Download PDF
Planta Med 2015; 81(10): 771-783
DOI: 10.1055/s-0035-1546173
Reviews
Georg Thieme Verlag KG Stuttgart · New York

Polyphenolic Compounds as Pancreatic Lipase Inhibitors

Tina Buchholz
Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
,
Matthias F. Melzig
Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
› Author Affiliations
Further Information

Publication History

received 14 November 2014
revised 25 March 2015

accepted 03 May 2015

Publication Date:
01 July 2015 (online)

   Permissions and Reprints

Abstract

Obesity and its associated diseases such as diabetes mellitus and coronary heart diseases are a major challenge for our society. An important target for the treatment of obesity includes the development of inhibitors of nutrient digestion and absorption. Inhibition of pancreatic lipase and the associated reduction of lipid absorption is an attractive approach for the discovery of potent agents. Currently, the only clinically approved pharmacologic agent as pancreatic lipase inhibitor is Orlistat. However, its usage is compromised by unpleasant gastrointestinal adverse reactions (oily stools, oily spotting, flatulence). The use of botanical materials as a potential source of new drugs is of increasing importance and application. Natural products that are interesting for obesity treatment are generally considered to have less toxic and side effects than totally synthetic drugs. One of the most important sources of potential pancreatic lipase inhibitors represents the class of polyphenols. This article summarizes most studied subclasses of polyphenols including flavonoids, hydroxycinnamic acids, hydroxybenzoic acids and lignans with pancreatic lipase inhibitory effects. A structural comparison of potent inhibitors shows an increased inhibitory effect depending on number and position of phenolic hydroxyl groups, degree of polymerization and elimination of glycosylation during digestion.

Key words

fat-digestion - anti-obesity - pancreatic lipase inhibition - polyphenols
 

  • References

  • 1 WHO. 10 facts on obesity. Geneva: World Health Organization; 2014
    Google Scholar
  • 2 Kopelman PG. Obesity is a medical problem. Nature 2000; 404: 635-643
    CrossrefPubMedGoogle Scholar
  • 3 Trigueros L, Peña S, Ugidos AV, Sayas-Barberá E, Pérez-Álvarez JA, Sendra E. Food ingredients as anti-obesity agents: a review. J Food Sci Nutr 2013; 53: 929-942
    PubMedGoogle Scholar
  • 4 Foster-Schubert KE, Cummings DE. Emerging therapeutic strategies for obesity. Endocr Rev 2006; 27: 779-793
    CrossrefPubMedGoogle Scholar
  • 5 Thomson AB, de Pover A, Keelan M, Jarocka-Cyrta E, Clandinin MT. Inhibition of lipid absorption is an approach to the treatment of obesity. Meth Enzymol 1997; 286: 3-41
    PubMedGoogle Scholar
  • 6 Ros E. Intestinal absorption of triglyceride and cholesterol. Dietary and pharmacological inhibition to reduce cardiovascular risk. Atherosclerosis 2000; 151: 357-379
    CrossrefPubMedGoogle Scholar
  • 7 Slanc P, Doljak B, Kreft S, Lunder M, Janes D, Strukelj B. Screening of selected food and medicinal plant extracts for pancreatic lipase inhibition. Phytother Res 2009; 23: 874-877
    CrossrefPubMedGoogle Scholar
  • 8 Liu D, Wang F, Tang J, Steglich W, Zhu H. Vibralactone: a lipase inhibitor with an unusual fused beta-lactone produced by cultures of the basidomycete Boreostereum vibrans . Org Lett 2006; 8: 5749-5752
    CrossrefPubMedGoogle Scholar
  • 9 Slanc P, Doljak B, Mlinaric A, Strukelj B. Screening of wood damaging fungi and macrofungi for inhibitors of pancreatic lipase. Phytother Res 2004; 18: 758-762
    CrossrefPubMedGoogle Scholar
  • 10 Bitou N, Ninomiya M, Tsujita T, Okuda H. Screening of lipase inhibitors from marine algae. Lipids 1999; 34: 441-445
    CrossrefPubMedGoogle Scholar
  • 11 Weibel EK, Hadvary P, Hochuli E, Kupfer E, Lengsfeld H. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J Antibiot 1987; 40: 1081-1085
    CrossrefPubMedGoogle Scholar
  • 12 de la Garza AL, Milagro FI, Boque N, Campión J, Martínez JA. Natural inhibitors of pancreatic lipase as new players in obesity treatment. Planta Med 2011; 77: 773-785
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Chaput JP, St-Pierre S, Tremblay A. Currently available drugs for the treatment of obesity: Sibutramine and Orlistat. Med Chem 2007; 7: 3-10
    PubMedGoogle Scholar
  • 14 Bustanji Y, Mohammad M, Hudaib M, Tawaha K, Al-Masri IM, AlKhatib HS, Issa A, Alali FQ. Screening of some medicinal plants for their pancreatic lipase inhibitory potential. Jordan J Pharm Sci 2011; 4: 81-88
    PubMedGoogle Scholar
  • 15 Gholamhoseinian A, Shahouzehi B, Sharifi-far F. Inhibitory effect of some plant extracts on pancreatic lipase. Int J Pharmacol 2010; 6: 18-24
    CrossrefPubMedGoogle Scholar
  • 16 Knasmüller S. Krebs und Ernährung. Stuttgart: Georg Thieme Verlag KG; 2014
    Article in Thieme ConnectGoogle Scholar
  • 17 Field JA, Lettinga G. Toxicity of tannic compounds to microorganisms. In: Hemingway RW, Laks PE, editors Plant polyphenols: Basic life sciences 59. Heidelberg: Springer Verlag; 1992: 673-692
    Google Scholar
  • 18 Lambert JD, Sang S, Yang CS. Possible controversy over dietary polyphenols: benefits vs. risks. Chem Res Toxicol 2007; 20: 583-585
    CrossrefPubMedGoogle Scholar
  • 19 Roh C, Jung U. Screening of crude plant extracts with anti-obesity activity. Int J Mol Sci 2012; 13: 1710-1719
    CrossrefPubMedGoogle Scholar
  • 20 Singh S, Jarial R, Kanwar SS. Therapeutic effect of herbal medicines on obesity: herbal pancreatic lipase inhibitors. Wudpecker J Med Plants 2013; 2: 53-65
    PubMedGoogle Scholar
  • 21 World Health Organization. Obesity and overweight. Factsheet. Geneva: WHO; 2015: 311
    Google Scholar
  • 22 American Medical Association House of Delegates. Resolution 420 (A-13).. Available online: http://www.npr.org/documents/2013/jun/ama-resolution-obesity.pdf Accessed: June 11, 2015
    PubMedGoogle Scholar
  • 23 Tucci SA, Boyland EJ, Halford JCG. The role of lipid and carbohydrate digestive enzyme inhibitors in the management of obesity: a review of current and emerging therapeutic agents. Diabetes Metab Syndr Obes 2010; 3: 125-143
    CrossrefPubMedGoogle Scholar
  • 24 Carey MC, Hernell O. Digestion and absorption of fat. Gastroint Dis 1992; 3: 189-208
    PubMedGoogle Scholar
  • 25 Winkler FK, DʼArcy A, Hunziker W. Structure of human pancreatic lipase. Nature 1990; 343: 771-774
    CrossrefPubMedGoogle Scholar
  • 26 Kimura H, Futami Y, Tarui S, Shinomiya T. Activation of human pancreatic lipase activity by calcium and bile salts. J Biochem 1982; 92: 243-251
    CrossrefPubMedGoogle Scholar
  • 27 Birari RB, Bhutani KK. Pancreatic lipase inhibitors from natural sources: unexplored potential. Drug Discov Today 2007; 12: 879-889
    CrossrefPubMedGoogle Scholar
  • 28 Zeitz VM, Caspary WF, Bockemühl J, Lux G. Ökosystem Darm V. Heidelberg: Springer Verlag; 1993
    CrossrefGoogle Scholar
  • 29 Ebermann R, Elmadfa I. Lehrbuch Lebensmittelchemie und Ernährung. Heidelberg: Springer Verlag; 2011
    CrossrefGoogle Scholar
  • 30 Kuksis A, Shaikh NA, Hoffman AG. Lipid absorption and metabolism. Environ Health Perspect 1979; 33: 45-55
    CrossrefPubMedGoogle Scholar
  • 31 Mole S, Waterman PG. Tannic acid and proteolytic enzymes: Enzyme inhibition or substrate deprivation?. Phytochemistry 1986; 26: 99-102
    CrossrefPubMedGoogle Scholar
  • 32 Griffiths DW. The inhibition of digestive enzymes by extracts of field bean (Vicia faba). J Sci Food Agric 1979; 30: 458-462
    CrossrefPubMedGoogle Scholar
  • 33 Haslam E. Plant Polyphenols: Vegetable Tannins revisited. Chemistry and Pharmacology of natural Products University of Cambridge Oriental Publications. Cambridge: CUP Archive; 1989
    Google Scholar
  • 34 Sergent T, Vanderstraeten J, Winand J, Beguin P, Schneider YJ. Phenolic compounds and plant extracts as potential natural anti-obesity substances. Food Chem 2012; 135: 68-73
    CrossrefPubMedGoogle Scholar
  • 35 Lee EM, Lee SS, Chung BY, Cho JY, Lee IC, Ahn SR, Jang SJ, Kim TH. Pancreatic lipase inhibition by C-glycosidic flavones isolated from Eremochloa ophiuroides . Molecules 2010; 15: 8251-8259
    CrossrefPubMedGoogle Scholar
  • 36 Wu YHS, Chiu CH, Yang DJ, Lin YL, Tseng JK, Chen YC. Inhibitory effects of litchi (Litchi chinensis Sonn.) flower-water extracts on lipase activity and diet-induced obesity. J Funct Foods 2013; 5: 923-929
    CrossrefPubMedGoogle Scholar
  • 37 Marrelli M, Loizzo MR, Nicoletti M, Menichini F, Conforti F. In vitro investigation of the potential health benefits of wild Mediterranean dietary plants as anti-obesity agents with α-amylase and pancreatic lipase inhibitory activities. J Sci Food Agric 2014; 94: 2217-2224
    CrossrefPubMedGoogle Scholar
  • 38 You Q, Chen F, Wang X, Jiang Y, Lin S. Anti-diabetic activities of phenolic compounds in muscadine against alpha-glucosidase and pancreatic lipase. LWT – Food Sci Technol 2012; 46: 164-168
    CrossrefPubMedGoogle Scholar
  • 39 Nakai M, Fukui Y, Asami S, Toyoda-Ono Y, Iwashita T, Shibata H, Mitsunaga T, Hashimoto F, Kiso Y. Inhibitory effects of oolong tea polyphenols on pancreatic lipase in vitro . J Agric Food Chem 2005; 53: 4593-4598
    CrossrefPubMedGoogle Scholar
  • 40 Yuda N, Tanaka M, Suzuki M, Asano Y, Ochi H, Iwatsuki K. Polyphenols extracted from black tea (Camellia sinensis) residue by hot-compressed water and their inhibitory effect on pancreatic lipase in vitro . J Food Sci 2012; 77: H254-H261
    CrossrefPubMedGoogle Scholar
  • 41 Cha KH, Song DG, Kim SM, Pan CH. Inhibition of gastrointestinal lipolysis by green tea, coffee, and gomchui (Ligularia fischeri) tea polyphenols during simulated digestion. J Agric Food Chem 2012; 60: 7152-7157
    CrossrefPubMedGoogle Scholar
  • 42 Karamać M, Amarowicz R. Inhibition of pancreatic lipase by phenolic acids – examination in vitro . Z Naturforsch 1996; 51: 903-905
    PubMedGoogle Scholar
  • 43 Batubara I, Kuspradini H, Muddathir AM, Mitsunaga T. Intsia palembanica wood extracts and its isolated compounds as Propionibacterium acnes lipase inhibitor. J Wood Sci 2014; 60: 169-174
    CrossrefPubMedGoogle Scholar
  • 44 Jeong JY, Jo YH, Lee KY, Do SG, Hwang BY, Lee MK. Optimization of pancreatic lipase inhibition by Cudrania tricuspidata fruits using response surface methodology. Bioorg Med Chem Lett 2014; 24: 2329-2333
    CrossrefPubMedGoogle Scholar
  • 45 Yoshikawa M, Shimoda H, Nishida N, Takada M, Matsuda H. Salacia reticulata and its polyphenolic constituents with lipase inhibitory and lipolytic activities have mild antiobesity effects in rats. J Nutr 2002; 132: 1819-1824
    PubMedGoogle Scholar
  • 46 Park HJ, Jung UJ, Lee MK, Cho SJ, Jung HK, Hong JH, Park YB, Kim SR, Shim S, Jung J, Choi MS. Modulation of lipid metabolism by polyphenol-rich grape skin extract improves liver steatosis and adiposity in high fat fed mice. Mol Nutr Food Res 2012; 57: 360-364
    PubMedGoogle Scholar
  • 47 Spencer JPE. Flavonoids: modulators of brain function?. Br J Nutr 2008; 99 (E Suppl. 1) ES60-ES77
    PubMedGoogle Scholar
  • 48 Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004; 79: 727-747
    PubMedGoogle Scholar
  • 49 Wollgast J, Anklam E. Review on polyphenols in Theobroma cacao: changes in composition during the manufacture of chocolate and methodology for identification and quantification. Food Res Int 2000; 33: 423-447
    CrossrefPubMedGoogle Scholar
  • 50 Bhagwat S, Haytowitz DB, Holden JM. USDA Database for the Flavonoid Content of Selected Foods (2001, 3).. Available online: http://www.ars.usda.gov/SP2UserFiles/Place/80400525/Data/Flav/Flav_R03.pdf Accessed: June 15, 2015
    PubMedGoogle Scholar
  • 51 Assini JM, Mulvihill EE, Huff MW. Citrus flavonoids and lipid metabolism. Curr Opin Lipidol 2013; 24: 34-40
    CrossrefPubMedGoogle Scholar
  • 52 Zhang HM, Zhou QC, Geng J. Lipase inhibitory effects of flavonoids from Xanthoceras sorbifolia Bunge. World J Pharm Sci 2014; 3: 184-194
    PubMedGoogle Scholar
  • 53 Kawaguchi K, Mizuno T, Aida K, Uchino K. Hesperidin as an inhibitor of lipases from porcine pancreas and Pseudomonas. Biosci Biotechnol Biochem 1997; 61: 102-104
    CrossrefPubMedGoogle Scholar
  • 54 Eidenberger T, Selg M, Fuerst S, Krennhuber K. In-vitro inhibition of human lipase PS by polyphenols from Kiwi fruit. J Food Res 2014; 3: 71-77
    PubMedGoogle Scholar
  • 55 Grove KA, Lambert JD. Laboratory, epidemiological, and human intervention studies show that tea (Camellia sinensis) may be useful in the prevention of obesity. J Nutr 2010; 140: 446-453
    CrossrefPubMedGoogle Scholar
  • 56 Wolfram S, Wang Y, Thielecke F. Anti-obesity effects of green tea: from bedside to bench. Mol Nutr Food Res 2006; 50: 176-187
    CrossrefPubMedGoogle Scholar
  • 57 Huang J, Wang Y, Xie Z, Zhou Y, Zhang Y, Wan X. The anti-obesity effects of green tea in human intervention and basic molecular studies. Eur J Clin Nutr 2014; 68: 1075-1087
    CrossrefPubMedGoogle Scholar
  • 58 Nagao T, Komine Y, Soga S, Meguro S, Hase T, Tanaka Y, Tokimitsu I. Ingestion of a tea rich in catechins leads to a reduction in body fat and malondialdehyde-modified LDL in men. Am J Clin Nutr 2005; 81: 122-129
    PubMedGoogle Scholar
  • 59 Tsuchida T, Itakura H, Nakamura H. Reduction of body fat in humans by long-term ingestion of catechins. Prog Med 2002; 22: 2189-2203
    PubMedGoogle Scholar
  • 60 Gu Y, Hurst WJ, Stuart DA, Lambert JD. Inhibition of key digestive enzymes by cocoa extracts and procyanidins. J Agric Food Chem 2011; 59: 5305-5311
    CrossrefPubMedGoogle Scholar
  • 61 Quesada H, del Bas JM, Pajuelo D, Díaz S, Fernandez-Larrea J, Pinent M, Arola L, Salvadó MJ, Bladé C. Grape seed proanthocyanidins correct dyslipidemia associated with a high-fat diet in rats and repress genes controlling lipogenesis and VLDL assembling in liver. Int J Obes (Lond) 2009; 33: 1007-1012
    CrossrefPubMedGoogle Scholar
  • 62 Bladé C, Arola L, Salvadó MJ. Hypolipidemic effects of proanthocyanidins and their underlying biochemical and molecular mechanisms. Mol Nutr Food Res 2010; 54: 37-59
    CrossrefPubMedGoogle Scholar
  • 63 Shimura S, Itoh Y, Yamashita A, Kitano A, Hatano T, Yoshida T, Okuda T. Inhibitory effects of flavonoids on lipase. Nippon Shokuhin Kogyo Gakkaishi 1994; 41: 847-850
    CrossrefPubMedGoogle Scholar
  • 64 You Q, Chen F, Wang X, Luo PG, Jiang Y. Inhibitory effects of muscadine anthocyanins on α-glucosidase and pancreatic lipase activities. J Agric Food Chem 2011; 59: 9506-9511
    CrossrefPubMedGoogle Scholar
  • 65 Kato E, Yama M, Nakagomi R, Shibata T, Hosokawa K, Kawabata J. Substrate-like water soluble lipase inhibitors from Filipendula kamtschatica . Bioorg Med Chem Lett 2012; 22: 6410-6412
    CrossrefPubMedGoogle Scholar
  • 66 Sakulnarmrat K, Srzednicki G, Konczak I. Composition and inhibitory activities towards digestive enzymes of polyphenolic-rich fractions of Davidsonʼs plum and quandong. LWT – Food Sci Technol 2014; 57: 366-375
    CrossrefPubMedGoogle Scholar
  • 67 Kumar S, Alagawadi KR. Anti-obesity effects of galangin, a pancreatic lipase inhibitor in cafeteria diet fed female rats. Pharm Biol 2013; 51: 607-613
    CrossrefPubMedGoogle Scholar
  • 68 Zhang B, Deng Z, Ramdath DD, Tang Y, Chen PX, Liu R, Liu Q, Tsao R. Phenolic profiles of 20 Canadian lentil cultivars and their contribution to antioxidant activity and inhibitory effects on α-glucosidase and pancreatic lipase. Food Chem 2015; 172: 862-872
    CrossrefPubMedGoogle Scholar
  • 69 Tao Y, Zhang Y, Wang Y, Cheng Y. Hollow fiber based affinity selection combined with high performance liquid chromatography – mass spectroscopy for rapid screening lipase inhibitors from lotus leaf. Anal Chim Acta 2013; 785: 75-81
    CrossrefPubMedGoogle Scholar
  • 70 Dalar A, Türker M, Zabaras D, Konczak I. Phenolic composition, antioxidant and enzyme inhibitory activities of Eryngium bornmuelleri leaf. Plant Foods Hum Nutr 2014; 69: 30-36
    CrossrefPubMedGoogle Scholar
  • 71 Kawsar SMA, Huq E, Nahar N, Ozeki Y. Identification and quantification of phenolic acids in Macrotyloma uniflorum by reversed phase HPLC. J Plant Physiol 2008; 3: 165-172
    CrossrefPubMedGoogle Scholar
  • 72 Bengoechea L, Hernandez T, Quesada C, Bartolome B, Estrella I, Gomez-Cordoves C. Structure of hydroxycinnamic acid derivatives established by high-perfomance liquid chromatography with photodiode-array detection. Chromatographia 1995; 41: 95-98
    PubMedGoogle Scholar
  • 73 Meyer AS, Donovan JL, Pearson DA, Waterhouse AL, Frankel EN. Fruit hydroxycinnamic acids inhibit human low-density lipoprotein oxidation in vitro . J Agric Food Chem 1998; 46: 1783-1787
    CrossrefPubMedGoogle Scholar
  • 74 Herrmann K. Ueber den Gehalt und die Lokalisation der phenolischen Inhaltsstoffe im Gemuese. Qual Plant 1976; 25: 231-246
    CrossrefPubMedGoogle Scholar
  • 75 Watzl B, Rechkemmer G. Phenolsäuren. Ernährungs-Umschau 2001; 48: 413-416
    PubMedGoogle Scholar
  • 76 Gironés-Vilaplana A, Moreno DA, García-Viguera C. Phytochemistry and biological activity of Spanish Citrus fruits. Food Funct 2014; 5: 764-772
    CrossrefPubMedGoogle Scholar
  • 77 Bustanji Y, Issa A, Mohammad M, Hudaib M, Tawah K, Alkhatib H, Almasri I, Al-Khalidi B. Inhibition of hormone sensitive lipase and pancreatic lipase by Rosmarinus officinalis extract and selected phenolic constituents. J Med Plant Res 2010; 4: 2235-2242
    PubMedGoogle Scholar
  • 78 Khadem S, Marles RJ. Monocyclic phenolic acids; hydroxy- and polyhydroxybenzoic acids: Occurrence and recent bioactivity studies. Molecules 2010; 15: 7985-8005
    CrossrefPubMedGoogle Scholar
  • 79 Shahidi F, Ho CT. Phenolics in food and natural health products: an overview. Phenolic compounds in foods and natural health products. ACS Symposium Series. Am Chem Soc 2005; 1: 2-8
    PubMedGoogle Scholar
  • 80 Jo YH, Kim SB, Ahn JH, Liu Q, Hwang BY, Lee MK. Inhibitory activity of benzophenones from Anemarrhena asphodeloides on pancreatic lipase. Nat Prod Commun 2013; 8: 481-483
    PubMedGoogle Scholar
  • 81 Adlercreutz H. Lignans and human health. Crit Rev Clin Lab Sci 2007; 44: 483-525
    CrossrefPubMedGoogle Scholar
  • 82 Meagher LP, Beecher GR. Assessment of data on the lignan content of foods. J Food Compos Anal 2000; 13: 935-947
    CrossrefPubMedGoogle Scholar
  • 83 Ahn JH, Shin EJ, Liu Q, Kim SB, Choi KM, Yoo HS, Hwang BY, Lee MK. Lignan derivatives from Fraxinus rhynchophylla and inhibitory activity on pancreatic lipase. Nat Prod Sci 2012; 18: 116-120
    PubMedGoogle Scholar