Protective effect of boswellic acids versus pioglitazone in a rat model of diet-induced non-alcoholic fatty liver disease: influence on insulin resistance and energy expenditure

  • Sawsan A. Zaitone
  • Bassant M. Barakat
  • Shymaa E. Bilasy
  • Manal S. Fawzy
  • Eman Z. Abdelaziz
  • Noha E. Farag
Original Article
First Online:
Received:
Accepted:

Abstract

Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance, oxidative stress, and cytokine imbalance. Boswellic acids, a series of pentacyclic triterpene molecules that are produced by plants in the genus Boswellia, has been traditionally used for the treatment of a variety of diseases. This study aimed at evaluating the protective effect of boswellic acids in a model of diet-induced NAFLD in rats in comparison to the standard insulin sensitizer, pioglitazone. Rats were fed with a high-fat diet (HFD) for 12 weeks to induce NAFLD. Starting from week 5, rats received boswellic acids (125 or 250 mg/kg) or pioglitazone parallel to the HFD. Feeding with HFD induced hepatic steatosis and inflammation in rats. In addition, liver index, insulin resistance index, activities of liver enzymes, and serum lipids deviated from normal. Further, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cyclooxygenase 2 were elevated; this was associated with an increase in hepatic expression of inducible nitric oxide synthase (iNOS) and formation of 4-hydroxy-2-nonenal (HNE). Rats treated with boswellic acids (125 or 250 mg/kg) or pioglitazone showed improved insulin sensitivity and a reduction in liver index, activities of liver enzymes, serum TNF-α and IL-6 as well as hepatic iNOS expression and HNE formation compared to HFD group. Furthermore, at the cellular level, boswellic acids (250 mg/kg) ameliorated the expression of thermogenesis-related mitochondrial uncoupling protein-1 and carnitine palmitoyl transferase-1 in white adipose tissues. Data from this study indicated that boswellic acids might be a promising therapy in the clinical management of NAFLD if appropriate safety and efficacy data are available.

Keywords

Boswellic acids High-fat diet Insulin resistance Non-alcoholic fatty liver diseases Pioglitazone Thermogenesis 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors wish to acknowledge Dr. Abeer Shaalan, Pathology department, Faculty of Dentistry, Cairo University and Mister Mohamed Saad, Department of clinical pathology, Faculty of Medicine, Suez Canal University for their help in immunostaining. The authors also wish to thank Dr. Mohamed Kamal, Department of Pathology, Faculty of Medicine, Suez Canal University for his help in photomicrography and histopathological examination. Finally, authors are grateful to Dr. Mohamed Mandour, Department of Clinical Pathology, Faculty of Medicine, Suez Canal University for technical support.

Conflicts of interests

The authors declare no conflicts of interest.

References

  1. Abo-Elmatty DM, Zaitone SA (2011) Topiramate induces weight loss and improves insulin sensitivity in dietary obese rats: comparison to sibutramine. Eur Rev Med Pharmacol Sci 15:1187–1195PubMedGoogle Scholar
  2. Adams LA, Feldstein AE (2011) Non-invasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis. J Dig Dis 12:10–16CrossRefPubMedGoogle Scholar
  3. Agrawal S, Saraswati S, Mathur R, Pandey M (2011) Antiangiogenic and cytotoxic activity of boswellic acid on breast cancer MCF-7 cells. Biomed Prev Nut 2:31–37Google Scholar
  4. Ammon HP (2002) Boswellic acids (components of frankincense) as the active principle in treatment of chronic inflammatory diseases. Wien Med Wochenschr 152(15–16):373–378CrossRefPubMedGoogle Scholar
  5. Ammon HP (2006) Boswellic acids in chronic inflammatory diseases. Planta Med 72:1100–1116CrossRefPubMedGoogle Scholar
  6. Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888PubMedGoogle Scholar
  7. Buchele B, Zugmaier W, Simmet T (2003) Analysis of pentacyclic triterpenic acids from frankincense gum resins and related phytopharmaceuticals by high-performance liquid chromatography. Identification of lupeolic acid, a novel pentacyclic triterpene. J Chromatogr B 791(1):21–30CrossRefGoogle Scholar
  8. Cao H, Yu R, Choi Y, Ma ZZ, Zhang H, Xiang W, Lee DYW, Berman BM, Moudgil KD, Fong HHS (2010) Discovery of cyclooxygenase inhibitors from medicinal plants used to treat inflammation. Pharmacol Res 61:519–524CrossRefPubMedCentralPubMedGoogle Scholar
  9. Chaudhry J, Ghosh NN, Roy K, Chandra R (2007) Antihyperglycemic effect of a new thiazolidinedione analogue and its role in ameliorating oxidative stress in alloxan induced diabetic rats. Life Sci 80:1135–1142CrossRefPubMedGoogle Scholar
  10. Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA (1994) Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135:798–800PubMedGoogle Scholar
  11. Chiarelli F, Di Marzio D (2008) Peroxisome proliferator-activated receptor-γ agonists and diabetes: current evidence and future perspectives. Vasc Health Risk Manag 4:297–304PubMedCentralPubMedGoogle Scholar
  12. Culioli G, Mathe C, Archier P, Vieillescazes C (2003) A lupane triterpene from frankincense (Boswellia sp., Burseraceae). Phytochemistry 62:537–541CrossRefPubMedGoogle Scholar
  13. Dhiman AK (2006) Ayurvedic Drug Plants. Daya Publishing House, Delhi, pp 326–327Google Scholar
  14. Franceschi VR, Krokene P, Christiansen E, Krekling T (2005) Anatomical and chemical defenses of conifer bark against bark beetles and other pests. New Phytol 167:353–376CrossRefPubMedGoogle Scholar
  15. Fujita K, Yoneda M, Wada K, Mawatari H, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y, Maeyama S, Saito S, Iwasaki T, Terauchi Y, Nakajima A (2007) Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. Dig Dis Sci 52:3455–3464CrossRefPubMedGoogle Scholar
  16. Garcia-Monzon C, Majano PL, Zubia I, Sanz P, Apolinario A, Moreno-Otero R (2000) Intrahepatic accumulation of nitrotyrosine in chronic viral hepatitis is associated with histological severity of liver disease. J Hepatol 32:331–338CrossRefPubMedGoogle Scholar
  17. Gayathri B, Manjula N, Vinaykumar K, Lakshmi B, Balakrishnan A (2007) Pure compound from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse macrophages through inhibition of TNFα, IL-1β. NO and MAP kinases. Int Immunopharmacol 7:473–482CrossRefPubMedGoogle Scholar
  18. Gerhardt H, Seifert F, Buvari P, Vogelsang H, Repges R (2001) Therapy of active Crohn disease with Boswellia serrata extract H 15. Z Gastroenterol 39:11–17CrossRefPubMedGoogle Scholar
  19. Gupta I, Parihar A, Malhotra P, Singh GB, Ludtke R, Safayhi H, Ammon HP (1997) Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res 2:37–43PubMedGoogle Scholar
  20. Gupta I, Gupta V, Parihar A, Gupta S, Ludtke R, Safayhi H, Ammon HP (1998) Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. Eur J Med Res 3:511–514PubMedGoogle Scholar
  21. Ha SK, Chae C (2010) Inducible nitric oxide distribution in the fatty liver of a mouse with high fat diet-induced obesity. Exp Animal 59:595–604CrossRefGoogle Scholar
  22. Han X, Li H, Su L, Zhu W, Xu W, Li K, Zhao Q, Yang H, Liu H (2014) Effect of celecoxib plus standard chemotherapy on serum levels of vascular endothelial growth factor and cyclooxygenase-2 in patients with gastric cancer. Biomed Rep 2(2):183–187PubMedCentralPubMedGoogle Scholar
  23. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance. Science 271:665–668CrossRefPubMedGoogle Scholar
  24. Hsiao PJ, Hsieh TJ, Kuo KK, Hung WW, Tsai KB, Yang CH, Yu ML, Shin SJ (2008) Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet. BMC Mol Biol 9:82CrossRefPubMedCentralPubMedGoogle Scholar
  25. Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC (2003) Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 285:E906–916CrossRefPubMedGoogle Scholar
  26. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:E745–751PubMedGoogle Scholar
  27. Kimmatkar N, Thawani V, Hingorani L, Khiyani R (2003) Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee: a randomized double blind placebo controlled trial. Phytomedicine 10:3–7CrossRefPubMedGoogle Scholar
  28. Kopec KL, Burns D (2011) Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract 26(5):565–576CrossRefPubMedGoogle Scholar
  29. Krohn K, Rao MS, Raman NV, Khalilullah M (2001) High performance thin layer chromatographic analysis of anti-inflammatory triterpenoids from Boswellia serrata Roxb. Phytochem Anal 12:374–376CrossRefPubMedGoogle Scholar
  30. Larsen PJ, Jensen PB, Sørensen RV, Larsen LK, Vrang N, Wulff EM, Wassermann K (2003) Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis. Diabetes 52(9):2249–2259CrossRefPubMedGoogle Scholar
  31. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270:12953–12956CrossRefPubMedGoogle Scholar
  32. Loeb WF, Quimby FW (1989) The clinical chemistry of laboratory animals. Pergamon, New YorkGoogle Scholar
  33. Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55:434–438PubMedGoogle Scholar
  34. Mahajan B, Taneja SC, Sethi VK, Dhar KL (1995) Two triterpenoids from Boswellia serrata gum resin. Photochemistry 39:453–455CrossRefGoogle Scholar
  35. Majithiya JB, Parmar AN, Trivedi CJ, Balaraman R (2005) Effect of pioglitazone on L-NAME induced hypertension in diabetic rats. Vascul Pharmacol 43:260–266CrossRefPubMedGoogle Scholar
  36. Marx N, Froehlich J, Siam L, Ittner J, Wierse G, Schmidt A, Scharnagl H, Hombach V, Koenig W (2003) Antidiabetic PPAR γ activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 23:283–288CrossRefPubMedGoogle Scholar
  37. Mathe C, Culioli G, Archier P (2004) Characterization of archeological frankincense by gas chromatography mass spectrometry. J Chromatography 1023:277–285CrossRefGoogle Scholar
  38. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetology 28:412–419CrossRefGoogle Scholar
  39. Miyazaki Y, Pipek R, Mandarino LJ, DeFronzo RA (2003) Tumor necrosis factor-α and insulin resistance in obese type 2 diabetic patients. Int J Obes Relat Metab Disord 227:88–94CrossRefGoogle Scholar
  40. Noeman SA, Hamooda HE, Baalash AA (2013) Biochemical study of oxidative stress markers in the liver, kidney and heart of high fat diet induced obesity in rats. Diabetol Metab Syndr 3(1):17CrossRefGoogle Scholar
  41. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358CrossRefPubMedGoogle Scholar
  42. Pan M, Song YL, Xu JM, Gan HZ (2006) Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats. J Pineal Res 41:79–84CrossRefPubMedGoogle Scholar
  43. Pouliot M, Gilbert C, Borgeat P, Poubelle PE, Bourgoin S, Créminon C, Maclouf J, Mccoll SR, Naccache PH (1998) Expression and activity of prostaglandin endoperoxide synthase-2 in agonist-activated human neutrophils. FASEB J 12:1109–1123PubMedGoogle Scholar
  44. Pratt DS, Kaplan MM (2000) Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 342:1266–1271CrossRefPubMedGoogle Scholar
  45. Rall B, Ammon HP, Safayhi H (1996) Boswellic acids and protease activities. Phytomedicine 3:75–76CrossRefPubMedGoogle Scholar
  46. Reid AE (2001) Nonalcoholic steatohepatitis. Gastroenterology 121:710–723CrossRefPubMedGoogle Scholar
  47. Romano M, Guagnano MT, Pacini G, Vigneri S, Falco A, Marinopiccoli M, Manigrasso MR, Basili S, Davi G (2003) Association of inflammation markers with impaired insulin sensitivity and coagulative activation in obese healthy women. J Clin Endocrinol Metab 88:5321–5326CrossRefPubMedGoogle Scholar
  48. Safayhi H, Rall B, Sailer ER, Ammon HPT (1997) Inhibition by boswellic acids of human leukocyte elastase. J Pharmacol Exp Ther 281:460–463PubMedGoogle Scholar
  49. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279:32345–2353CrossRefPubMedGoogle Scholar
  50. Satoh K (1978) Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta 90(1):37–43CrossRefPubMedGoogle Scholar
  51. Schweizer S, von Brocke AF, Boden SE, Bayer E, Ammon HP, Safayhi H (2000) Workup-dependent formation of 5-lipoxygenase inhibitory boswellic acids analogues. J Nat Prod 63:1058–1061CrossRefPubMedGoogle Scholar
  52. Sebokova E, Kurthy M, Mogyorosi T, Nagy K, Demcakova E, Ukropec J, Koranyi L, Klimes I (2002) Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance. Ann NY Acad Sci 967:424–430CrossRefPubMedGoogle Scholar
  53. Sharma S, Thawani V, Hingorani L (2004) Pharmacokinetic study of 11-keto-beta-boswellic acid. Phytomedicine 11:255–260CrossRefPubMedGoogle Scholar
  54. Siddiqui MZ (2011) Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci 73(3):255–261PubMedCentralPubMedGoogle Scholar
  55. Siemoneit U, Hofmann B, Kather N, Lamkemeyer T, Madlung J, Franke L, Schneider G, Jauch J, Poecke D, Werz O (2008) Identification and functional analysis of cyclooxygenase-1 as a molecular target of boswellic acids. Biochem Pharmacol 75:503–513CrossRefPubMedGoogle Scholar
  56. Singh Ahuja H, Liu S, Crombie DL, Boehm M, Leibowitz MD, Heyman RA, Depre C, Nagy L, Tontonoz P, Davies PJ (2001) Differential effects of rexinoids and thiazolidinediones on metabolic gene expression in diabetic rodents. Mol Pharmacol 59(4):765–773PubMedGoogle Scholar
  57. Singh GB, Atal CK (1986) Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent. Agents Actions 18(3–4):407–412CrossRefPubMedGoogle Scholar
  58. Singh S, Khajuria A, Taneja SC, Khajuria RK, Singh J, Johri RK, Qazi GN (2008) The gastric ulcerprotective effect of boswellic acids, a leukotriene inhibitor from Boswellia serrata, in rats. Phytomedicine: Int J Phytother Phytopharmacol 15(6–7):408–415CrossRefGoogle Scholar
  59. Sugimoto M, Arai H, Tamura Y, Murayama T, Khaengkhan P, Nishio T, Ono K, Ariyasu H, Akamizu T, Ueda Y (2009) Mulberry leaf ameliorates the expression profile of adipocytokines by inhibiting oxidative stress in white adipose tissue in db/db mice. Atherosclerosis 204:388–394CrossRefPubMedGoogle Scholar
  60. Taslimi S, Esteghamati A, Rashidi A, Tavakkoli HM, Nakhjavani M, Kebriaee-Zadeh A (2013) Treatment with pioglitazone is associated with decreased preprandial ghrelin levels: a randomized clinical trial. Peptides 40:89–92CrossRefPubMedGoogle Scholar
  61. Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P et al (2006) Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 116:1983–1993CrossRefPubMedCentralPubMedGoogle Scholar
  62. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM (1994) mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8:1224–1234CrossRefPubMedGoogle Scholar
  63. Umar S, Umar K, Sarwar AH, Khan A, Ahmad N, Ahmad S, Katiyar CK, Husain SA, Khan HA (2014) Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis. Phytomed: Int J Phytother Phytopharmacol 21(6):847–856CrossRefGoogle Scholar
  64. Wang TD, Chen WJ, Lin JW, Chen MF, Lee YT (2004) Effects of rosiglitazone on endothelial function, C-reactive protein, and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome. Am J Cardiol 93:362–365CrossRefPubMedGoogle Scholar
  65. Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM (1996) The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem 39:665–668CrossRefPubMedGoogle Scholar
  66. Winking M, Sarikaya S, Rahmanian A, Jodicke A, Boker DK (2000) Boswellic acids inhibit glioma growth: a new treatment option? J Neurooncol 46(2):97–103CrossRefPubMedGoogle Scholar
  67. Xu MQ, Shuai XR, Yan ML, Zhang MM, Yan LN (2005) Nuclear factor-kappaB decoy oligonucleotides attenuate ischemia/reperfusion injury in rat liver graft. World J Gastroenterol 11:6960–6967PubMedGoogle Scholar
  68. Xu P, Zhang X, Li Y, Yu C, Xu L, Xu G (2006) Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats. J Zhejiang Univ (Sci) B7:627–633CrossRefGoogle Scholar
  69. Yalniz M, Bahcecioglu IH, Kuzu N, Celebi S, Ataseven H, Ustundag B, Ozercan IH, Sahin K (2007) Amelioration of steatohepatitis with pentoxifylline in a novel nonalcoholic steatohepatitis model induced by high-fat diet. Dig Dis Sci 52:2380–2386CrossRefPubMedGoogle Scholar
  70. Yan E, Durazo F, Tong M, Hong K (2007) Nonalcoholic fatty liver disease: pathogenesis, identification, progression, and management. Nutr Rev 65:376–384CrossRefPubMedGoogle Scholar
  71. Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106–1118CrossRefPubMedGoogle Scholar
  72. Yoshida Y, Ichikawa M, Ohta M, Kanai S, Kobayash M, Ichimaru Y, Shimazoe T, Watanabe S, Funakoshi A, Miyasak K (2002). A peroxisome proliferator-activated receptor gamma agonist influenced daily profile of energy expenditure in genetically obese diabetic rats. Jpn J Pharmacol Mar;88(3):279–284Google Scholar
  73. Zaitone SA, Abo-Gresha NM (2012) Rosuvastatin promotes angiogenesis and reverses isoproterenol-induced acute myocardial infarction in rats: role of iNOS and VEGF. Eur J Pharmacol 961:134–142CrossRefGoogle Scholar
  74. Zaitone SA, Essawy S (2012) Addition of a low dose of rimonabant to orlistat therapy decreases weight gain and reduces adiposity in dietary obese rats. Clin Exp Pharmacol Physiol 39:551–559CrossRefPubMedGoogle Scholar
  75. Zaitone SA, Hassan N, El-Orabi N, El-Awady E (2011) Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease. Eur J Pharmacol 622:70–77CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Sawsan A. Zaitone
    • 1
  • Bassant M. Barakat
    • 2
  • Shymaa E. Bilasy
    • 3
  • Manal S. Fawzy
    • 4
  • Eman Z. Abdelaziz
    • 5
  • Noha E. Farag
    • 6
  1. 1.Department of Pharmacology and Toxicology, Faculty of PharmacySuez Canal UniversityIsmailiaEgypt
  2. 2.Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls)Al-Azhar University CairoEgypt
  3. 3.Department of Biochemistry, Faculty of PharmacySuez Canal UniversityIsmailiaEgypt
  4. 4.Department of Medical Biochemistry, Faculty of MedicineSuez Canal UniversityIsmailiaEgypt
  5. 5.Department of Pharmacology, Faculty of MedicineSuez Canal UniversityIsmailiaEgypt
  6. 6.Department of Human Physiology, Faculty of MedicineSuez Canal UniversityIsmailiaEgypt

Personalised recommendations