Planta Med 2011; 77(8): 773-785
DOI: 10.1055/s-0030-1270924
Reviews
© Georg Thieme Verlag KG Stuttgart · New York

Natural Inhibitors of Pancreatic Lipase as New Players in Obesity Treatment

Ana Laura de la Garza1 , Fermín I. Milagro1 , Noemí Boque1 , Javier Campión1 , J. Alfredo Martínez1
  • 1Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Pamplona, Spain
Further Information

Prof. J. Alfredo Martinez

Department of Nutrition and Food Sciences, Physiology and Toxicology
University of Navarra

c/Irunlarrea 1

31008 Pamplona

Spain

Phone: +34 9 48 42 56 00

Fax: +34 9 48 42 56 49

Email: jalfmtz@unav.es

Publication History

received Dec. 7, 2010 revised February 11, 2011

accepted February 21, 2011

Publication Date:
16 March 2011 (eFirst)

Table of Contents #

Abstract

Obesity is a multifactorial disease characterized by an excessive weight for height due to an enlarged fat deposition such as adipose tissue, which is attributed to a higher calorie intake than the energy expenditure. The key strategy to combat obesity is to prevent chronic positive impairments in the energy equation. However, it is often difficult to maintain energy balance, because many available foods are high-energy yielding, which is usually accompanied by low levels of physical activity.

The pharmaceutical industry has invested many efforts in producing antiobesity drugs; but only a lipid digestion inhibitor obtained from an actinobacterium is currently approved and authorized in Europe for obesity treatment. This compound inhibits the activity of pancreatic lipase, which is one of the enzymes involved in fat digestion.

In a similar way, hundreds of extracts are currently being isolated from plants, fungi, algae, or bacteria and screened for their potential inhibition of pancreatic lipase activity. Among them, extracts isolated from common foodstuffs such as tea, soybean, ginseng, yerba mate, peanut, apple, or grapevine have been reported. Some of them are polyphenols and saponins with an inhibitory effect on pancreatic lipase activity, which could be applied in the management of the obesity epidemic.

#

Introduction

Obesity is becoming one of the greatest threats to global health in this century, with more than 1.5 billion overweight adults and at least 400 million of clinically obese subjects [1]. Due to these increasing obesity rates, the World Health Organization (WHO) has prompted to consider it as the epidemic of XXI century and to promote strategies to prevent and control its progress [2].

The development of obesity is characterized by a chronic imbalance between energy intake and energy expenditure [3], [4], [5], and it is often ascribed to changing lifestyles and inadequate dietary habits [3]. Also, decreased energy expenditure is often associated with an inherited low basal metabolic rate, low energy cost of physical activity, and low capacity for fat oxidation [6]. To reduce body weight and adiposity, a change in lifestyle habits is still the crucial cornerstone [7]. Physical activity might be helpful in the prevention of obesity by elevating the average daily metabolic rate and increasing energy expenditure [3]. Unfortunately, this clinical approach is not long-term lasting, and weight regain is often seen. Drugs that prevent weight regain appear necessary in obesity treatment [7]. Thus, the development of natural products for the treatment of obesity is a challenging task, which can be launched faster and cheaper than conventional single-entity pharmaceuticals [8]. Many medicinal plants may provide safe, natural, and cost-effective alternatives to synthetic drugs [9], [10]. Currently, one of the most important strategies in the treatment of obesity includes development of inhibitors of nutrient digestion and absorption. For example, acarbose is an antidiabetic drug that inhibits glycoside hydrolases, thus preventing the digestion of complex carbohydrates and decreasing postprandial hyperglycemia [11], [12]. Similar compounds with alpha-amylase inhibiting activity that can be used for diabetes control are being isolated from different plants. The list includes valoneaic acid dilactone [13], obtained from banaba (Lagerstroemia speciosa), the ethanol extract obtained from chestnut astringent skin [14], or the purified pancreatic alpha-amylase inhibitor isolated from white beans (Phaseolus vulgaris), which is able to reduce glycemia in both nondiabetic and diabetic rats [15].

In this context, since dietary lipids represent the major source of unwanted calories, the inhibition of fat digestion is an interesting approach for reducing fat absorption [16]. Orlistat is the only authorized antiobesity drug in Europe and has been shown to act through inhibition of pancreatic lipase (PL), which is a key enzyme for the digestion of dietary triglycerides [17]. Orlistat is the saturated derivative of lipstatin, an inhibitor of PL isolated from the bacterium Streptomyces toxytricini [18]. This molecule exerts a modest weight lowering effect when accompanying a suitable dietary advice. Thus, in a recent meta-analysis [19], the mean BMI change with Orlistat (120 mg three times daily) was a reduction of 0.83 kg m−2 (95 % CI: 0.47–1.19) compared with placebo. Accompanying this antiobesity action, Orlistat is also able to modestly reduce blood pressure, improve oral glucose tolerance and prevent the onset of type 2 diabetes [20], [21].

Now, extracts from hundreds of species of medicinal plants, vegetables, and fruits [22] as well as products from microorganisms [9], fungi [23] and marine algae [24] are being screened for potential lipase inhibitory activity. Ideally, these treatments will be viewed as adjuncts to behavioral and lifestyle changes aimed at maintenance of weight loss and improved health [8].

#

Obesity and High-Fat Diets

Epidemiological studies have shown a direct relation between the incidence of overweight/obesity and dietary fat consumption [3], [6], [25].

Humans are frequently exposed to fat rich foods, which are usually associated with a high-energy intake [6], [26]. Thus, those foods with a high-energy and dietary fat content are considered to promote body fat storage and weight gain in humans [8]. One explanation is that, in commercially available food items, the percentage of energy derived from fat is highly correlated with energy density. Given that fat contains 9 kcal/g compared with 4 kcal/g for carbohydrates and proteins, foods rich in fat are often high in energy density. Thus, when a similar volume of food is consumed, energy intake will be higher in high-fat diets compared with low-fat diets [3].

On the other hand, independently of an increased energy intake, specific dietary constituents may promote the development of obesity. This statement means that even consuming an equal amount of energy, the diet composition is important, especially the balance between nutrients [27], [28].

Thus, a macronutrient profile (high-protein, high-carbohydrate, and high-lipid diets) can affect diet-induced thermogenesis, the oxidation pathway, energy intake, gene expression, or the level of some hormones [29]. Following a high-fat diet, the diet-induced thermogenesis is lower than following high-protein and carbohydrate diets, and also fat is more effectively absorbed from the gastrointestinal tract than are carbohydrates, which translates into lower energy expenditure when following a high-fat diet [26]. So, high-fat diets produce a metabolically more efficient state, at least in part because of the lower postprandial thermogenic effect of lipids in comparison with carbohydrates [30].

Furthermore, the consumption of a high-fat diet has the capacity to modulate the gastrointestinal responses to ingested fat and, thereby, may lead to impairments in appetite regulation that favour the development of obesity. Dietary fat usually implies an increase in energy consumption because it has a lower potential for inducing satiety than carbohydrates and protein [6], [31].

Hence, high-fat diets may play an important role in the increased prevalence of obesity and can be a triggering factor in the development of hyperglycemia and hyperinsulinemia [3], [32]. Moreover, the intake of dietary fats is usually accompanied by a higher intake of refined sweet carbohydrates (fast food, desserts), where the high intake of sucrose promotes weight gain, visceral adiposity, and the development of diseases that are related with obesity, such as diabetes and cardiovascular diseases [33]. Therefore, low-fat diets often are prescribed in the prevention and treatment of overweight and obesity because a reduction in dietary lipids without restriction of total energy intake could cause weight loss [26].

#

Fat digestion

Recent studies indicate that fat digestion is a prerequisite for the effects of fat on gastric emptying, gastrointestinal hormone secretion, appetite, and energy intake [6]. An increasing number of gastrointestinal enzymes involved in nutrient digestion are being identified and characterized, representing a rich pool of potential therapeutic targets for obesity and other metabolic disorders [9]. Especially interesting are those enzymes that are related with dietary fat, which includes pre-duodenal lipases (lingual and gastric lipases), pancreatic lipase (PL), cholesterol-ester lipase, and bile-salt stimulated lipase [34].

Most dietary fat is ingested as triglycerides (90–95 %), and their hydrolysis starts in the mouth, then goes on through the stomach by an acid stable gastric lipase, and continues in the duodenum through the synergistic actions of gastric and colipase-dependent pancreatic lipases (PL), leading to the formation of monoglycerides and free fatty acids (FFA) ([Fig. 1]). FFA are absorbed by the enterocyte to synthesize new triglyceride molecules, which are transported to the different organs via lipoproteins, especially chylomicrons, after a meal [34].

Zoom Image

Fig. 1 Fat metabolism in humans. Dietary fats are hydrolyzed in the gastrointestinal tract, where some lipases are involved.

Pancreatic lipase (PL), encoded by the PNLIP gene in humans, plays a key role in the efficient digestion of triglycerides [35]. It is secreted into the duodenum through the duct system of the pancreas and is responsible for the hydrolysis of 50–70 % of total dietary fats [9]. This enzyme has been widely used for the determination of the potential efficacy of natural products as antiobesity agents [36].

Orlistat is currently the only clinically approved drug for obesity management in Europe. This molecule acts by inhibiting PL activity and the reduction of triglyceride absorption, and its long-term administration accompanying an energy restricted diet, results in weight loss [37]. Reduction on intestinal lipid digestion has been related to a decrease in the intra-abdominal fat content [7]. Thus, this compound is associated with a small, but statistically significant weight loss of about 3 % more than diet alone in overweight and obese people [1]. In addition to losing weight, Orlistat within a prescribed diet has been shown to be safe and more effective than diet alone in modifying some of the risk of coronary artery disease and other obesity-related comorbidities. The most commonly reported adverse effects of Orlistat are a range of gastrointestinal side effects, including steathorrhea, bloating, oily spotting, fecal urgency, and fecal incontinence, as well as hepatic adverse effects [19], [38]. These adverse effects are similar to those observed for other lipase inhibitors tested in phase II studies, such as Cetilistat (ATL-962) [39].

On the other hand, the inhibition of fat absorption could be accompanied by fat-soluble vitamin deficiencies, which could be prevented by the vitamin supplementation strategy, as other authors have recommended when vitamin deficiency occurs in patients undergoing Orlistat therapy [40].

Hence the interest in the search for new natural substances that show potent inhibitory activity against PL and have fewer side effects than the current ones.

#

Natural inhibitors of pancreatic lipase

In the continued search for effective antiobesity agents, several bacterial, fungal, and marine species have been screened to find new compounds with PL inhibitory activity.

Many metabolic products from microorganisms, such as different kinds of Streptomyces (toxytricini, sp. NR 0619, albolongus, aburaviensis, and lavendulae) have a potent inhibitory activity of PL [9]. Lipstatin was isolated from an actinobacterium, Streptomyces toxytricini, and the catalytic hydrogenation product of lipstatin is the approved antiobesity drug tetrahydrolipstatin (Orlistat; marketed by Roche as Xenical™) [18]. Panclicins, analogs of tetrahydrolipstatin isolated from Streptomyces sp. NR0619, also present strong anti-lipase activity [41]. Other compounds which also act as potent inhibitors of PL, at least in vitro, are ebelactones A and B, isolated from Streptomyces aburaviensis [42], and vibralactone, isolated from the culture broth of the polypore Boreostereum vibrans [43]. Finally, other examples of lipase inhibitors have been obtained from yeasts and fungi such as Candida antarctica, Candida rugosa, Gestrichum candidum, Humicola lanuginose, and Pseudomonas glumae, which have received special attention and are widely used in the pharmaceutical industry [44].

Due to the biodiversity and unexplored resources, the fungal kingdom has been particularly searched to find new substances with lipase inhibitory activity. In a thorough screening of lipase inhibitors of fungal origin in Slovenia [23], extracts obtained from three species, Laetiporus sulphureus, Tylopilus felleus, and Hygrocybe conica, exhibited very high lipase inhibitory activities (83 % ± 5 %, 96 % ± 3 %, and 97 % ± 5 %, respectively), even higher than Orlistat. Pleurotus eryngii water extract also shows a significant inhibitory activity against PL, preventing postprandial hyperlipidemia through low intestinal absorption of dietary fat [45]. Finally, the water and ethanol extracts from fruiting bodies of Phellinus linteus show a potent lipase inhibitory and antiobesity effect [46]. A special case is that of monascus pigments from Monascus sp., which have been used for many years as natural colorants and as a healthy food in East Asia, being employed in the production of certain fermented foods. Various monascus derivatives with incorporated unnatural amino acids show inhibitory activities against lipase [47].

In the same way, marine products are an especially rich source of bioactive compounds [48]. In a milestone study, Bitou et al. [24] screened the lipase inhibitory activities of methanol and ethyl acetate extracts from 54 species of marine algae. These investigations observed a very high activity (almost 100 % inhibition) in the methanol extracts from Caulerpa taxifolia and Asparagopsis tociformis, although the methanolic extracts of other Chlorophyta (i.e., Caulerpa okamurae or Codium latum), Rhodophyta (i.e., Gloiopeltis tenax or Hypnea charoides), and Phaeophyta (i.e., Sargassum muticum, Dictyopteris latiuscula, or Cutleria cylindrica), were also very promising. In this sense, Phaeophyta generally contains large amounts of polyphenols, such as tannins, with lipase-inhibiting activity. In fact, most compounds with a porphyrin structure are able to inhibit lipase activity [49]. Two algae whose extracts inhibit gastric and pancreatic lipases are Caulerpa prolifera, which may be a source of a potential antiobesity agent [50], and Caulerpa taxifolia, which synthesizes the toxin caulerpenyne [24]. On the other hand, carotenoids from Undaria pinnatifida and Sargassum fulvellum, specifically fucoxanthin that is metabolized in vivo to fucoxanthinol, suppress triglyceride absorption via the inhibition of PL in the intestinal lumen [51].

Medicinal plants have been used as dietary supplements for body weight management and control in many countries. In this sense, presence of PL inhibitors has been demonstrated in different plant species ([Table 1]), although more research is needed for identifying and characterizing effective lipase inhibitors [52]. Lipase inhibitors of plant origin include certain proteins, such as those from soybean [53] and from wheat bran and germ [54]. Other proteins that strongly inhibit hydrolysis of triglycerides are the basic protein protamine [55] and ε-polylysine [56], which could act, as several amphiphilic proteins like ovoalbumin and β-lactoglobulin [57], by the desorption of lipase from its substrate due to a change in interfacial quality [58].

Table 1 Plant extracts that showed over 40 % inhibitory activity in vitro of pancreatic lipase and part of the plant from which the extract has been isolated.

Family

Scientific name

Common name

Part of plant

Ref

Family

Scientific name

Common name

Part of plant

Ref

Aeraceae

Acer pseudosieboldianum

Korean maple

Whole

[138]

Lamiaceae

Spirodela polyrhiza

Common duckmeat

Whole

[138]

Anacardiaceae

Pistacia vera

Pistachio

Fruits hull

[52]

Lamiaceae

Thymus pulegoides

Lemon thyme

Whole

[22]

Apiaceae

Levisticum officinale

Garden lovage

Whole

[52]

Lauraceae

Cinnamomum zeylanicum

Cinnamon

Derm

[52]

Apiaceae

Sanicula chinensis

Bian Dou Cai

Whole

[138]

Lauraceae

Lindera glauca

Grayblue spicebush

Whole

[138]

Araliaceae

Eleutherococcus senticosus

Siberian ginseng

Leaves

[114]

Liliaceae

Asparagus cochinchinesis

Shiny asparagus

Radix

[138]

Aspidiaceaes

Cyrtomium falcatum

Japanese holly fern

Whole

[138]

Liliaceae

Scilla scilloides

Chinese scilla

Whole

[138]

Asteraceae

Artemisia scoparia

Redstem wormwood

Whole

[138]

Linaceae

Linum usitatissimum

Oil flax

Seed

[139]

Asteraceae

Helianthus annus

Common sunflower

Seed

[139]

Lythraceae

Lythrum salicaria

Purple loosestrife

Whole

[138]

Brassicaceae

Brassica nigra

Black mustard

Radix

[22]

Musaeae

Musa sapientum

French plantain

Fructus

[22]

Brassicaceae

Brassica oleracea capitata

Cabbage

Folium

[22]

Myricaceae

Myrika spp

Bayberry

Bark

[140]

Brassicaceae

Raphanus sativus

Radish

Radix

[22]

Myrtaceae

Myrtus communis

True myrtle

Leaves

[52]

Caprifoliaceae

Lonicera japonica

Japanese honeysuckle

Whole

[138]

Myrtaceae

Solanum tuberosum

Potato

Flowers

[22]

Celastraceae

Euonymus sachalinensis

Spindletree

Whole

[138]

Oleaceae

Olea europeae

Olive

Folium

[22]

Crassulaceae

Rhodiola rosea

Roseroot stonecrop

Whole

[141]

Orchidaceae

Gastrodia elata

Tien Ma

Whole

[138]

Cucurbitaceae

Cucurbita pepo

Field pumpkin

Whole

[138]

Oxalidaceae

Oxalis corniculata

Sleeping beauty

Whole

[138]

Cucurbitaceae

Momordica cochinchinensis

Spiny bittergourd

Whole

[138]

Poaceae

Eriochloa villosa

Hairy cupgrass

Whole

[138]

Cyperaceae

Bulbostylis barbata

Watergrass

Whole

[138]

Poaceae

Hemarthria sibirica

Weed

Whole

[138]

Cyperaceae

Carex kobomugi

Japanese sedge

Whole

[138]

Poaceae

Panicum dichotomiflorum

Fall panicgrass

Whole

[138]

Cyperaceae

Cyperus amuricus

Asian flatsedge

Whole

[138]

Poaceae

Setaria italica

Foxtail bristlegrass

Whole

[138]

Eleagnaceae

Elaeagnus macrophylla

Oleaster

Whole

[138]

Polygalaceae

Polygala tenuifolia

Yuan Zhi

Whole

[138]

Ericaceae

Arctostaphylos uva-ursi

Bear berry

Folium

[22]

Polygonaceae

Reynoutria elliptica

Black bindweed

Whole

[138]

Ericaceae

Vaccinium myrtillus

Bilberry

Fructus

[22]

Polygonaceae

Rheum ribes

Rhubarb

Rhizomes

[52]

Eriocaulaceae

Eriocaulon sieboldianum

Flattened pipewort

Whole

[138]

Potamogetonaceae

Potamogeton distinctus

Pondweed

Whole

[138]

Fabaceae

Alhagi camelorum

Camelthorn

Aerial parts

[52]

Rosaceae

Rosa damascene

Damask rose

Floret

[52]

Fabaceae

Glycyrrhiza uralensis

Gan Cao

Whole

[138]

Rosaceae

Rubus idaeus

Raspberry

Fructus

[22]

Fabaceae

Lespedeza cuneata

Chinese bush clover

Whole

[138]

Rosaceae

Malus domestica

Apple

Fructus

[22]

Fabaceae

Phaseolus vulgaris

Common bean

Whole

[22]

Rubiaceae

Gardenia jasminoides

Cape jasmine

Whole

[138]

Fabaceae

Pisum sativum

Garden pea

Fructus

[22]

Rubiaceae

Rubia akane

Asian madder

Whole

[138]

Fabaceae

Pueraria thunbergiana

Kudzu

Whole

[138]

Rutaceae

Citrus aurantifolium

Lime

Whole

[138]

Fabaceae

Quercus infectoria

Aleppo oak

Galls

[52]

Rutaceae

Murraya koeninggi

Curryleaf tree

Leaves

[142]

Juncaceae

Juncus effusus

Soft rush

Whole

[138]

Rutaceae

Orixa japonica

Pearl frost

Whole

[138]

Lamiaceae

Agastache rugosa

Purple giant hyssop

Whole

[138]

Saxifragaceae

Chrysosplenium grayanum

Golden saxifrage

Whole

[138]

Lamiaceae

Origanum vulgare

Oregano

Herba

[22]

Simaroubaceae

Ailanthus altissima

Tree of heaven

Whole

[138]

Lamiaceae

Prunella vulgaris

Common selfheal

Whole

[73]

Tiliaceae

Tilia platyphyllos

Largeleaf linden

Whole

[22]

Lamiaceae

Rosmarinus officinalis

Rosemary

Folium

[22]

Urticaceae

Urtica urens

Dwarf nettle

Aerial parts

[52]

Lamiaceae

Salvia officinalis

Salvia

Folium

[22]

Zingiberaceae

Afromomum meleguetta

Meleguetta pepper

Seed

[143]

Other lipase inhibitors from plant origin are basic polysaccharides, especially chitosan oligosaccharides, water-soluble chitosan (46 kDa) and polydextrose when a basic group is introduced [59], [60], phytic acid and other myoinositol phosphate esters [61], phenylboronic acid, a potent inhibitor of lipase from Oryza sativa [62], and carnosic acid, a diterpene isolated from the methanolic extract of the leaves of sage (Salvia officinalis) and rosemary [63]. Korean and Chinese researchers have been very active in the search of new lipase inhibitors of herbal origin. Among the most promising compounds, there are platycodin D, isolated from the fresh roots of Platycodon grandiflorum [64], [65], dioscin from Dioscorea nipponica [66], licochalcone A from the roots of Glycyrrhiza uralensis [67], phenolic constituents from the leaves of Nelumbo nucifera [68], the aqueous ethanol extracts of Juniperus communis or common juniper (bark) and Illicium religiosum (wood) [69], the ethanol extract from stem bark and leaves from mango tree (Mangifera indica), which is able to prevent weight gain induced by feeding a high-fat diet to Wistar rats [70], a pomegranate leaf extract rich in ellagic acid and tannins [71], Rhei rhizoma (rhubarb) and the combinatorial drug Chunghyuldan [72], Prunella vulgaris, Rheum palmatum, and other herbs [73]. Most of the common compounds that are found in different plant species are polyphenols, saponins, and terpenes ([Table 2]).

Table 2 Some classes of natural compounds that have been reported to inhibit pancreatic lipase activity in vitro and species from which the compound has been obtained.

Metabolites

Scientific name

Common name

Family

References

Flavonoids

Alpinia officinarum

Lesser galangal

Zingiberaceae

[144], [145]

Flavonoids

Taraxacum officinale

Dandelion

Asteraceae

[103]

Flavonoids, triterpenes

Actinidia arguta

Kiwi

Actinidiaceae

[146]

Polyphenols

Arachis hypogaea

Peanut

Fabaceae

[9]

Polyphenols

Mangifera indica

Mango

Anacardiaceae

[9]

Polyphenols

Medicago sativa

Alfalfa

Fabaceae

[78]

Polyphenols

Nelumbo nucifera

Sacred lotus

Nelumbonaceae

[9]

Polyphenols

Salacia reticulate

Kotala himbutu

Celastraceae

[101]

Polyphenols

Salix matsudana

Corkscrew willow

Salicaceae

[147]

Polyphenols, proanthocyanidins, catechins

Camellia sinensis

Green, black, oolong tea

Theaceae

[89]

Polyphenols, saponins

Ilex paraguariensis

Yerba mate

Aquifoliaceae

[99]

Proanthocyanidins

Cassia mimosoides

Nomame herba

Fabaceae

[148]

Proanthocyanidins

Cinnamomum sieboldii

Cinnamon

Lauraceae

[86]

Proanthocyanidins

Theobroma cacao

Cocoa

Malvaceae

[86]

Proanthocyanidins, saponins

Vitis vinifera

Grape vine

Vitaceae

[79], [104]

Saponins

Aesculus hippocastanum

Horse chestnut

Sapindaceae

[32]

Saponins

Aesculus turbinate

Japanese horse chestnut

Hippocastanaceae

[110]

Saponins

Arctostaphylos uva-ursi

Bearberry

Ericaceae

[32]

Saponins

Ardisia japonica

Marlberry

Myrsinaceae

[152]

Saponins

Avena sativa

Oat

Poaceae

[149]

Saponins

Coffea Arabica

Coffee

Rubiaceae

[32]

Saponins

Cyclocarya paliurus

Wheel wingnut

Juglandaceae

[9]

Saponins

Dioscorea nipponica

Yam

Dioscoreaceae

[9]

Saponins

Eleutherococcus senticosus

Siberian ginseng

Araliaceae

[114]

Saponins

Eleutherococcus sessiliflorus

Sessiloside

Araliaceae

[9]

Saponins

Gardenia jasminoides

Cape jasmine

Rubiaceae

[118]

Saponins

Gypsophila oldhamiana

Oldham's baby's-breath

Caryophyllaceae

[119]

Saponins

Kochia scoparia

Burningbush

Chenopodiaceae

[150]

Saponins

Malus domestica

Apple

Rosaceae

[32]

Saponins

Momordica charantia

Balsampear

Cucurbitaceae

[151]

Saponins

Olea europeae

Olive

Oleaceae

[32]

Saponins

Panax ginseng

Ginseng

Araliaceae

[109]

Saponins

Panax japonicus

Japanese ginseng

Araliaceae

[120]

Saponins

Panax quinquefolium

American ginseng

Araliaceae

[122]

Saponins

Platycodi radix

Doraji

Campanulaceae

[64]

Saponins

Platycodon grandiflorum

Balloon flower

Campanulaceae

[103]

Saponins

Sapindus rarak

Soapberry

Sapindaceae

[127]

Saponins

Scabiosa tschiliensis

Pincushions

Dipsacaceae

[9]

Saponins

Solanum lycopersicum

Tomato

Solanaceae

[32]

Terpenes

Salvia officinalis

Salvia

Lamiaceae

[32]

Triterpenes

Aloe vera

Aloe vera

Asphodelaceae

[32]

Triterpenes

Betula alba

Birch

Betulaceae

[32]

Triterpenes

Calendula officinalis

Pot marigold

Asteraceae

[32]

Triterpenes

Melissa officinalis

Lemon balm

Lamiaceae

[32]

Triterpenes

Origanum vulgare

Oregano

Lamiaceae

[32]

In the following chapters more information will be given out about the most thoroughly studied compounds, classified according to their biochemical structure.

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Polyphenols

A number of studies have revealed various health benefits of plant polyphenols and their importance in foods, beverages, and natural medicine. In this context, polyphenols have some potential efficacy for preventing obesity. They inhibit enzymes related to fat metabolism including PL, lipoprotein lipase, and glycerophosphate dehydrogenase [74]. Polyphenol extracts are able to decrease the blood levels of glucose, triglycerides, and LDL cholesterol, increase energy expenditure and fat oxidation, and reduce body weight and adiposity [75], [76]. In fact, many polyphenols, including flavones, flavonols, tannins, and chalcones, have shown an inhibitory activity of PL [9], [22].

Flavonoids are a type of plant secondary metabolites that are characterized as containing two or more aromatic rings, each bearing at least one aromatic hydroxyl and connected with a carbon bridge [76]. Some of them are polymerized into large molecules, either by the plants themselves or as a result of food processing. These polymers are called tannins, and three subclasses (condensed tannins, derived tannins, and hydrolysable tannins) exhibit a variety of beneficial effects on health [76]. A flavonoid with PL inhibitory activity is hesperidin, obtained from the peels of Citrus unshiu [77].

Proanthocyanidins (PA), also known as condensed tannins, are the most common group of flavonoids in the Western diet. They consist of monomeric units of flavans linked through carbon-carbon and ether linkages, which are considered the second most abundant group of natural phenolics after lignins [78]. PA can be found in such common foodstuffs as cereals, legumes, fruits, vegetables, and beverages (red wine and tea in particular) [75], [79]. They have a putative role as antioxidants, showing beneficial effects on inflammatory processes, cardiovascular diseases, and other pathological conditions [80], [81]. For example, these compounds actively reduce plasma triglycerides by inhibiting the absorption of dietary lipids [79] and possess inhibitory effects on different digestive enzymes, such as trypsin, amylase, and lipase [36].

Some examples of polyphenols with inhibitory action on PL are proanthocyanidins from edible herbs, such as those from Cassia mimosoides [82], and tea catechins, especially (−)-catechin gallate and (−)-gallocatechin gallate, [83]. Some of the most thoroughly studied polyphenol extracts in relation to PL inhibition are the following:

Arachis hypogaea: Peanut (Arachis hypogaea) shells (hulls, seed coats), which are by-products of the peanut industry, provide several compounds showing PL inhibitory activity in a dose dependent manner (1 mg/mL = 42 % inhibitory effect) that are able to reduce body weight gain in rats fed a high-fat diet [84]. This plant contains several bioactive molecules, such as luteolin ([Fig. 2]), certain fatty acids, caffeic, ferulic, and benzoic acids, all of which are able to inhibit lipases [9]. Coumarin derivates and phenolic acids were assumed to be the major active constituents. However the authors have not examined the individual effects of each compound.

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Fig. 2 Selected polyphenols with PL inhibitory activity: Luteolin (1) from Arachis hypogaea, catechin (2) from Camellia sinensis, daidzein (3) from Glycine max, quercetin (4) from Ilex paraguariensis, structure of a procyanidin (5) from Vitis vinifera.

Camellia sinensis: Camellia sinensis or tea plant (green tea, black tea, or oolong tea) contains over 60 polyphenols, some of them with a potent PL inhibitory activity. It is likely the plant whose extracts have been more thoroughly used for searching new PL inhibitors. The major polyphenols are catechins ([Fig. 2]), which constitute about one-third of its total dry weight. A serving of tea is moderate to high in flavonoid and/or tannin content [85], [86], [87], [88], [89]. Nakai et al. [90] found that the polyphenols with more potent PL inhibitory effect were flavan-3-ol digallate esters isolated from oolong tea, such as (−)-epigallocatechin-3,5-digallate. Oolong tea-polymerized polyphenols reduced postprandial hypertriglyceridemia in olive oil-loaded rats and mice [91]. Also (−)-epigallocatechin, abundant in the green tea extract, is a weak inhibitor of PL and is able to decrease the postprandial hypertriglyceridemia in rodents [92].

The administration of black-tea polyphenols suppressed postprandial hypertriglyceridemia in a dose-dependent manner in rats, with theaflavin-3,3′-digallate as the most effective PL inhibitor [93], whereas other authors point out to thearubigins [94]. These extracts are able to prevent increases in body weight and adiposity in mice fed a high-fat diet [95]. The PL inhibitory and hypotriglyceridemic effects of tea extracts were corroborated by Tanaka et al. [96], who orally administered mixed fermented tea extracts and Loquat tea extracts to rats with a 10 % soybean oil emulsion.

Finally, cocoa tea extract (Camellia sinensis var. ptilophylla) is rich in polyphenols with PL inhibitory effect. A single oral administration of this extract produces an inhibition of plasma triglyceride levels in olive oil-loaded ICR mice and triolein-loaded rats [97].

Glycine max: Daidzein ([Fig. 2]) belongs to the group of isoflavones and is produced almost exclusively by the members of the Fabaceae/Leguminosae (bean) family such as soybean. In one study, Guo et al. [98] investigated the effects of daidzein on body weight, adipose tissue, blood, and liver lipid levels in obese mice fed a high-fat diet, finding that daidzein reduced body and white adipose tissue weights in obese mice and ameliorated the hyperlipidemia induced by the high-fat diet. The authors attributed this effect to the inhibition of PL activity and fat digestion.

Ilex paraguariensis: Yerba mate (MT) is a plant from the subtropical region of South America that is widely consumed in Brazil, Argentina, Paraguay, and Uruguay. Yerba mate contains polyphenols, such as flavonoids (quercetin and rutin) ([Fig. 2]) and phenolic acids (chlorogenic and caffeic acids), and is also rich in caffeine and saponins [99]. These substances act on the lipid metabolism by inhibiting PL activity in a concentration value of 1.5 mg/mL [99]. Several triterpene saponins and monoterpene oligoglycosides from the leaves of yerba mate were found to exhibit potent inhibitory activity on porcine PL [100].

Malus domestica: Apples (Malus domestica) belong to the Rosaceae family whose fruits contain several phenolic substances (cholorogenic acid, catechin, epicatechin, phloridzin, and procyanins). Procyanidins in apples are mainly composed of various polymerized catechins, with some of them showing a PL inhibitory activity and reducing triglyceride absorption [36]. In corn oil-loaded mice, a single oral administration of apple polyphenols reduced plasma triglyceride levels, and a test diet containing 600 mg of apple polyphenols significantly inhibited triglyceride elevation at 6 h after ingestion, indicating an inhibition of triglyceride absorption [36].

Salacia reticulata: Salacia reticulata contains a high concentration of polyphenols, including catechins and condensed tannins. In hot water-soluble extract from the roots of Salacia reticulata (SRHW) the concentration is about 24 % polyphenols [74]. The polyphenols from Salacia reticulata inhibit enzymes related to fat metabolism, including PL, lipoprotein lipase, and glycerophosphate dehydrogenase, and are effective in preventing obesity [101]. In fact, Salacia extract markedly improved metabolic syndrome symptoms (including body weight, adiposity, glucose intolerance, hypertension, and peripheral neuropathy) in TSOD mice [102].

Taraxacum officinale: Dandelion (Taraxacum officinale) is a perennial herbaceous plant of the family Asteraceae that has been used as a phytomedicine due to its choleretic, antirhemetic, diuretic, and anti-inflammatory properties [103]. Extracts from this plant have shown hypolipidemic effects and an inhibitory activity of PL, decreasing AUC (area under curve) for the postprandial triglyceride response curve [103].

Vitis vinifera: Grapevine (Vitis vinifera) has become a model plant for studying proanthocyanidin biosynthesis. Grapevine proanthocyanidins ([Fig. 2]) consist of two major flavan 3-ol monomers, catechin and epicatechin, that have inhibitory activity on PL [79], [104].

Polyphenol-rich extracts from a range of berries, particularly cloudberry, are able to inhibit PL activity in vitro, which has been attributed to their content in ellagitannins and proanthocyanidins [105].

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Saponins

Saponins are a major family of secondary metabolites that occur in a wide range of plants species [106]. These compounds have been isolated from different parts of the plants, including the roots, rhizomes, stems, bark, leaves, seeds, and fruits. Occasionally, the whole plant has been used [107].

Saponins are categorized into two major classes, the triterpenoid and the steroid saponins, which are both derived from the 30 carbon atoms containing precursor oxidosqualene [107], [108]. Some of the triterpene-rich plant materials are common foodstuffs consumed in large amounts in Mediterranean countries. Therefore, the correlation of a triterpene-rich diet and the beneficial effects of consuming a Mediterranean diet should be investigated in more detail [32]. These types of plant secondary metabolites are found to inhibit PL and, thus, may represent potential effective treatments for obesity and related disorders [9], [22].

Aesculus turbinata: The Japanese horse chestnut (Aesculus turbinata) is a medicinal plant widely used in East Asia. The saponin mixture extracted from the seeds is called escins and has a strong inhibitory activity on PL [110]. In mice fed a high-fat diet, total escins suppressed the increase in body weight, adiposity, and liver fat and increased triglyceride level in the feces, whereas it decreased plasma triglycerides after the oral administration of a lipid emulsion [111], [112].

Dioscorea nipponica: The methanol extract of Dioscorea nipponica Makino powder has a potent inhibitory activity against porcine PL, with an IC50 value of 5–10 µg/mL [66]. In fact, the saponin dioscin and its aglycone, diosgenin, both suppressed the increase of blood triacylglycerols when orally injected with corn oil to mice. Rats fed a high-fat diet containing 5 % Dioscorea nipponica Makino gained significantly less body weight and adipose tissue than control animals [66], and a similar result has been observed after administering the aqueous extract of this rhizome to mice fed a high-fat diet [113].

Eleutherococcus senticosus: Eleutherococcus senticosus is a shrub, belonging to the family Araliaceae, which is commonly distributed in north-eastern Asia. It is used as a traditional Chinese medicine against ischemic heart diseases, neurasthenia, hypertension, arthritis, and tumors [114]. At least fifteen triterpenoid saponins with in vitro PL inhibitory activity ([Fig. 3]) have been isolated from the fruits of Eleutherococcus senticosus [115]. The total saponin fraction obtained from the fruits of Eleutherococcus senticosus exhibits inhibitory activity on PL with an IC50 value of 3.63 mg/mL [114].

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Fig. 3 Selected isoprenoids with PL inhibitory activity: Eleutheroside (6) from Eleutherococcus senticosus, geniposide (7) from Gardenia jasminoides, general structure of dammaran aglycons of ginsenosides (8) in Panax ginseng, betulin (9) from Betula alba.

Eleutherococcus sessiliflorus: Different lupine-type triterpene triglycosides isolated from a hot water extract of Eleutherococcus sessiliflorus leaves are able to inhibit PL activity in vitro and to suppress the body weight gain of mice fed a high-fat diet [116].

Gardenia jasminoides: Crocin is a glycosylated carotenoid extracted from the fructus of Gardenia jasminoides ([Fig. 3]). Gardeniae Fructus is used in Asian countries as a natural colorant, and in Chinese traditional medicine for its antioxidant, cytotoxic, antitumor, and neuroprotective effects. Crocin and crocetin are effective hypolipidemic agents that act by reducing the absorption of fat and cholesterol through inhibition of PL activity [117]. Sheng et al. demonstrated that crocin selectively inhibited the activity of PL as a competitive inhibitor [118].

Gypsophila oldhamiana: Gypsophila oldhamiana (Caryophyllaceae) is a plant distributed in the north of China whose roots have high amounts of saponins, sterols, and fatty acids. The extract from this plant shows a potent inhibitory activity of PL with an IC50 value of 0.54 mg/ml [118], [119] and different triterpenoid saponins, gypsosaponins A–C, as the more efficient compounds [119].

Panax ginseng: Ginseng is one of the most popular medicinal herbs and is commonly consumed as powder, a beverage, or a food supplement. Roots of Panax ginseng contain high levels of ginsenosides ([Fig. 3]), which are steroidal saponins that show beneficial effects on lipid metabolism. Saponins from ginseng roots suppressed the expected increase in body weight and plasma triacylglycerols in mice following a high-fat diet, which was probably mediated by inhibiting PL with an IC50 value of 500 µg/mL [109].

Panax japonicus: The rhizomes of Panax japonicus (Japanese ginseng) are used in folk medicine for the treatment of arteriosclerosis, hyperlipidemia, hypertension, and diabetes mellitus. Chikusetsusaponins prevented the increase in body weight and parametrial adipose tissue weight induced by a high-fat diet and inhibited the elevation of postprandial plasma triacylglycerols due to their inhibitory action of PL on dietary fat [120]. The delay in intestinal fat absorption was also behind the antiobesity effects observed for Korean white ginseng extract in high-fat diet-induced obese mice [121].

Panax quinquefolium: American ginseng (Panax quinquefolium) is a native plant from North America. The saponins isolated from stems and leaves of Panax quinquefolium may prevent fat storage in adipose tissue and postprandial elevations of plasma triacylglycerols by inhibiting the intestinal absorption of dietary fat through the inhibition of PL activity [122].

Platycodi grandiflorum: Platycodi radix, widely used in traditional Oriental medicines as a remedy for respiratory disorders, is rich in saponins, which are responsible for a diversity of effects including anti-inflammation, antiallergy, antitumor, and immunostimulation [64]. Given its inhibitory action on PL [123], with platycodin D as the most efficient compound [124], it ameliorated high fat-induced obesity in mice [125] and rats [64]. SK1 is an edible saponin-rich compound from Platycodi Radix that is able to reduce body weight and fat accumulation by increasing fecal lipid outputs in high-fat fed mice [126].

Sapindus rarak: The methanolic extract from the pericarps of Sapindus rarak (Lerak) shows a PL inhibitory activity that is probably due to diverse saponins and sesquiterpene glycosides [127].

Scabiosa tschiliensis: Different triterpenoid saponins isolated from the Mongol and Chinese traditional medicinal herb Scabiosa tschiliensis have shown strong inhibition of PL in vitro [128]. Due to the difficult task of isolating scabiosaponins and the scarceness of this type of saponin in nature, some of them have been successfully synthesized in the laboratory [129].

Tea saponins: At least three kinds of tea (oolong, green, and black) have been used as healthy drinks. Tea saponins suppress the increases in body and parametrial adipose tissue weights and adipocyte diameters induced by a high-fat diet in mice by inhibiting PL and also reduce the elevation in plasma triacylglycerol levels after oral administration of a lipid emulsion. The Ki value of tea saponins was determined to be 0.25 mg/mL [85]. Thus, the crude saponin fraction from the flower buds of Chinese tea plant exhibits accelerating effects on gastrointestinal transit in mice and inhibitory effects against porcine PL, and three floratheasaponins (A–C) showed inhibitory effects on serum triglyceride elevation [130].

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Triterpenes

Terpenes are the primary constituents of the essential oils of many types of plants and are classified by the number of terpene units in the molecule (diterpenes, triterpenes, among others). The pharmacological relevance of triterpenes has increased during the last two decades demonstrating multitarget properties such as wound healing, anti-inflammatory, antibacterial, antiviral, hepatoprotective, and antitumoral effects, combined with low toxicity [32]. Triterpene extracts are safe and provide a high potential for further pharmaceutical and pharmacological research [131], some of them inhibiting PL activity.

Betula alba: Bark of birch (Betula alba) contains pentacyclic triterpenes ([Fig. 3]). This triterpene extract is safe and provides a high potential for further pharmaceutical and pharmacological research [32], [131], displaying an inhibitory activity on PL [22].

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Clinical Studies about Pancreatic Lipase Inhibitors

A number of plants and natural products have been screened for their PL inhibitory activity but just some of them have gone up to clinical studies. In this line, only one product derived from natural compounds (Orlistat) is currently in clinical use, although others are under investigation. Some of them are Panax ginseng [132], Camellia sinensis [133], Eleutherococcus senticosus [134], Malus domestica [135], and Arachis hypogaea [136].

In one study [132], the administration of an extract of Panax ginseng in humans for 8 weeks decreased circulating cholesterol, triglyceride, and low-density lipoprotein levels (LDL). Each subject ingested 2 g of Panax ginseng extract three times a day.

Lee et al. [134] reported that healthy postmenopausal women treated for 6 months with Eleutherococcus senticosus supplementation showed significant decreases in serum LDL levels and LDL/HDL ratios.

In other study, Sugiyama et al. [135] assessed six healthy male volunteers that followed a high-fat diet with 40 g of fat with 10 control or 10 apple polyphenol (Malus domestica) capsules (600 or 1500 mg). In this study, they demonstrated that apple polyphenols may prevent obesity in humans by a PL inhibitory mechanism.

Green tea (Camellia sinensis) has been extensively studied in relation to obesity and other metabolic disorders. Thus, Chantre and Lairon [133] showed that green tea consumption may be useful to treat obesity by both, increasing thermogenesis and inhibiting PL. Thus, a green tea extract showed a direct in vitro inhibition of gastric and pancreatic lipases [133]. In moderately obese patients, green tea lowered body weight by stimulating thermogenesis and increasing energy expenditure when each subject received 2 times/d a green tea extract (2 capsules morning, 2 capsules midday). Ingestion of 4 capsules containing AR25 (Exolise) provided a daily total intake of 375 mg catechins, of which 270 mg was epigallocatechin gallate. Also, He et al. [137] administered daily 8 g of oolong tea for 6 weeks to 102 obese subjects. As a result, 70 % of the obese subjects decreased more than 1 kg in body weight. In vitro studies suggested that the effect of oolong tea on body weight could be partially attributed to the inhibition of PL [68].

According to these data, a number of common herbal products that are being studied in animal ([Table 3]) and human models for obesity treatment contain different metabolites that act on lipid digestion and absorption. However, it is very difficult to establish in in vivo studies whether these antiobesity effects are only or mainly due to PL activity inhibition. The clinical implications of this therapeutic approach have yet to be determined.

Table 3 Plant extracts that showed in vivo inhibitory activity of pancreatic lipase, doses and effects. IC50 is indicated when available.

Scientific name

Common name

IC50

Doses

Model

Effects

References

Aesculus turbinate

Japanese horse chestnut

IC50 24 mg/mL

0.1–0.5 % of diet

DIO mice

TG plasma levels and body weight gain

[153]

Arachis hypogaea

Peanut

IC50 0.029 µg/mL

1 % of diet

DIO rats

Body weight gain

[136]

Camellia sinensis

Green, black, oolong tea

IC50 0.091 mg/mL

3 % of HFD

Rats

Body weight gain and visceral fat

[89]

Cassia mimosoides

Nomame herba

IC50 0.1–0.71 mg/mL

1–3.5 % of diet

DIO rats

Body weight gain

[154]

Coffea arabica

Coffee

0.5 % of standard diet

Mice

Body weight gain

[155]

Cyclocarya paliurus

Wheel wingnut

IC50 9.1 µg/mL

250 mg/kg; VO

Mice

TG plasma levels and blood glucose levels

[156]

Dioscorea nipponica

Yam

IC50 5–10 mg/mL

5 % of HFD

Rats

TG plasma levels and body weight gain

[157]

Eleutherococcus senticosus

Siberian ginseng

IC50 0.22–0.29 mM

12 mg/kg

DIO rats

Abdominal fat, TG in liver and serum and LDL in serum

[158]

Eleutherococcus sessiliflorus

Sessiloside

IC50 0.36–0.75 mg/mL

100–300 mg/kg; VO

Mice

TG plasma levels

[159]

Gardenia jasminoides

Cape jasmine

IC50 2.1 mg/mL

50 mg/kg/d

Mice

Body weight gain

[118]

Humulus lupulus

Common hop

0.2–1.2 % (w/w) of extract

Mice

Body weight gain and blood glucose levels

[160]

Ilex paraguariensis

Yerba mate

0.24 % of HFD

Rats

Body weight gain

[99]

Kochia scoparia

Burningbush

3 % of HFD

Mice

Body weight gain

[150]

Malus domestica

Apple

IC50 5.6 µg/mL

200 mg/kg; VO

Mice

TG plasma levels

[161]

Myrica spp

Bayberry

TG plasma levels

[140]

Nelumbo nucifera

Sacred lotus

IC50 0.46 mg/mL

5 % of diet

Mice

TG plasma levels and body weight gain

[162]

Panax ginseng

Ginseng

IC50 500 µg/mL

200 mg/kg with HFD

Rats

Body weight gain

[109]

Panax japonicus

Japanese ginseng

1–3 % of diet

DIO mice

Body weight gain

[120]

Platycodi radix

Doraji

Ki 0.18 mM

70 mg/kg, with HFD

Sprague Dawley rats

Body weight gain

[64]

Rhodiola rosea

Roseroot stonecrop

IC50 0.093 mM

150 mg/kg

Mice

TG plasma levels

[141]

Rosmarinus officinalis

Rosemary

200 mg/kg HFD

Mice

Body weight and fat mass

[163]

Salacia reticulata

Kotala himbutu

IC50 264 mg/L

125 mg/kg; VO HFD

Rats

Body weight gain

[101]

Salix matsudana

Corkscrew willow

5 % of HFD

Wistar rats

Body weight gain

[147]

DIO: Diet-induced obesity; HFD: High-fat diet; VO: Via oral. (Daily food intake is approximately: rats: 20 g/day; mice: 4.5 g/day)

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Conclusions

Orlistat is the only drug authorized and present in Europe for the treatment of obesity within an adequate energy intake, which acts by inhibiting the lipolytic activity of PL. With the aim of finding new compounds more potent or with less secondary effects than Orlistat, new natural products are being identified and screened for their PL inhibitory potential. Some of these extracts are obtained from plants that are rich in polyphenols and saponins and show inhibitory effects on fat digestion, whereas other extracts come from algae, fungi, and microorganisms. Thus, natural products provide an exciting opportunity and promise for the development of new therapeutic approaches to the treatment of obesity by blocking the digestion and absorption of dietary lipids, and constitute a valuable alternative to other pharmacological agents. Some of the products reviewed in this article show potentially promising effects for weight control. In particular apple, green tea, soybean, and ginseng seem to have great potential as sources of molecules with PL inhibitory activity. For all of them more data are needed to define effects, optimal dose required, and mechanism of action, as well as their possible side or toxic effects.

Thus, there is an urgent need to update the knowledge on the numerous natural sources that could act as inhibitors of PL in order to screen them as new potential therapeutic antiobesity agents with low secondary effects.

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Acknowledgements

The authors thank Línea Especial (LE/97) from the University of Navarra (Spain) and the CENIT PRONAOS Program (MICINN, Spain) for financial support. A. L. de la Garza and N. Boqué hold pre-doctoral grants from Ibercaja. We also acknowledge Marta Díaz Hernando for her contribution to the figures design.

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References

Prof. J. Alfredo Martinez

Department of Nutrition and Food Sciences, Physiology and Toxicology
University of Navarra

c/Irunlarrea 1

31008 Pamplona

Spain

Phone: +34 9 48 42 56 00

Fax: +34 9 48 42 56 49

Email: jalfmtz@unav.es

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References

Prof. J. Alfredo Martinez

Department of Nutrition and Food Sciences, Physiology and Toxicology
University of Navarra

c/Irunlarrea 1

31008 Pamplona

Spain

Phone: +34 9 48 42 56 00

Fax: +34 9 48 42 56 49

Email: jalfmtz@unav.es

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Fig. 1 Fat metabolism in humans. Dietary fats are hydrolyzed in the gastrointestinal tract, where some lipases are involved.

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Fig. 2 Selected polyphenols with PL inhibitory activity: Luteolin (1) from Arachis hypogaea, catechin (2) from Camellia sinensis, daidzein (3) from Glycine max, quercetin (4) from Ilex paraguariensis, structure of a procyanidin (5) from Vitis vinifera.

Zoom Image

Fig. 3 Selected isoprenoids with PL inhibitory activity: Eleutheroside (6) from Eleutherococcus senticosus, geniposide (7) from Gardenia jasminoides, general structure of dammaran aglycons of ginsenosides (8) in Panax ginseng, betulin (9) from Betula alba.