Pounis et al. 2012). Reduced hepatic
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VLDL production or increased de novo lipogenesis, are the other mechanisms that showed by
Schonewille et al. In this study high fat diet-fed mice supplemented with 3.1% PSA or PSE for 3
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weeks showed less plasma TG level than control group. Results showed that HFD-fed mice had a
higher VLDL-TG production than treated mice with PSA or PSE. Increased liver mitochondrial
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β-oxidation by PSA or PSE was mediated by an increase in the gene expression of hepatic
Acacb(Acc2), Apoa4 and Cpt1a (Schonewille, Brufau et al. 2014).
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Aloe vera
Aloe vera (synonym: Aloe barbadensis Miller, family Liliaceal) is a plant with lipid lowering
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efficacy especially TG. It was shown that use of A. vera gel (1 ml dose daily for 45 days)
reduced plasma TG and LDL cholesterol level in rats with polycystic ovarian syndrome (PCOS)
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(Maharjan, Nagar et al. 2010, Surjushe, Vasani et al. 2008). Oral administration of processed A.
vera gel with doses of 25, 50, and 100 mg/kg for 8 weeks in a mouse model of non-insulin-
dependent diabetes mellitus significantly lowered TG levels in liver and plasma (Kim, Kim et al.
2009). One of the best studies about TG lowering effect of A. vera is the study performed by
Ageawal on five thousand patients with angina pectoris in a 5 year period of time. The lowering
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lipid profile (including serum TG level) was in relation with a reduction in the frequency of
anginal attacks (Agarwal 1985).
Anethum graveolens (Dill)

Anethum graveolens (family Apiaceae) has hypolipidemic effect. In Mirhoseini et al. study, dill
was able to significantly reduce serum TG level compared to control group after 2 months in 91
hyperlipidemic patients. This result is very similar to the effect of gemfibrozile (900 mg/day) as

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a potent drug for TG reducing purpose in this study (Mirhosseini, Baradaran et al. 2014). In a

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similar study water extract of A. graveolens leaves reduced serum TG level about 50% in
hyperlipidemic high fat diet rats after 14 days of study (Yazdanparast and Alavi 2001). α-

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phellandrene (32%), limonene (28%) and carvone (28%) are three major components of A.
graveolens essential oil with a potent TG lowering effect activity (Hajhashemi and Abbasi 2008).

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In a clinical study performed on 24 patients with metabolic syndrome, dill extract (600 mg/day)
treatment had a beneficial effect in reducing TG from baseline after 3 months (Mansouri, Nayebi
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et al. 2012). 300 mg/kg/day hydroalcoholic dill extract significantly reduced serum TG in
diabetic rats in Madani et al study (Madani, Ahmady Mahmoodabady et al. 2005). The effect of
dill on reducing serum cholesterol level than TG level is more obviously and based on its
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mechanisms as follow: a) the flavonoids content in A. graveolens that can modify LDL/HDL
ratio, b) increasing LDL receptors and uptake of LDL and inhibition acetyl-CoA carboxylase
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activity, c) reduction in cholesterol absorption from intestine and d) decreasing HMG-COA

reductase activity and suppression of cholesterol and fatty acids synthesis (Mobasseri, Payahoo
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et al. 2014).
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Apium graveolens
Apium graveolens (family Apiaceae) is another plant with lowering TG effect. Hypolipidemic
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effect of A. graveolens was mediated by various mechanisms including inhibition of hepatic

cholesterol biosynthesis, increasing fecal bile acid excretion, enhancing plasma lecithin:
cholesterol acyltransferase activity and reduction of lipid absorption in the intestine. 3n
butylphthalideor is a major constituent responsive to lipid lowering effect. The ethanolic extract
of A. graveolens with a dose of 213 and 425 mg/ kg for 60 days significantly reduced serum TG
compared to before treatment with extract in rats (Mansi, Abushoffa et al. 2009). TG lowering
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effect of A. graveolens has been shown in many studies (Tsi, Das et al. 1995; Ahmed and
Sayedda 2012).

Commiphora mukul (Guggul)

Guggul (family Burseraceae) is approved in India to treat lipid disorders, contains resin, volatile
oils, and gum. The extract isolates ketonic steroid compounds known as guggulsterones. These

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compounds have been shown to provide the cholesterol- and TG-lowering actions noted for

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guggul (Ghritlahare, Satapathy et al. 2017). TG lowering effect of guggul has been shown in
many studies (Chander, Khanna et al. 1996; Mehta, Balaraman et al. 2003).

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Ketonic steroid compounds, guggulsterone-Z, and guggulsterone-E responsible for its
hypolipidemic property. Guggulsterones in the body are easily reduced to guggulsterols which

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behave as powerful antioxidants that has its TG lowering effect. Also, they antagonize the bile
acid receptor, farnesoid X receptor (FXR), which is an important regulator of cholesterol
homeostasis (Urizar and Moore 2003). Several possible mechanisms have been proposed for the
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hypolipidemic activity of guggulsterone. Conversion of cholesterol to bile acids and subsequent
excretion through the enterohepatic circulation represent a major pathway to remove excessive
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cholesterol from the body (Deng 2007). Guggulsterone has the capability of inhibiting oxidative
modification of LDL. Guggul markedly inhibits liver cholesterol biosynthesis. Guggul increases
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fecal excretion of bile acids (cholic and deoxycholic acids) & cholesterol and lowers intestinal
absorption of fat and cholesterol. Guggul stimulates the LDL receptor binding activity in
hepatocytes and enhances its catabolism. It also inhibits oxidative modification of LDL due to its
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constituent gugglusterone. Guggul has been found to have the capacity to enhance production of
thyroxin (T4), triidothyronine (T3) (thermogenic activity), which also account for its lipid
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lowering activity. Thyroid hormones increase metabolism of carbohydrates, enhance protein

synthesis, and stimulate use and breakdown of lipids (Anurekha 2006). In a study performed by
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Khanna et al. C. mukul alcoholic extract administered to rabbits at a dose of 100 mg/kg/day for 6
weeks significantly reduced serum TG due to its enhancing antioxidant power like superoxide
dismutase and catalase activity (Khanna, Arora et al. 2010). Rats treated with guggulsterone at a
dose of 25 mg/kg body weight for ten days exhibited a 30% decrease in serum triglyceride levels
(Singh, Kaul et al. 1990). In a study of the crude gum guggul, 40 patients with serum TG
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levels>200 mg/dl) were administered a dose of 4.5 grams daily for 16 weeks. Serum TG level
was lowered by 27% (Verma and Bordia 1988).

Plantago ovata (Psyllium)

Plantago ovate routinely called psyllium (family Plantaginaceae) is a type of fiber. There is a lot
of supporting research on the positive effects of psyllium on high cholesterol, but psyllium may

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also lower TG. Psyllium is a very effective agent to maintain lipid profile parameters at normal

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limits in hyperlipidemic patients (Shah murad 2010).
Psyllium stimulates bile acid synthesis through 7α-hydroxylase activity. Another mode of action

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of psyllium fibers to reduce cholesterol is diversion of hepatic cholesterol synthesis to bile acid
production. Effect of psyllium on the absorption of cholesterol and fat appeared minimal but it is

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a small contribution to cholesterol lowering effect. Another mode of actions of psyllium to
reduce cholesterol synthesis is inhibition of hepatic cholesterol synthesis by propionate (Shah
murad 2010)
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The mechanism of action of psyllium's hypocholesterolemic effects has not been fully
elucidated. Psyllium was shown to stimulate bile acid synthesis (7 α-hydroxylase activity) in
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animal models and in humans. The diversion of hepatic cholesterol for bile acid production has
long been established as a mechanism for reducing serum cholesterol. Psyllium's effect on the
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absorption of cholesterol and fat appears minimal but may make a small contribution to
cholesterol lowering. Additional mechanisms, such as inhibition of hepatic cholesterol synthesis
by propionate and secondary effects of slowing glucose absorption, may also play a role
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(Anderson, Davidson et al. 2000).

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Red Yeast Rice

Peace Health says red yeast rice is primarily used to treat high cholesterol, but it also appears to
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lower TG significantly. Red yeast rice may work similarly to cholesterol-lowering drugs. RYR
appears to be a safe and effective lipid-lowering agent (Peng, Fong et al. 2017). The first
documentation of the biomolecular action of red yeast rice was published in 2002. The results
indicated one of the anti-hyperlipidemic actions of red yeast rice is a consequence of an
inhibitory effect on cholesterol biosynthesis in hepatic cells. The lipid lowering properties of red
yeast rice do appear to be multifactorial. One of the first and more obvious mechanisms to be
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supported is red yeast rice's ability to inhibit the activity of the rate limiting step of hepatic
cholesterol biosynthesis in a dose-dependent manner. This is due to its ability to inhibit the
activity of the enzyme, HMG CoA reductase (Man, Lynn et al. 2002).
In a meta-analysis study performed by Li et al., red yeast rice is an effective plant for TG
lowering purpose. In this study total of 13 randomized, placebo-controlled trials containing 804
participants were analyzed. It exhibited significant lowering effects on serum TG [WMD = −0.23

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(95% CI: −0.31, −0.14) mmol/L, P<0.001] (Li, Jiang et al. 2014).

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Camellia sinensis (green tea)

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Camellia sinensis (commonly known as green tea, family Theaceae) contains catechins as potent
ingredients with various pharmacological properties (Esmaeelpanah, Razavi et al. 2017;

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Rameshrad, Razavi et al. 2017). TG lowering effect of green tea is related to its effect on
inhibition of hepatic lipogenesis involving sterol regulatory element-binding transcription factor
1 (SREBP-1) and its responsive genes without affecting lipoprotein assembly (Shrestha, Ehlers
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et al. 2009). Catechins effectively lower the intestinal absorption of lipids. Among the catechins,
epigallocatechin gallate (EGCG) is the most potent inhibitor of lipid absorption. The potent
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inhibitory effect of EGCG appears to be associated with its ability to form complexes with lipids
and lipolytic enzymes, thereby interfering with the luminal processes of emulsification,
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hydrolysis, micellar solubilization, and subsequent uptake of lipids (Koo and Noh 2007).
Catechins inhibit the key enzymes involved in lipid biosynthesis and reduce intestinal lipid
absorption, thereby improving blood lipid profile. Catechins can up-regulate hepatic LDL
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receptor expression, thereby modulating biosynthesis, excretion and intracellular processing of

lipids (Babu, Pon et al. 2008). Also high polyphenolic content of green tea is responsive to its
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TG lowering effect (Snoussi, Ducroc et al. 2014).

Aqueous extract of green tea (250 mg/kg) after 4 weeks significantly reduced serum TG in
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alloxan-induced diabetic rats (Al-Lami 2015). Green tea aqueous extract (1% per weight in rats
fed with high sucrose diet after 25 days) significantly reduced liver TG content (Yang, Wang et
al. 2001). In similar study, Green tea aqueous extract (25, 50 and 100 mg/kg/day after 11 days
treatment period) significantly reduced serum TG in rats treated by olanzapine, an agent whcich
induced obesity and serious metabolic disturbances (Razavi, Lookian et al. 2017). Many other
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studies confirmed TG lowering effect of green tea (Miura, Chiba et al. 2001; Murase, Nagasawa
et al. 2002).

Beta vulgaris
Beta vulgaris (family Amaranthaceae) with high flavonoid and saponin content could reduce
serum TG. B. vulgaris (beet root extract) with doses of 250 and 500 mg/kg body weight reduced

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serum TG in hypercholesterolemic rats (Al-Dosari, Alqasoumi et al. 2011). In another study

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beneficial TG lowering effect of B. vulgaris was shown in diabetic rats (Khalili and Vaez

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Mahdavi 2010).

Glycine max (Soy)

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Glycine max commonly known as soybean (family Fabaceae), is rich in isoflavones, which are a
type of plant compound with numerous health benefits. This is especially true when it comes to
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lowering LDL cholesterol. Particularly, it has been shown in a study that soy protein reduced
blood TG levels (Taku, Umegaki et al. 2007). Consumption of relatively high levels of soy
protein decreased TG levels in hypercholesterolemic subjects, an effect which appears to be in
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part attributable to the suppression of TG and Fatty acid biosynthesis. In contrast to the effect of
soy protein on TG metabolism, soy protein moderately reduced TG and LDL-C levels in
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hypercholesterolemic subjects in a manner that is not due to a reduction in cholesterol

biosynthesis. Other mechanisms such as suppressed cholesterol absorption, increased cholesterol
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removal from the tissues, or increased cholesterol and bile acid excretion may be involved
(Wang, Jones et al. 2004).
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In a randomized double-blind, parallel study performed on 210 type 2 diabetic men that received
30g soy protein with 66mg of phytoestrogens or without it, serum TG significantly reduced after
12 weeks of treatment compared to control group (Sathyapalan, Kilpatrick et al. 2014). The first
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meta-analysis about the effects of soy protein intake on serum lipids performed by Anderson et
al. in the year of 1995. Results of this study (comprises of 38 studies) showed that the
consumption of soy protein is associated with significant decreases in serum TG concentrations
(Anderson, Johnstone et al. 1995).

Andrographis paniculata
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Andrographis paniculata (Family Acanthaceae) contains andrographolide, as a labdane

diterpenoid that has been isolated from the stem and leaves of A. paniculata. Andrographolide
has potent hypolipidemic effects and protects the cardiovascular system without significant liver
damage by lowering total cholesterol, TG, HDL, and LDL in mice and rats. The purified extract
of A. paniculata significantly decreased the levels of blood glucose, TG, and LDL. (Jayakumar,
Hsieh et al. 2013). In patients with modest HTg with lifestyle intervention, A. paniculata extract

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(APE) reduced the TG level comparable to the effect of gemfibrozil 300 mg/day. APE treatment

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was as tolerable as gemfibrozil treatment. Hence, A. paniculata might be used as an alternative
medicine in treating hypertriglyceridemic patients (Phunikhom, Khampitak et al. 2015).

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Berberis aristata and Berberis vulgaris

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Berberis aristata (family Berberidaceae), also known as Indian barberry with berberine as a
natural plant extract from bark, that reduces cholesterolemia by increasing LDL-Cholesterol
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receptor on the liver cell surface and inhibiting TG biosynthesis via the inhibition of proprotein
convertase subtilisin/kexin type 9 (PCSK9) and the activation of 5’AMP activated proteokinase
(Cicero and Colletti 2016). B. aristata at a dose of 25 mg/kg revealed a significant reduction in
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serum cholesterol, TG and LDL in high cholesterol diet regimen of rabbit after 45 days therapy
(Razzaq, Khan et al. 2011). B. aristata induces a significant reduction of total cholestrol, TG and
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LDL levels and a significant increase of HDL levels, without major adverse effects. It
significantly increases hepatic LDLRs expression (Pirillo and Catapano 2015).
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Cardiac fatty acid transport protein-1, fatty acid transport proteins, fatty acid beta-oxidase, as
well as PPARγ activities were increased by B. vulgaris effect. Increase in adenosine
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monophosphate-activated protein kinase (AMPK) phosphorylation and activity that inhibits

synthesis of fatty acids, cholesterol, and TG, and activates fatty acid uptake and β-oxidation. The
final results of this actions are attenuation of lipid profile and reduction in serum TG level
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(Imenshahidi and Hosseinzadeh 2016; Tabeshpour, Imenshahidi et al. 2017). In 32

hypercholesterolemic patients berberine, as active ingredient of B. vulgaris with dose of 0.5 g
twice per day after 3 months significantly reduced serum TG (35% compared to healthy group)
(Zhao, Xue et al. 2008). In a similar study berberine (0.5 g per day) after 6 months significantly
reduced serum TG in hypercholesterolemic patients (16.3% compared to healthy group) (Mazza,
Lenti et al. 2015).
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Silybum marianum (Silymarin)

Silybum marianum (commonly known as silymarin, family Asteraceae) composed of silibinin
(about 90%) together with small amounts of other silibinin stereoisomers. It has been shown that
silymarin and its polyphenolic fraction reduces cholesterol absorption and TG content in liver
tissue (Zhang, Hong et al. 2013). Silymarin partially antagonized the increase in the liver TG

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content induced by carbon tetrachloride exposure in rats, and also silymarin decreased VLDL

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synthesis (Vaughu, Gotto et al. 2006).

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Arachis hypogaea (Peanut)
Seeds of Arachis hypogaea (peanut, family Leguminosae), have hypolipidemic effects. Peanut
activates PPARα receptors up-regulation and their function. Also, peanut reduces mRNA

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expression of FAS and SREBP-1c. Peanut sprout extract decreases the expression of PPARγ,
adipogenic transcription factor, and the target gene, adiponectin and finally decreases weight
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gain and reduces body fat contents in adipose tissues. Above mechanisms are the main
hypolipidemic mechanisms for this plant especially its effect on serum TG due to its high
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polyphenoloic content (Bansode, Randolph et al. 2012; Kang, Ha et al. 2014).

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Asparagus officinalis

Hypolipidemic effect of Asparagus officinalis (family Asparagaceae) was shown in many

studies. In a study performed by Zhao et al. aqueous extract (100, 200 and 400 mg/kg) reduced
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fasting serum TG in diabetic rats after 21 days (Zhao, Zhang et al. 2011). Both of aqueous and
ethanolic extract of A. officinalis have this effect of the treatment of 200 mg/kg of both extracts
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for 8 weeks significantly reduced serum TG in mice fed a high-fat diet (Zhu, Zhang et al. 2010).
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Other plants

Above mentioned plants are the main ones with TG lowering properties. It must be noted that
there are more plants with this effect but we articulated the important plants in detail. The rest of
the plants are summarized in table 4. Table 5 shows three important reviwe articles aboute 3
plants with TG lowering effect.
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Toxicity

The dosage of plants extracts and main ingredients of them which have used in this review article
did not reveal any side effects during the course of the treatment in each original in vivo study.

Conclusion

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In this review, we aimed to present a summary of the main medicinal plants with TG lowering

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effect, their family and their active ingredients liable for this. Among hundreds of plants that
have been studied for this purpose, only a small fraction has been tested in animal studies and is

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under clinical trials. Their mechanisms in this area have been shown about most of them but the
exact mechanism(s) were not established entirely (Figure 1). These plants, particularly A.

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sativum, N.sativa, C. longa, A. graveolens and C. mukul had the best exact mechanisms of action
with the best TG lowering effect than other plants mentioned in this review. Therefore, it seems
that use of these plants as complementary therapeutics along with currently available drugs will
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improve the management of hypertrigelyceridemic patients.
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Declaration of Conflicting Interests

The authors declare not to have any conflicts of interest.

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Table legends
Table 1. Classification of TG levels based on NCEP ATP III.
Table 2. Classification of TG levels based on Endocrine Society.
Table 3. Hypertriglyceridemia classification (modified Fredrickson).
Table 4. Important plants with TG lowering effect.
Table 5. Three main review articles about plants with TG lowering effect.

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Figure 1 Medicinal plants in treatment of hypertriglyceridemia with their mechanism of actions

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Table 1.
Clinical Definition Plasma TG level
Normal <150 (mg/dL), (<1.7 mmol/L)
Border line 150-199 (mg/dL), (1.7–2.3 mmol/L)
High 200-499 (mg/dL), (2.3–5.6 mmol/L)
Very high >500 (mg/dL), (>5.6 mmol/L)

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Table 2.
Clinical Definition Plasma TG level (mg/dL)

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Normal <150 (mg/dL), (<1.7 mmol/L)
Mild 150-199 (mg/dL), (1.7–2.3 mmol/L)
Moderate 200–999 (mg/dL), (2.3–11.2 mmol/L)
Severe
Very Severe
US 1000–1999 (mg/dL), (11.2–22.4 mmol/L)
>2000 (mg/dL), (>22.4 mmol/L)
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Table 3.
Type Condition Manifestations TG status
I Primary Chylomicronemia Chylomicron and ↑↑
VLDL increased
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IIa Familial LDL increased --

Hypercholesterolemia
IIb Familial Combined VLDL and LDL ↑
Hyperlipidemia increased
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III Dysbetalipoproteinemia IDL increased ↑

IV Familial Chylomicron and ↑↑
Hypertriglyceridemia VLDL increased
↑↑
PT

V Familial Chylomicron remnant

Dysbetalipoproteinemia and VLDL remnant
increased
CE
AC
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Table 4. Important plants with TG lowering effect.

Plant Family Type of extract Reference

Bauhinia Fabaceae Aqueous Root Extract (Reddy, Reddy et al. 2003)
variegata
(Kumar 2016)
Fabaceae Methanolic Leaves
Bauhinia
variegata Extract

T
IP
Methanolic Stem and
(Balamurugan and
Root Barks Extract Muralidharan 2010)

CR
Bellis perennis Asteraceae Methanolic Extract and (Morikawa, Li et al. 2008)
Saponin Fraction of the
Flowers
Brassica rapa
Caesalpinia
crista
Brassicaceae
Fabaceae US
Ethanolic Root Extract
Aqueous Extract
(An, Han et al. 2010)
(Kumar and Kumar 2013)
AN

Calotropis Apocynaceae Aqueous and (VH and Ajay 2009)

M

procera Methanolic Root

Extract
ED

Aqueous Seed Extract (Saghir, Sadiq et al. 2012)

Carum carvi Apiaceae Aqueous Fruit Extract (Haidari, Seyed-Sadjadi et

PT

al. 2011)
Scutellaria Lamiaceae Aqueous Flower (Song, Lee et al. 2013)
CE

baicalensis Extract
Allium sativum Alliaceae Standardized Tablet (Superko and Krauss 2000)
AC

(300 mg/tab)
Curcuma Zingiberaceae Rhizome Powder (0.5, (Tariq, Imran et al. 2016)
Zedoaria Roscoe 1 and 1.5 g/day)
Argania Sapotaceae Methanolic Pericarp (Berrougui, Cherki et al.
Spinosa (argan
Extract 2007)
oil)
Glycine max Fabaceae Soy Seed (30 g/day) (Borodin, Menshikova et al.
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(Soybean) 2009)
Rheum Polygonaceae Decoction Rhizome (Mousa-Al-Reza
turkestanicum
Extract Hadjzadeh, Khodaei et al.
2017)
Hippophae Elaeagnaceae Ethanolic Seed Extract (Yang, Wang et al. 2017)
rhamnoides

T
Solanum Solanaceae Juice (200 ml/day) (Hirose, Terauchi et al.
lycopersicum

IP
2015)
(tomato)
Cornus mas Cornaceae Fruit (100 mg/kg/day) (Sozański, Kucharska et al.

CR
2014)
Portulaca oleracea Portulacaceae Aqueous Leaves (Zidan, Bouderbala et al.

US
Extract
2014)
AN
Camellia sinensis Theaceae Lyophilized Powder (Shrestha, Ehlers et al.
(Green tea) (0.5 and 1% of diet)
2009)
M
ED
PT
CE
AC
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Table 5.

Plant Family Reference

Garcinia mangostana Clusiaceae (Tousian, Razavi et al. 2017)
Persea Americana Lauraceae (Tabeshpour, Razavi et al.
(Avocado) 2017)

T
Rosmarinus officinalis Lamiaceae (Hassani, Shirani et al. 2016)

IP
(Rosemary)

CR
US
AN
M
ED
PT
CE
AC