{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:04:24Z","timestamp":1772118264713,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T00:00:00Z","timestamp":1582675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Institute of Planning &amp; Evaluation for Technology in Food, Agriculture Forestry &amp; Fisheries (IPET)","award":["316065-3 and 116032-3"],"award-info":[{"award-number":["316065-3 and 116032-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Our previous study demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) has hypo-cholesterolemic and anti-obesity activity. However, the molecular mechanisms of its effects are poorly characterized. We hypothesized that 5-uRCK and one of its major bioactive compounds, ellagic acid, decrease cellular and plasma cholesterol levels. Thus, we investigated the hypocholesterolemic activity and mechanism of 5-uRCK in both hepatocytes and a high-cholesterol diet (HCD)-induced rat model. Cholesterol in the liver and serum was significantly reduced by 5-uRCK and ellagic acid. The hepatic activities of HMG-CoA and CETP were reduced, and the hepatic activity of LCAT was increased by both 5-uRCK extract and ellagic acid, which also caused histological improvements. The MDA content in the aorta and serum was significantly decreased after oral administration of 5-uRCK or ellagic acid. Further immunoblotting analysis showed that AMPK phosphorylation in the liver was induced by 5-uRCK and ellagic acid, which activated AMPK, inhibiting the activity of HMGCR by inhibitory phosphorylation. In contrast, 5-uRCK and ellagic acid suppressed the nuclear translocation and activation of SREBP-2, which is a key transcription factor in cholesterol biosynthesis. In conclusion, our results suggest that 5-uRCK and its bioactive compound, ellagic acid, are useful alternative therapeutic agents to regulate blood cholesterol.<\/jats:p>","DOI":"10.3390\/nu12030610","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T03:21:16Z","timestamp":1582773676000},"page":"610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Regulates AMPK, SREBP-2, HMGCR, and INSIG-1 Signaling and Cholesterol Metabolism In Vitro and In Vivo"],"prefix":"10.3390","volume":"12","author":[{"given":"Ki Hoon","family":"Lee","sequence":"first","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eui-Seon","family":"Jeong","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goeun","family":"Jang","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju-Ryun","family":"Na","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soyi","family":"Park","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan Seok","family":"Kang","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hakjoon","family":"Choi","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Seok","family":"Kim","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0407-6339","authenticated-orcid":false,"given":"Sunoh","family":"Kim","sequence":"additional","affiliation":[{"name":"B&amp;Tech Co., Ltd., Central R&amp;D Center, Gwangju 61239, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2015.01.036","article-title":"A century of cholesterol and coronaries: From plaques to genes to statins","volume":"161","author":"Goldstein","year":"2015","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1001\/jama.2018.2525","article-title":"Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: A systematic review and meta-analysis","volume":"319","author":"Navarese","year":"2018","journal-title":"JAMA"},{"key":"ref_3","unstructured":"von Haehling, S., and Anker, S. (2008). Statins: Much more than cholesterol reduction. Arch. Med Sci. Spec. Issues, Available online: https:\/\/www.termedia.pl\/-Statins-much-more-than-cholesterol-reduction,52,9748,0,1.html."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1185\/03007990903098081","article-title":"Role and significance of statins in the treatment of hypertensive patients","volume":"25","author":"Stepien","year":"2009","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.drudis.2016.09.001","article-title":"Statin-associated myopathy and the quest for biomarkers: Can we effectively predict statin-associated muscle symptoms?","volume":"22","author":"Muntean","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1080\/14656566.2016.1197202","article-title":"Expert opinion: The therapeutic challenges faced by statin intolerance","volume":"17","author":"Patel","year":"2016","journal-title":"Expert Opin. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/ijnp\/pyy060","article-title":"Risk of neuropsychiatric adverse effects of lipid-lowering drugs: A mendelian randomization study","volume":"21","author":"Alghamdi","year":"2018","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1161\/CIRCULATIONAHA.117.028271","article-title":"Primary prevention with statin therapy in the elderly: New meta-analyses from the contemporary JUPITER and HOPE-3 randomized trials","volume":"135","author":"Ridker","year":"2017","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1042\/BJ20120546","article-title":"AMP-activated protein kinase: New regulation, new roles?","volume":"445","author":"Carling","year":"2012","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.tips.2004.12.011","article-title":"AMPK, the metabolic syndrome and cancer","volume":"26","author":"Luo","year":"2005","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1152\/physrev.00011.2008","article-title":"AMPK in health and disease","volume":"89","author":"Steinberg","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.cmet.2011.03.009","article-title":"AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice","volume":"13","author":"Li","year":"2011","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1124\/mol.107.041012","article-title":"Regulatory cross-talk between drug metabolism and lipid homeostasis: Constitutive androstane receptor and pregnane X receptor increase Insig-1 expression","volume":"73","author":"Roth","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_14","first-page":"241","article-title":"Report: Antioxidant and nutraceutical value of wild medicinal Rubus berries","volume":"28","author":"Ahmad","year":"2015","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_15","unstructured":"Moon, G.S. (1991). Constituents and uses of medicinal herbs. Ilweolseogak Seoul Korea, 310\u2013311."},{"key":"ref_16","first-page":"110","article-title":"Comparison of the phenolic composition and antioxidant activity of Korean black raspberry, Bokbunja, (Rubus coreanus Miquel) with those of six other berries","volume":"15","author":"Yang","year":"2017","journal-title":"CyTA J. Food"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1248\/bpb.b12-00022","article-title":"Water extracts of immature Rubus coreanus regulate lipid metabolism in liver cells","volume":"35","author":"Bhandary","year":"2012","journal-title":"Biol. Pharm. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"259","DOI":"10.7783\/KJMCS.2012.20.4.259","article-title":"Antioxidant, anticancer and immune activation of anthocyanin fraction from Rubus coreanus Miquel fruits (Bokbunja)","volume":"20","author":"Choung","year":"2012","journal-title":"Korean J. Med. Crop Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s00394-012-0358-9","article-title":"Ellagic acid attenuates high-carbohydrate, high-fat diet-induced metabolic syndrome in rats","volume":"52","author":"Panchal","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/j.foodchem.2011.11.137","article-title":"Variation of total phenolics, anthocyanins, ellagic acid and radical scavenging capacity in various raspberry (Rubus spp.) cultivars","volume":"132","author":"Venskutonis","year":"2012","journal-title":"Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/ptr.2274","article-title":"Antiinflammatory activities of Rubus coreanus depend on the degree of fruit ripening","volume":"22","author":"Yang","year":"2008","journal-title":"Phytother. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20","DOI":"10.9734\/IJBCRR\/2015\/12680","article-title":"Anti-obesity effects on unripe Rubus coreanus Miquel extract in high fat diet-induced obese mice","volume":"5","author":"Jung","year":"2015","journal-title":"IJBcRR"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4357656","DOI":"10.1155\/2016\/4357656","article-title":"Antiobesity effects of unripe Rubus coreanus Miquel and its constituents: An in vitro and in vivo characterization of the underlying mechanism","volume":"2016","author":"Oh","year":"2016","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"650","DOI":"10.3746\/jkfn.2014.43.5.650","article-title":"Effects of unripe Rubus coreanus Miquel extract on improvement of lipid metabolism in C57BL\/6 mice fed a high-cholesterol diet","volume":"43","author":"Jung","year":"2014","journal-title":"J. Korean Soc. Food Sci. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"549","DOI":"10.11002\/kjfp.2018.25.5.549","article-title":"Comparison of ellagic acid contents in Korean and Chinese cultivated species of unripe black raspberries","volume":"25","author":"Lee","year":"2018","journal-title":"Korean J. Food Preserv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/19768354.2014.992953","article-title":"Hypocholesterolemic effects of Curcuma longa, L. with Nelumbo nucifera leaf in an in vitro model and a high cholesterol diet-induced hypercholesterolemic mouse model","volume":"19","author":"Jung","year":"2015","journal-title":"Anim. Cells Syst."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.3390\/nu6093696","article-title":"Hypolipidemic and antioxidative effects of aqueous enzymatic extract from rice bran in rats fed a high-fat and -cholesterol diet","volume":"6","author":"Wang","year":"2014","journal-title":"Nutrients"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipids from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.foodres.2015.03.041","article-title":"Barley sprout extract containing policosanols and polyphenols regulate AMPK, SREBP2 and ACAT2 activity and cholesterol and glucose metabolism in vitro and in vivo","volume":"72","author":"Lee","year":"2015","journal-title":"Food Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1093\/clinchem\/21.10.1523","article-title":"Indirect assessment of hydroxymethylglutaryl-CoA reductase (NADPH) activity in liver tissue","volume":"21","author":"Rao","year":"1975","journal-title":"Clin. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.drudis.2008.07.004","article-title":"Natural products in drug discovery","volume":"13","author":"Harvey","year":"2008","journal-title":"Drug Discov. Today"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S1388-1981(00)00161-X","article-title":"Cholesterol and atherosclerosis","volume":"1529","author":"Libby","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1194\/jlr.M700109-JLR200","article-title":"ACAT2 stimulates cholesteryl ester secretion in apoB-containing lipoproteins","volume":"48","author":"Temel","year":"2007","journal-title":"J. Lipid Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.gene.2012.10.042","article-title":"Hypocholesterolemic effect of rice protein is due to regulating hepatic cholesterol metabolism in adult rats","volume":"512","author":"Yang","year":"2013","journal-title":"Gene"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kosmas, C.E., DeJesus, E., Rosario, D., and Vittorio, T.J. (2016). CETP Inhibition: Past failures and future hopes. Clinical medicine insights. Cardiology, 37\u201342.","DOI":"10.4137\/CMC.S32667"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"124","DOI":"10.12688\/f1000research.4396.1","article-title":"CETP inhibitors and cardiovascular disease: Time to think again","volume":"3","author":"Miller","year":"2014","journal-title":"F1000Research"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s42003-019-0749-z","article-title":"Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles","volume":"3","author":"Manthei","year":"2002","journal-title":"Commun. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1046\/j.1523-1755.2003.00041.x","article-title":"HMG-CoA reductase, cholesterol 7\u03b1-hydroxylase, LCAT, ACAT, LDL receptor, and SRB-1 in hereditary analbuminemia","volume":"64","author":"Liang","year":"2003","journal-title":"Kidney Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0308-8146(03)00155-9","article-title":"Antioxidant action of flavonoids from Mangifera indica and Emblica officinalis in hypercholesterolemic rats","volume":"83","author":"Anila","year":"2003","journal-title":"Food Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7954","DOI":"10.1021\/jf2008056","article-title":"Stilbenes and tyrosol as target compounds in the assessment of antioxidant and hypolipidemic activity of Vitis vinifera red wines from southern Brazil","volume":"59","author":"Gris","year":"2011","journal-title":"J. Agric. Food Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/3\/610\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:01:49Z","timestamp":1760173309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/3\/610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,26]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["nu12030610"],"URL":"https:\/\/doi.org\/10.3390\/nu12030610","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,26]]}}}