[논문]고콜레스테롤 식이 섭취 쥐에서 quercetin의 간 AMPK 및 microRNA-21 조절을 통한 지질대사 개선 효과

이막순; 김양하

doi:10.4163/jnh.2022.55.1.36

고콜레스테롤 식이 섭취 쥐에서 quercetin의 간 AMPK 및 microRNA-21 조절을 통한 지질대사 개선 효과
Effects of quercetin on the improvement of lipid metabolism through regulating hepatic AMPK and microRNA-21 in high cholesterol diet-fed mice 원문보기

Journal of nutrition and health, v.55 no.1, 2022년, pp.36 - 46

이막순 (이화여자대학교 식품영양학과) , 김양하 (이화여자대학교 식품영양학과)

초록
AI-Helper

Quercetin의 지질대사 개선 효과에 대한 작용기전을 확인하기 위해 C57BL/6J mouse를 사용하여 실험을 수행하였다. 고콜레스테롤혈증을 유도하기 위해 6주간 1% 콜레스테롤과 0.5% cholic acid를 함유하는 고콜레스테롤 식이를 급여하였으며, quercetin은 0.05%와 0.1%의 수준으로 고콜레스테롤 식이에 추가하여 같은 기간 동안 제공하였다. Quercetin은 혈청과 간의 중성지방 및 콜레스테롤 수준을 용량 의존적으로 감소하는 것으로 나타났다. 고콜레스테롤 식이를 섭취한 쥐의 간에서 지방 합성을 촉진하는 SREBP-1c, ACC1 및 FAS 유전자 발현이 quercetin 섭취에 의해 억제되는 것을 확인하였다. Quercetin은 간세포 내에서 에너지 대사를 조절하는 AMPK 활성을 증가시켰다. 이에 반해 암세포 증식을 촉진하고 지방간에서 높게 발현되는 miR-21 발현은 quercetin 섭취에 의해 감소되었다. 본 연구의 결과는 quercetin이 고콜레스테롤 식이 섭취 쥐에서 혈청과 간의 지질 수준을 낮추는 지질대사 개선 효과가 있으며, 이러한 효과의 일부는 간 내 지방합성 유전자 (SREBP-1c, ACC1 및 FAS) 발현, AMPK 활성 및 miR-21 조절을 통해 매개된다는 것을 시사한다.

Abstract ▼ AI-Helper

Purpose: Quercetin is a polyphenolic flavonoid abundant in many fruits and vegetables. It has potential health-beneficial properties, such as antioxidant, anti-obesity, anti-cancer, anti-diabetic and anti-inflammatory effects. The purpose of this study was to investigate whether the lipid metabolism improvement effect of quercetin affected the regulation of AMP-activated protein kinase (AMPK) activity and microRNA (miR)-21 expression in the liver of mice fed a high-cholesterol diet. Methods: Male C57BL/6J mice were fed with normal diet, quercetin-free diet and diets containing 0.05% or 0.1% quercetin for six weeks. Hypercholesterolemia was induced by adding 1% cholesterol and 0.5% cholic acid to all diets. Serum and liver triglyceride (TG), and total cholesterol (TC) concentrations were analyzed using a commercial enzymatic colorimetric kit. AMPK activity was quantified using an AMPK kinase assay kit. The levels of miR-21 and genes involved in lipid metabolism were measured by real-time quantitative polymerase chain reaction. Results: Supplementation of quercetin reduced serum and hepatic TG and TC levels without changing body weight and food intake. Dietary quercetin significantly inhibited the mRNA levels of hepatic sterol-regulatory element binding protein-1c, acetyl-CoA carboxylase 1 and fatty acid synthesis, which are involved in hepatic lipogenesis. Dietary quercetin enhanced AMPK activity and suppressed miR-21 expression, promoting hepatic lipid accumulation. Conclusion: These results suggest that the lipid-lowering effect of quercetin on the serum and liver of mice may be partially mediated by the regulation of lipogenic gene expression, AMPK activity and miR-21 expression in the liver of mice fed a high-cholesterol diet.

주제어

표/그림 (6)

표 Table 1. Experimental diet composition¹⁾ (unit: g/kg diet)
표 Table 2. Efects of quercetin on body weight and food intake in C57BL/6J mice
표 Table 3. Efects of quercetin on lipid profles in the serum and liver
그림 Fig. 1. Effects of quercetin on the expression of genes related to lipid metabolism in the liver. The mRNA levels of SREBP-1c, ACC and FAS were measured by RT-qPCR and normalized to β-actin. Values are expressed as the fold change compared to the HC group (mean ± SEM, n = 6). Different letters indicate statistically significant differences at p < 0.05. ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SREBP-1c, sterol regulatory element-binding protein-1c; ND, normal diet; HC, high-cholesterol diet contained 1% cholesterol and 0.5% cholic acid; QL, HC + 0.05% quercetin; QH, HC + 0.1% quercetin; mRNA, messenger RNA.
그림 Fig. 2. Effects of quercetin on AMPK activity in the liver. AMPK activity was measured using an AMPK kinase kit and normalized to total protein contents of each sample. Values are expressed as the fold change compared to the HC group (mean ± SEM, n = 6). Different letters indicate statistically significant differences at p < 0.05. AMPK, AMP-activated protein kinase; ND, normal diet; HC, high-cholesterol diet contained 1% cholesterol and 0.5% cholic acid; QL, HC + 0.05% quercetin; QH, HC + 0.1% quercetin.
그림 Fig. 3. Effects of quercetin on miR-21 expression in the liver. The miR-21 level was analyzed using RT-qPCR and normalized to U6 snRNA. Values are expressed as the fold change compared to the HC group (mean ± SEM, n = 6). Different letters indicate statistically significant differences at p < 0.05. miR, microRNA; ND, normal diet; HC, high-cholesterol diet contained 1% cholesterol and 0.5% cholic acid; QL, HC + 0.05% quercetin; QH, HC + 0.1% quercetin.

참고문헌 (39)

Wald NJ, Law MR. Serum cholesterol and ischaemic heart disease. Atherosclerosis 1995; 118 Suppl: S1-S5.

상세보기
Barquera S, Pedroza-Tobias A, Medina C, Hernandez-Barrera L, Bibbins-Domingo K, Lozano R, et al. Global overview of the epidemiology of atherosclerotic cardiovascular disease. Arch Med Res 2015; 46(5): 328-338.

상세보기
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63(25 Pt B): 2889-2934.

상세보기
Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009; 458(7241): 1056-1060.

상세보기
Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13(4): 251-262.

상세보기
Ojuka EO, Jones TE, Nolte LA, Chen M, Wamhoff BR, Sturek M, et al. Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca 2+ . Am J Physiol Endocrinol Metab 2002; 282(5): E1008-E1013.

상세보기
Makinde AO, Gamble J, Lopaschuk GD. Upregulation of 5'-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res 1997; 80(4): 482-489.

상세보기
Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011; 13(9): 1016-1023.

상세보기
Foretz M, Carling D, Guichard C, Ferre P, Foufelle F. AMP-activated protein kinase inhibits the glucoseactivated expression of fatty acid synthase gene in rat hepatocytes. J Biol Chem 1998; 273(24): 14767-14771.

상세보기
Woods A, Azzout-Marniche D, Foretz M, Stein SC, Lemarchand P, Ferre P, et al. Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol Cell Biol 2000; 20(18): 6704-6711.

상세보기
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116(2): 281-297.

상세보기
Loyer X, Paradis V, Henique C, Vion AC, Colnot N, Guerin CL, et al. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression. Gut 2016; 65(11): 1882-1894.

상세보기
Zhang J, Li D, Zhang R, Gao P, Peng R, Li J. The miR-21 potential of serving as a biomarker for liver diseases in clinical practice. Biochem Soc Trans 2020; 48(5): 2295-2305.

상세보기
Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 2008; 585(2-3): 325-337.

상세보기
Reyes-Farias M, Carrasco-Pozo C. The anti-cancer effect of quercetin: molecular implications in cancer metabolism. Int J Mol Sci 2019; 20(13): 3177.

상세보기
Eid HM, Haddad PS. The antidiabetic potential of quercetin: underlying mechanisms. Curr Med Chem 2017; 24(4): 355-364.

상세보기
Dong J, Zhang X, Zhang L, Bian HX, Xu N, Bao B, et al. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKα1/SIRT1. J Lipid Res 2014; 55(3): 363-374.

상세보기
Chen S, Jiang H, Wu X, Fang J. Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes. Mediators Inflamm 2016; 2016(28): 9340637.
Pei Y, Otieno D, Gu I, Lee SO, Parks JS, Schimmel K, et al. Effect of quercetin on nonshivering thermogenesis of brown adipose tissue in high-fat diet-induced obese mice. J Nutr Biochem 2021; 88: 108532.

상세보기
Eid HM, Nachar A, Thong F, Sweeney G, Haddad PS. The molecular basis of the antidiabetic action of quercetin in cultured skeletal muscle cells and hepatocytes. Pharmacogn Mag 2015; 11(41): 74-81.

상세보기
Alshammari GM, Al-Qahtani WH, AlFaris NA, Alzahrani NS, Alkhateeb MA, Yahya MA. Quercetin prevents cadmium chloride-induced hepatic steatosis and fibrosis by downregulating the transcription of miR-21. Biofactors 2021; 47(3): 489-505.

상세보기
Nozari E, Moradi A, Samadi M. Effect of atorvastatin, curcumin, and quercetin on miR-21 and miR-122 and their correlation with TGFβ1 expression in experimental liver fibrosis. Life Sci 2020; 259: 118293.

상세보기
American Institute of Nutrition. Report of the American Institute of Nutrition ad hoc committee on standards for nutritional studies. J Nutr 1997; 107(7): 1340-1348.

상세보기
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18(6): 499-502.

상세보기
Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959; 37(8): 911-917.

상세보기
Lee MS, Kim Y. Mulberry fruit extract ameliorates adipogenesis via increasing AMPK activity and downregulating microRNA-21/143 in 3T3-L1 adipocytes. J Med Food 2020; 23(3): 266-272.

상세보기
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2 -ΔΔC(T) method. Methods 2001; 25(4): 402-408.

상세보기
Lee MS, Kim Y. Chrysanthemum morifolium flower extract inhibits adipogenesis of 3T3-L1 cells via AMPK/SIRT1 pathway activation. Nutrients 2020; 12(9): 2726.

상세보기
Jia Q, Cao H, Shen D, Li S, Yan L, Chen C, et al. Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1. Int J Mol Med 2019; 44(3): 893-902.
Jeong SM, Kang MJ, Choi HN, Kim JH, Kim JI. Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice. Nutr Res Pract 2012; 6(3): 201-207.

원문보기 상세보기
Li X, Wang R, Zhou N, Wang X, Liu Q, Bai Y, et al. Quercetin improves insulin resistance and hepatic lipid accumulation in vitro in a NAFLD cell model. Biomed Rep 2013; 1(1): 71-76.

상세보기
Kamohara T, Koshiguchi M, Maeda-Yamamoto M, Shinoda Y, Kametani N, Hirai S, et al. The combination of 'Benifuuki' with quercetin suppresses hepatic fat accumulation in high-fat high-cholesterol diet-fed rats. J Nutr Sci Vitaminol (Tokyo) 2019; 65(2): 196-201.

상세보기
Jayachandran M, Zhang T, Wu Z, Liu Y, Xu B. Isoquercetin regulates SREBP-1C via AMPK pathway in skeletal muscle to exert antihyperlipidemic and anti-inflammatory effects in STZ induced diabetic rats. Mol Biol Rep 2020; 47(1): 593-602.

상세보기
Zhang F, Feng J, Zhang J, Kang X, Qian D. Quercetin modulates AMPK/SIRT1/NF-κB signaling to inhibit inflammatory/oxidative stress responses in diabetic high fat diet-induced atherosclerosis in the rat carotid artery. Exp Ther Med 2020; 20(6): 280.
Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF, Shan Q, et al. Quercetin activates AMP-activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol-induced neurotoxicity. J Pathol 2010; 222(2): 199-212.

상세보기
Najjary S, Mohammadzadeh R, Mokhtarzadeh A, Mohammadi A, Kojabad AB, Baradaran B. Role of miR-21 as an authentic oncogene in mediating drug resistance in breast cancer. Gene 2020; 738: 144453.

상세보기
Seeger T, Fischer A, Muhly-Reinholz M, Zeiher AM, Dimmeler S. Long-term inhibition of miR-21 leads to reduction of obesity in db/db mice. Obesity (Silver Spring) 2014; 22(11): 2352-2360.

상세보기
Cao Y, Hu J, Sui J, Jiang L, Cong Y, Ren G. Quercetin is able to alleviate TGF-β-induced fibrosis in renal tubular epithelial cells by suppressing miR-21. Exp Ther Med 2018; 16(3): 2442-2448.
Yang FQ, Liu M, Li W, Che JP, Wang GC, Zheng JH. Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA-21. Mol Med Rep 2015; 11(2): 1085-1092.

상세보기

저자의 다른 논문 :

표제어: PCR

동의어: Packet Collision Rate

용어 설명 출처 목록 (6)

용어 설명: PCR은 세균 특이성이 있는 primer를 이용하여 적은 수의 세균이 있을지라도 쉽게 검출할 수 있는 유용한 방법이며, 이를 이용하여 구강 내 치면세균막이나 타액에서 직접 세균을 검출할 수 있게 되었다[8].

내보내기 구분	파일저장 인쇄 메일전송
구성항목	기본정보 상세정보 관리번호, 논문명, 저널/프로시딩명, 저자 , 발행년, 권, 호, 시작페이지, 끝페이지, 발행기관 관리번호, 논문명, 대등논문명, 저자 , 저널/프로시딩명, 발행기관, 발행년, 발행언어, 권, 호, 시작페이지, 끝페이지, ISBN, ISSN, 주제분야, 키워드, 초록(한글), 초록(영문), 저자(소속기관)
저장형식	Text(ASCII format) Excel format RefWorks Direct Export RIS format (for Reference Manager, ProCite, EndNote), Scholar's Aids, Mendeley
메일정보	받는사람 (필수) @ 보내는사람 (선택) @ 제목 내용 KISTI 검색결과 이메일 서비스
안내	총 건의 자료가 검색되었습니다. 다운받으실 자료의 인덱스를 입력하세요. (1-10,000) 검색결과의 순서대로 최대 10,000건 까지 다운로드가 가능합니다. 데이타가 많을 경우 속도가 느려질 수 있습니다.(최대 2~3분 소요) 다운로드 파일은 UTF-8 형태로 저장됩니다. 파일의 내용이 제대로 보이지 않을실 때는 웹브라우저 상단의 보기 -> 인코딩 -> 자동선택 여부를 확인하십시오. ~ Text(ASCII format) Excel format

연합인증