Nutr Res Pract.  2014 Feb;8(1):20-26.

Effect of combined mulberry leaf and fruit extract on liver and skin cholesterol transporters in high fat diet-induced obese mice

Affiliations
  • 1Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
  • 2Department of Food and Nutrition, Kyung Hee University, 26, Kyunghee-ro, Dongdaemun-gu, Seoul 130-701, Korea. ylim@khu.ac.kr
  • 3Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze, University of Siena, Siena, Italy.

Abstract

Obesity is an epidemic disease characterized by an increased inflammatory state and chronic oxidative stress with high levels of pro-inflammatory cytokines and lipid peroxidation. Moreover, obesity alters cholesterol metabolism with increases in low-density lipoprotein (LDL) cholesterols and triglycerides and decreases in high-density lipoprotein (HDL) cholesterols. It has been shown that mulberry leaf and fruit ameliorated hyperglycemic and hyperlipidemic conditions in obese and diabetic subjects. We hypothesized that supplementation with mulberry leaf combined with mulberry fruit (MLFE) ameliorate cholesterol transfer proteins accompanied by reduction of oxidative stress in the high fat diet induced obesity. Mice were fed control diet (CON) or high fat diet (HF) for 9 weeks. After obesity was induced, the mice were administered either the HF or the HF with combination of equal amount of mulberry leaf and fruit extract (MLFE) at 500mg/kg/day by gavage for 12 weeks. MLFE treatment ameliorated HF induced oxidative stress demonstrated by 4-hydroxynonenal (4-HNE) and modulated the expression of 2 key proteins involved in cholesterol transfer such as scavenger receptor class B type 1 (SR-B1) and ATP-binding cassette transporter A1 (ABCA1) in the HF treated animals. This effect was mainly noted in liver tissue rather than in cutaneous tissue. Collectively, this study demonstrated that MLFE treatment has beneficial effects on the modulation of high fat diet-induced oxidative stress and on the regulation of cholesterol transporters. These results suggest that MLFE might be a beneficial substance for conventional therapies to treat obesity and its complications.

Keyword

ATP-binding cassette transporter A1; cholesterol metabolism; mulberry; obesity; scavenger receptor class B type 1

MeSH Terms

Animals
Cholesterol*
Cytokines
Diet
Diet, High-Fat
Fruit*
Lipid Peroxidation
Lipoproteins
Liver*
Metabolism
Mice
Mice, Obese*
Morus*
Obesity
Oxidative Stress
Receptors, Scavenger
Skin*
Triglycerides
Cholesterol
Cytokines
Lipoproteins
Receptors, Scavenger
Triglycerides

Figure

  • Fig. 1 Effect of MLFE supplementation on liver (A) and skin (B) morphology in high fat diet-induced obese mice. (magnitude × 100) CON: the mice fed the control diet, HF: the mice fed the high fat diet, MLFE: the mice fed the HF group administered with 1:1 ratio of MLE and MFE at dose of 500 mg/kg/day.

  • Fig. 2 Effect of MLFE supplementation on 4-HNE expression of liver (A) and skin (B) in high fat diet-induced obese mice. (magnitude × 100) (C) is a quantitative estimation for 4-HNE. CON: the mice fed the control diet, HF: the mice fed the high fat diet, MLFE: the mice fed the HF group administered with 1:1 ratio of MLE and MFE at dose of 500 mg/kg/day. *significant vs respective control. #significant within the same group. P < 0.05

  • Fig. 3 Effect of MLFE supplementation on liver SR-B1 (A) and ABCA1 (B) expressions in high fat diet-induced obese mice. (magnitude × 100) (C) is a quantitative estimation for SR-B1 and ABCA1. CON: the mice fed the control diet, HF: the mice fed the high fat diet, MLFE: the mice fed the HF group administered with 1:1 ratio of MLE and MFE at dose of 500 mg/kg/day. *significant vs respective control. #significant within the same group. P < 0.05

  • Fig. 4 Effect of MLFE supplementation on skin SR-B1 (A) and ABCA1 (B) expressions in high fat diet-induced obese mice. (magnitude × 100) (C) is a quantitative estimation for SR-B1 and ABCA1. CON: the mice fed the control diet, HF: the mice fed the high fat diet, MLFE: the mice fed the HF group administered with 1:1 ratio of MLE and MFE at dose of 500 mg/kg/day. *significant vs respective control. #significant within the same group. P < 0.05


Reference

1. Brundtland GH. From the World Health Organization. Reducing risks to health, promoting healthy life. JAMA. 2002; 288:1974.
2. Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, Esquivel-Soto J, Morales-González A, Esquivel-Chirino C, Durante-Montiel I, Sánchez-Rivera G, Valadez-Vega C, Morales-González JA. Inflammation, oxidative stress, and obesity. Int J Mol Sci. 2011; 12:3117–3132.
Article
3. Kopelman PG. Obesity as a medical problem. Nature. 2000; 404:635–643.
Article
4. Esposito K, Ciotola M, Schisano B, Misso L, Giannetti G, Ceriello A, Giugliano D. Oxidative stress in the metabolic syndrome. J Endocrinol Invest. 2006; 29:791–795.
Article
5. Pitocco D, Zaccardi F, Di Stasio E, Romitelli F, Santini SA, Zuppi C, Ghirlanda G. Oxidative stress, nitric oxide, and diabetes. Rev Diabet Stud. 2010; 7:15–25.
Article
6. Mukhtar H, Elmets CA. Photocarcinogenesis: mechanisms, models and human health implications. Photochem Photobiol. 1996; 63:356–357.
Article
7. Shindo Y, Witt E, Packer L. Antioxidant defense mechanisms in murine epidermis and dermis and their responses to ultraviolet light. J Invest Dermatol. 1993; 100:260–265.
Article
8. Shindo Y, Witt E, Han D, Epstein W, Packer L. Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin. J Invest Dermatol. 1994; 102:122–124.
Article
9. Mattson MP. Roles of the lipid peroxidation product 4-hydroxynonenal in obesity, the metabolic syndrome, and associated vascular and neurodegenerative disorders. Exp Gerontol. 2009; 44:625–633.
Article
10. Vincent HK, Powers SK, Dirks AJ, Scarpace PJ. Mechanism for obesity-induced increase in myocardial lipid peroxidation. Int J Obes Relat Metab Disord. 2001; 25:378–388.
Article
11. Fon Tacer K, Rozman D. Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation. J Lipids. 2011; 2011:783976.
Article
12. Trigatti BL, Krieger M, Rigotti A. Influence of the HDL receptor SR-BI on lipoprotein metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23:1732–1738.
Article
13. Spady DK, Kearney DM, Hobbs HH. Polyunsaturated fatty acids up-regulate hepatic scavenger receptor B1 (SR-BI) expression and HDL cholesteryl ester uptake in the hamster. J Lipid Res. 1999; 40:1384–1394.
Article
14. Hatahet W, Cole L, Kudchodkar BJ, Fungwe TV. Dietary fats differentially modulate the expression of lecithin:cholesterol acyltransferase, apoprotein-A1 and scavenger receptor b1 in rats. J Nutr. 2003; 133:689–694.
Article
15. Roberts CK, Liang K, Barnard RJ, Kim CH, Vaziri ND. HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, SR-B1, and ACAT in diet-induced syndrome X. Kidney Int. 2004; 66:1503–1511.
Article
16. Grefhorst A, Oosterveer MH, Brufau G, Boesjes M, Kuipers F, Groen AK. Pharmacological LXR activation reduces presence of SR-B1 in liver membranes contributing to LXR-mediated induction of HDL-cholesterol. Atherosclerosis. 2012; 222:382–389.
Article
17. Datar R, Kaesemeyer WH, Chandra S, Fulton DJ, Caldwell RW. Acute activation of eNOS by statins involves scavenger receptor-B1, G protein subunit Gi, phospholipase C and calcium influx. Br J Pharmacol. 2010; 160:1765–1772.
Article
18. Attia N, Fournier N, Vedie B, Cambillau M, Beaune P, Ziegler O, Grynberg A, Paul JL, Guerci B. Impact of android overweight or obesity and insulin resistance on basal and postprandial SR-BI and ABCA1-mediated serum cholesterol efflux capacities. Atherosclerosis. 2010; 209:422–429.
Article
19. Villarreal-Molina MT, Aguilar-Salinas CA, Rodríguez-Cruz M, Riaño D, Villalobos-Comparan M, Coral-Vazquez R, Menjivar M, Yescas-Gomez P, Königsoerg-Fainstein M, Romero-Hidalgo S, Tusie-Luna MT, Canizales-Quinteros S. Metabolic Study Group. The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities. Diabetes. 2007; 56:1881–1887.
Article
20. Dong SZ, Zhao SP, Wu ZH, Yang J, Xie XZ, Yu BL, Nie S. Curcumin promotes cholesterol efflux from adipocytes related to PPARgamma-LXRalpha-ABCA1 passway. Mol Cell Biochem. 2011; 358:281–285.
Article
21. Beulens JW, Sierksma A, van Tol A, Fournier N, van Gent T, Paul JL, Hendriks HF. Moderate alcohol consumption increases cholesterol efflux mediated by ABCA1. J Lipid Res. 2004; 45:1716–1723.
Article
22. Ehlers SJ, Larson SM, Rasmussen HE, Park YK, Lee JY. High-density lipoprotein metabolism in human apolipoprotein B(100) transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia. Appl Physiol Nutr Metab. 2011; 36:313–322.
Article
23. Yosipovitch G, DeVore A, Dawn A. Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol. 2007; 56:901–916.
Article
24. Seitz O, Schürmann C, Hermes N, Müller E, Pfeilschifter J, Frank S, Goren I. Wound healing in mice with high-fat diet- or ob gene-induced diabetes-obesity syndromes: a comparative study. Exp Diabetes Res. 2010; 2010:476969.
25. Wilson JA, Clark JJ. Obesity: impediment to wound healing. Crit Care Nurs Q. 2003; 26:119–132.
26. Lim HH, Yang SJ, Kim Y, Lee M, Lim Y. Combined treatment of mulberry leaf and fruit extract ameliorates obesity-related inflammation and oxidative stress in high fat diet-induced obese mice. J Med Food. 2013; 16:673–680.
Article
27. Lim HH, Lee SO, Kim SY, Yang SJ, Lim Y. Anti-inflammatory and antiobesity effects of mulberry leaf and fruit extract on high fat diet-induced obesity. Exp Biol Med (Maywood). 2013; 238:1160–1169.
Article
28. Barrera G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol. 2012; 2012:137289.
Article
29. Bełtowski J, Wójcicka G, Górny D, Marciniak A. The effect of dietary-induced obesity on lipid peroxidation, antioxidant enzymes and total plasma antioxidant capacity. J Physiol Pharmacol. 2000; 51:883–896.
30. Sticozzi C, Belmonte G, Pecorelli A, Arezzini B, Gardi C, Maioli E, Miracco C, Toscano M, Forman HJ, Valacchi G. Cigarette smoke affects keratinocytes SRB1 expression and localization via H2O2 production and HNE protein adducts formation. PLoS One. 2012; 7:e33592.
Article
31. Valacchi G, Davis PA, Khan EM, Lanir R, Maioli E, Pecorelli A, Cross CE, Goldkorn T. Cigarette smoke exposure causes changes in Scavenger Receptor B1 level and distribution in lung cells. Int J Biochem Cell Biol. 2011; 43:1065–1070.
Article
32. Sticozzi C, Belmonte G, Pecorelli A, Cervellati F, Leoncini S, Signorini C, Ciccoli L, De Felice C, Hayek J, Valacchi G. Scavenger receptor B1 post-translational modifications in Rett syndrome. FEBS Lett. 2013; 587:2199–2204.
Article
33. Fluiter K, Vietsch H, Biessen EA, Kostner GM, van Berkel TJ, Sattler W. Increased selective uptake in vivo and in vitro of oxidized cholesteryl esters from high-density lipoprotein by rat liver parenchymal cells. Biochem J. 1996; 319:471–476.
Article
34. Mardones P, Strobel P, Miranda S, Leighton F, Quiñones V, Amigo L, Rozowski J, Krieger M, Rigotti A. Alpha-tocopherol metabolism is abnormal in scavenger receptor class B type I (SR-BI)-deficient mice. J Nutr. 2002; 132:443–449.
Article
35. Tsuruoka H, Khovidhunkit W, Brown BE, Fluhr JW, Elias PM, Feingold KR. Scavenger receptor class B type I is expressed in cultured keratinocytes and epidermis. Regulation in response to changes in cholesterol homeostasis and barrier requirements. J Biol Chem. 2002; 277:2916–2922.
Article
36. Morán-Ramos S, Avila-Nava A, Tovar AR, Pedraza-Chaverri J, López-Romero P, Torres N. Opuntia ficus indica (nopal) attenuates hepatic steatosis and oxidative stress in obese Zucker (fa/fa) rats. J Nutr. 2012; 142:1956–1963.
Article
37. Parola M, Pinzani M, Casini A, Albano E, Poli G, Gentilini A, Gentilini P, Dianzani MU. Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen α1 (I) gene expression in human liver fat-storing cells. Biochem Biophys Res Commun. 1993; 194:1044–1050.
Article
38. Sarada S, Himadri P, Mishra C, Geetali P, Ram MS, Ilavazhagan G. Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med (Maywood). 2008; 233:1088–1098.
Article
39. Kalpana S, Dhananjay S, Anju B, Lilly G, Sai Ram M. Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain: molecular mechanisms of action of cobalt chloride. Toxicol Appl Pharmacol. 2008; 231:354–363.
Article
40. Hang CH, Shi JX, Li JS, Wu W, Yin HX. Concomitant upregulation of nuclear factor-kB activity, proinflammatory cytokines and ICAM-1 in the injured brain after cortical contusion trauma in a rat model. Neurol India. 2005; 53:312–317.
Article
41. Oram JF, Vaughan AM. ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins. Curr Opin Lipidol. 2000; 11:253–260.
Article
42. Srivastava N. ATP binding cassette transporter A1--key roles in cellular lipid transport and atherosclerosis. Mol Cell Biochem. 2002; 237:155–164.
43. Valacchi G, Vasu VT, Yokohama W, Corbacho AM, Phung A, Lim Y, Aung HH, Cross CE, Davis PA. Lung vitamin E transport processes are affected by both age and environmental oxidants in mice. Toxicol Appl Pharmacol. 2007; 222:227–234.
Article
44. Sticozzi C, Pecorelli A, Belmonte G, Valacchi G. Cigarette smoke affects ABCAl expression via liver X receptor nuclear translocation in human keratinocytes. Int J Mol Sci. 2010; 11:3375–3386.
Article
45. Kim SY, Lee WC, Kim HB, Kim AJ, Kim SK. Antihyperlipidemic effects of methanol extracts from mulberry leaves in cholesterol-induced hyperlipidemia rats. J Korean Soc Food Sci Nutr. 1998; 27:1217–1222.
46. Park SH, Jang MJ, Hong JH, Rhee SJ, Choi KH, Park MR. Effects of mulberry leaf extract feeding on lipid status of rats fed high cholesterol diets. J Korean Soc Food Sci Nutr. 2007; 36:43–50.
Article
47. Yang X, Yang L, Zheng H. Hypolipidemic and antioxidant effects of mulberry (Morus alba L.) fruit in hyperlipidaemia rats. Food Chem Toxicol. 2010; 48:2374–2379.
Article
48. Lee J, Chae K, Ha J, Park BY, Lee HS, Jeong S, Kim MY, Yoon M. Regulation of obesity and lipid disorders by herbal extracts from Morus alba, Melissa officinalis, and Artemisia capillaris in high-fat diet-induced obese mice. J Ethnopharmacol. 2008; 115:263–270.
Article
Full Text Links
  • NRP
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr