Download PDF
Planta Med 2019; 85(09/10): 719-728
DOI: 10.1055/a-0901-1307
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Z-ligustilide and n-Butylidenephthalide Isolated from the Aerial Parts of Angelica tenuissima Inhibit Lipid Accumulation In Vitro and In Vivo

Wonseok Lee   *
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Hye Ryoung Koo   *
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
You-Jin Choi
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Jin Gyu Choi
2   Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
,
Myung Sook Oh
3   Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of South Korea
4   Department of Oriental Pharmaceutical Sciences, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul, Republic of Korea
,
Xing Jin
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Munki Choo
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Sunghyouk Park
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Yoo-Seong Jeong
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Suk-Jae Chung
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
,
Byung-Hoon Lee
1   College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
› Author Affiliations
Further Information

Publication History

received 19 September 2018
revised 11 April 2019

accepted 23 April 2019

Publication Date:
28 May 2019 (online)

Also available at
    Permissions and Reprints

Abstract

Abnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of Angelica tenuissima Nakai (ATX) inhibited high-fat diet–induced hepatic steatosis in mice as well as oleic acid–induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes fasn and scd1. The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid–induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.

Key words

Angelica tenuissima Nakai - Apiaceae - lipid metabolism - nonalcoholic fatty liver disease - gene expression

* Wonseok Lee and Hye Ryoung Koo contributed to the paper equally.


Supporting Information

 

  • References

  • 1 Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol 1999; 83: 25-29
    PubMedSearch in Google Scholar
  • 2 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-1850
    CrossrefPubMedSearch in Google Scholar
  • 3 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73-84
    CrossrefPubMedSearch in Google Scholar
  • 4 Leite NC, Villela-Nogueira CA, Cardoso CR, Salles GF. Non-alcoholic fatty liver disease and diabetes: from physiopathological interplay to diagnosis and treatment. World J Gastroenterol 2014; 20: 8377-8392
    CrossrefPubMedSearch in Google Scholar
  • 5 Choi YJ, Lee CH, Lee KY, Jung SH, Lee BH. Increased hepatic fatty acid uptake and esterification contribute to tetracycline-induced steatosis in mice. Toxicol Sci 2015; 145: 273-282
    CrossrefPubMedSearch in Google Scholar
  • 6 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115: 1343-1351
    CrossrefPubMedSearch in Google Scholar
  • 7 Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008; 134: 556-567
    CrossrefPubMedSearch in Google Scholar
  • 8 Miquilena-Colina ME, Lima-Cabello E, Sanchez-Campos S, Garcia-Mediavilla MV, Fernandez-Bermejo M, Lozano-Rodriguez T, Vargas-Castrillon J, Buque X, Ochoa B, Aspichueta P, Gonzalez-Gallego J, Garcia-Monzon C. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 2011; 60: 1394-1402
    CrossrefPubMedSearch in Google Scholar
  • 9 Doege H, Grimm D, Falcon A, Tsang B, Storm TA, Xu H, Ortegon AM, Kazantzis M, Kay MA, Stahl A. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J Biol Chem 2008; 283: 22186-22192
    CrossrefPubMedSearch in Google Scholar
  • 10 Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 2007; 282: 22678-22688
    CrossrefPubMedSearch in Google Scholar
  • 11 Kim CM, Sin MK, Ahn DK, Lee KS. Dictionary of Chinese Materia Medica. Korean edition. Seoul: Jungdam Publishing; 1997: 255
    Search in Google Scholar
  • 12 Weeratunga P, Uddin MB, Kim MS, Lee BH, Kim TH, Yoon JE, Ma JY, Kim H, Lee JS. Interferon-mediated antiviral activities of Angelica tenuissima Nakai and its active components. J Microbiol 2016; 54: 57-70
    CrossrefPubMedSearch in Google Scholar
  • 13 Payne VA, Au WS, Gray SL, Nora ED, Rahman SM, Sanders R, Hadaschik D, Friedman JE, OʼRahilly S, Rochford JJ. Sequential regulation of diacylglycerol acyltransferase 2 expression by CAAT/enhancer-binding protein beta (C/EBPbeta) and C/EBPalpha during adipogenesis. J Biol Chem 2007; 282: 21005-21014
    CrossrefPubMedSearch in Google Scholar
  • 14 Van Herck MA, Vonghia L, Francque SM. Animal models of nonalcoholic fatty liver disease – a starterʼs guide. Nutrients 2017; 9: 1072
    CrossrefPubMedSearch in Google Scholar
  • 15 Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 2008; 134: 933-944
    CrossrefPubMedSearch in Google Scholar
  • 16 Sethi JK, Vidal-Puig AJ. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res 2007; 48: 1253-1262
    CrossrefPubMedSearch in Google Scholar
  • 17 Zhong W, Zhao Y, Tang Y, Wei X, Shi X, Sun W, Sun X, Yin X, Sun X, Kim S, McClain CJ, Zhang X, Zhou Z. Chronic alcohol exposure stimulates adipose tissue lipolysis in mice: role of reverse triglyceride transport in the pathogenesis of alcoholic steatosis. Am J Pathol 2012; 180: 998-1007
    CrossrefPubMedSearch in Google Scholar
  • 18 Jang MK, Yun YR, Kim JH, Park MH, Jung MH. Gomisin N inhibits adipogenesis and prevents high-fat diet-induced obesity. Sci Rep 2017; 7: 40345
    CrossrefPubMedSearch in Google Scholar
  • 19 Chang YC, Yang MY, Chen SC, Wang CJ. Mulberry leaf polyphenol extract improves obesity by inducing adipocyte apoptosis and inhibiting preadipocyte differentiation and hepatic lipogenesis. J Funct Foods 2016; 21: 249-262
    CrossrefPubMedSearch in Google Scholar
  • 20 Buque X, Martinez MJ, Cano A, Miquilena-Colina ME, Garcia-Monzon C, Aspichueta P, Ochoa B. A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats. J Lipid Res 2010; 51: 500-513
    CrossrefPubMedSearch in Google Scholar
  • 21 Lee JH, Wada T, Febbraio M, He J, Matsubara T, Lee MJ, Gonzalez FJ, Xie W. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology 2010; 139: 653-663
    CrossrefPubMedSearch in Google Scholar
  • 22 Abumrad N. Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm. Biochim Biophys Acta 1999; 1441: 4-13
    PubMedSearch in Google Scholar
  • 23 Doege H, Baillie RA, Ortegon AM, Tsang B, Wu Q, Punreddy S, Hirsch D, Watson N, Gimeno RE, Stahl A. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology 2006; 130: 1245-1258
    CrossrefPubMedSearch in Google Scholar
  • 24 Falcon A, Doege H, Fluitt A, Tsang B, Watson N, Kay MA, Stahl A. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am J Physiol Endocrinol Metab 2010; 299: E384-E393
    CrossrefPubMedSearch in Google Scholar
  • 25 Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, Novak S, Collins C, Welch CB, Lusis AJ, Erickson SK, Farese RV. Identification of a gene encoding an acyl CoA: diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci U S A 1998; 95: 13018-13023
    CrossrefPubMedSearch in Google Scholar
  • 26 Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, Farese jr. RV. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J Biol Chem 2004; 279: 11767-11776
    CrossrefPubMedSearch in Google Scholar
  • 27 Man WC, Miyazaki M, Chu K, Ntambi J. Colocalization of SCD1 and DGAT2: implying preference for endogenous monounsaturated fatty acids in triglyceride synthesis. J Lipid Res 2006; 47: 1928-1939
    CrossrefPubMedSearch in Google Scholar
  • 28 Lapornik B, Prošek M, Wondra AC. Comparison of extracts prepared from plant by-products using different solvents and extraction time. J Food Eng 2005; 71: 214-222
    CrossrefPubMedSearch in Google Scholar
  • 29 Sato Y, Itagaki S, Kurokawa T, Ogura J, Kobayashi M, Hirano T, Sugawara M, Iseki K. In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm 2011; 403: 136-138
    CrossrefPubMedSearch in Google Scholar
  • 30 Cho AS, Jeon SM, Kim MJ, Yeo J, Seo KI, Choi MS, Lee MK. Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induced-obese mice. Food Chem Toxicol 2010; 48: 937-943
    CrossrefPubMedSearch in Google Scholar
  • 31 Srinivasan M, Sudheer AR, Menon VP. Ferulic acid: therapeutic potential through its antioxidant property. J Clin Biochem Nutr 2007; 40: 92-100
    CrossrefPubMedSearch in Google Scholar
  • 32 Naowaboot J, Piyabhan P, Munkong N, Parklak W, Pannangpetch P. Ferulic acid improves lipid and glucose homeostasis in high-fat diet-induced obese mice. Clin Exp Pharmacol Physiol 2016; 43: 242-250
    CrossrefPubMedSearch in Google Scholar
  • 33 Zhang XY, Qiao H, Shi YB. HPLC method with fluorescence detection for the determination of ligustilide in rat plasma and its pharmacokinetics. Pharm Biol 2014; 52: 21-30
    CrossrefPubMedSearch in Google Scholar
  • 34 Wu HF, Wang XY, Deng JF, Quan SJ, Wang Q, Li WR. Pharmacokinetic profiling of butylidenephthalide and alisol B in Danggui-Shaoyao-San in rats. Eur J Drug Metab Pharmacokinet 2018; 43: 645-653
    CrossrefPubMedSearch in Google Scholar
  • 35 Qi W, Zhao T, Yang WW, Wang GH, Yu H, Zhao HX, Yang C, Sun LX. Comparative pharmacokinetics of chlorogenic acid after oral administration in rats. J Pharm Anal 2011; 1: 270-274
    CrossrefPubMedSearch in Google Scholar
  • 36 Li W, Guo J, Tang Y, Wang H, Huang M, Qian D, Duan JA. Pharmacokinetic comparison of ferulic acid in normal and blood deficiency rats after oral administration of Angelica sinensis, Ligusticum chuanxiong and their combination. Int J Mol Sci 2012; 13: 3583-3597
    CrossrefPubMedSearch in Google Scholar
  • 37 Lawrence XY, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm 1999; 186: 119-125
    CrossrefPubMedSearch in Google Scholar
  • 38 Winiwarter S, Bonham NM, Ax F, Hallberg A, Lennernäs H, Karlén A. Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. J Med Chem 1998; 41: 4939-4949
    CrossrefPubMedSearch in Google Scholar
  • 39 Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen YY, Knight R, Ahima RS, Bushman F, Wu GD. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 2009; 137: 1716-1724.e1-2
    CrossrefPubMedSearch in Google Scholar
  • 40 Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, Possemiers S, Van Holle A, Francois P, de Vos WM, Delzenne NM, Schrenzel J, Cani PD. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 2011; 60: 2775-2786
    CrossrefPubMedSearch in Google Scholar
  • 41 Anhe FF, Roy D, Pilon G, Dudonne S, Matamoros S, Varin TV, Garofalo C, Moine Q, Desjardins Y, Levy E, Marette A. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 2015; 64: 872-883
    CrossrefPubMedSearch in Google Scholar
  • 42 Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013; 110: 9066-9071
    CrossrefPubMedSearch in Google Scholar
  • 43 Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014; 63: 727-735
    CrossrefPubMedSearch in Google Scholar
  • 44 Kim JW, Yun H, Choi SJ, Lee SH, Park S, Lim CW, Lee K, Kim B. Evaluating the influence of side stream cigarette smoke at an early stage of non-alcoholic steatohepatitis progression in mice. Toxicol Res 2017; 33: 31-41
    CrossrefPubMedSearch in Google Scholar
  • 45 Sim WC, Yin HQ, Choi HS, Choi YJ, Kwak HC, Kim SK, Lee BH. L-serine supplementation attenuates alcoholic fatty liver by enhancing homocysteine metabolism in mice and rats. J Nutr 2015; 145: 260-267
    CrossrefPubMedSearch in Google Scholar