title: Ethanol extract of Zhongtian hawthorn lowers serum cholesterol in mice by inhibiting transcription of 3-hydroxy-3-methylglutaryl-CoA reductase via nuclear factor-kappa B signal pathway.
abstract: Hawthorn is a berry-like fruit from the species of Crataegus. In China, it has another more famous name, Shan-Zha, which has been used to improve digestion as a traditional Chinese medicine or food for thousands of years. Moreover, during the last decades, hawthorn has received more attention because of its potential to treat cardiovascular diseases. However, currently, only fruits of C. pinnatifida and C. pinnatifida var. major are included as Shan-Zha in the Chinese Pharmacopoeia. In this study, our results showed that the ethanol extract of Zhongtian hawthorn, a novel grafted cultivar of C. cuneata (wild Shan-Zha), could markedly reduce body weight and levels of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, and liver cholesterol of hyperlipidemia mice. It could suppress the stimulation effect of high-fat diet on the transcription of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and p65, and counteract the downregulation of CYP7A1 and LDLR. In addition, the results of luciferase reporter assay and Western blot showed that the transcriptional activity of HMGCR promoter was inhibited by Zhongtian hawthorn ethanol extract in a dose-dependent manner, while overexpression of p65 could reverse this transcriptional repression effect. These results suggested that Zhongtian hawthorn could provide health benefits by counteracting the high-fat diet-induced hypercholesteolemic and hyperlipidemic effects in vivo, and the mechanism underlying this event was mainly dependent on the suppressive effect of Zhongtian hawthorn ethanol extract on the transcription of HMGCR via nuclear factor-kappa B (NF-κB) signal pathway. Therefore, this novel cultivar of hawthorn cultivar which has much bigger fruits, early bearing, high yield, cold resistance, and drought resistance, might be considered as a good alternative to Shan-Zha and has great value in the food and medicine industry. In addition, to our best knowledge, this is also the first report that the extract of Crataegus could suppress the transcription of HMGCR via NF-κB signal pathway.
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Hai-Jie
authors.initials: HJ
authors.lastname: Hu
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China luoxuegang@hotmail.com.
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Luo
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Dong
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Ai
authors.initials: A
authors.lastname: Mu
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Guo-Long
authors.initials: GL
authors.lastname: Shi
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Qiu-Tong
authors.initials: QT
authors.lastname: Wang
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Chen
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, P. R. China Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China.
authors.forename: Tong-Cun
authors.initials: TC
authors.lastname: Zhang
authors.affiliation: Hezhou University, Hezhou 542800, P. R. China 805008426@qq.com.
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Pan
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000302:isolation & purification; D002784:Cholesterol / Q000097:blood*; D027825:Crataegus / Q000737:chemistry*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D006937:Hypercholesterolemia / Q000188:drug therapy; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000008:administration & dosage* / Q000302:isolation & purification; D044967:Serum / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000924:Anticholesteremic Agents; D016328:NF-kappa B; D010936:Plant Extracts; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: 3-hydroxy-3-methylglutaryl-CoA reductase; Zhongtian hawthorn; hypocholesteolemic; hypolipidemic; nuclear factor-kappa B; transcriptional regulation
references.citation: Molecules. 2014 Jan 30;19(2):1685-712
references.pmid: 24487567
references.citation: Life Sci. 2006 Jun 20;79(4):324-30
references.pmid: 16472823
references.citation: Eur J Clin Invest. 2010 Feb;40(2):89-94
references.pmid: 20015244
references.citation: World Rev Nutr Diet. 1995;77:147-54
references.pmid: 7732698
references.citation: Zhonghua Yi Shi Za Zhi. 2011 Nov;41(6):336-8
references.pmid: 22335842
references.citation: Biochim Biophys Acta. 2013 Oct;1832(10):1560-8
references.pmid: 23651731
references.citation: Evid Based Complement Alternat Med. 2014;2014:642058
references.pmid: 24876874
references.citation: Molecules. 2012 Dec 06;17(12):14490-509
references.pmid: 23222867
references.citation: Biochim Biophys Acta. 2015 May;1851(5):667-73
references.pmid: 25701719
references.citation: Evid Based Complement Alternat Med. 2011;2011:801272
references.pmid: 19228775
references.citation: Proc Soc Exp Biol Med. 2000 May;224(1):8-19
references.pmid: 10782041
references.citation: Mediators Inflamm. 2014;2014:720987
references.pmid: 24648660
references.citation: Oncol Rep. 2015 Mar;33(3):1019-39
references.pmid: 25607255
references.citation: Int J Cardiol. 2014 Feb 15;171(3):e93-5
references.pmid: 24360166
references.citation: Eur J Heart Fail. 2008 Jun;10 (6):587-93
references.pmid: 18490196
references.citation: Am J Health Syst Pharm. 2002 Mar 1;59(5):417-22
references.pmid: 11887407
references.citation: Exp Biol Med (Maywood). 2004 May;229(5):412-6
references.pmid: 15096653
references.citation: J Pharm Pharmacol. 2013 Feb;65(2):300-9
references.pmid: 23278698
references.citation: Evid Based Complement Alternat Med. 2013;2013:149363
references.pmid: 24459528
references.citation: J Ethnopharmacol. 2009 Jul 30;124(3):544-50
references.pmid: 19454308
references.citation: Planta Med. 2009 Sep;75(11):1203-8
references.pmid: 19350483
references.citation: Circulation. 2007 Mar 20;115(11):1363-70
references.pmid: 17353444
references.citation: Am J Pathol. 2009 Jan;174(1):54-62
references.pmid: 19095962
references.citation: Nutr Res Pract. 2014 Dec;8(6):632-7
references.pmid: 25489402
references.citation: Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2541-6
references.pmid: 22936343
references.citation: Am J Physiol Heart Circ Physiol. 2013 Mar 15;304(6):H874-84
references.pmid: 23335792
references.citation: Atherosclerosis. 2012 Jul;223(1):190-6
references.pmid: 22633472
references.citation: Phytother Res. 2013 Apr;27(4):545-51
references.pmid: 22674675
references.citation: Am J Chin Med. 2005;33(1):1-10
references.pmid: 15844828
references.citation: Semin Liver Dis. 1992 Nov;12(4):403-19
references.pmid: 1465624
references.citation: Atherosclerosis. 2007 Jun;192(2):313-22
references.pmid: 16963055
references.citation: Cochrane Database Syst Rev. 2013 Jan 31;(1):CD004816
references.pmid: 23440795
references.citation: Nutrition. 2014 Jul-Aug;30(7-8):915-9
references.pmid: 24985011
references.citation: Arterioscler Thromb Vasc Biol. 2005 May;25(5):904-14
references.pmid: 15731497
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17593-8
references.pmid: 15590771
references.citation: Thromb Res. 2011 Aug;128(2):117-23
references.pmid: 21636112
references.citation: Am Fam Physician. 2010 Feb 15;81(4):465-8
references.pmid: 20148500
references.citation: J Hepatol. 2009 Apr;50(4):789-96
references.pmid: 19231010
references.citation: Phytochemistry. 2012 Jul;79:5-26
references.pmid: 22608128
references.citation: N Engl J Med. 1992 May 21;326(21):1406-16
references.pmid: 1533273