{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:35:23Z","timestamp":1792805723044,"version":"4.5.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81703504"],"award-info":[{"award-number":["81703504"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["2019GSF107092"],"award-info":[{"award-number":["2019GSF107092"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["ZR2022MH295"],"award-info":[{"award-number":["ZR2022MH295"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["2019M662294"],"award-info":[{"award-number":["2019M662294"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Shandong Key Research and Development Program","award":["81703504"],"award-info":[{"award-number":["81703504"]}]},{"name":"Shandong Key Research and Development Program","award":["2019GSF107092"],"award-info":[{"award-number":["2019GSF107092"]}]},{"name":"Shandong Key Research and Development Program","award":["ZR2022MH295"],"award-info":[{"award-number":["ZR2022MH295"]}]},{"name":"Shandong Key Research and Development Program","award":["2019M662294"],"award-info":[{"award-number":["2019M662294"]}]},{"name":"Shandong Natural Science Foundation","award":["81703504"],"award-info":[{"award-number":["81703504"]}]},{"name":"Shandong Natural Science Foundation","award":["2019GSF107092"],"award-info":[{"award-number":["2019GSF107092"]}]},{"name":"Shandong Natural Science Foundation","award":["ZR2022MH295"],"award-info":[{"award-number":["ZR2022MH295"]}]},{"name":"Shandong Natural Science Foundation","award":["2019M662294"],"award-info":[{"award-number":["2019M662294"]}]},{"name":"China Postdoctoral Science Foundation","award":["81703504"],"award-info":[{"award-number":["81703504"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"crossref"}]},{"name":"China Postdoctoral Science Foundation","award":["2019GSF107092"],"award-info":[{"award-number":["2019GSF107092"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"crossref"}]},{"name":"China Postdoctoral Science Foundation","award":["ZR2022MH295"],"award-info":[{"award-number":["ZR2022MH295"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"crossref"}]},{"name":"China Postdoctoral Science Foundation","award":["2019M662294"],"award-info":[{"award-number":["2019M662294"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Aberrantly high dietary cholesterol intake and intestinal cholesterol uptake lead to dyslipidemia, one of the risk factors for cardiovascular diseases (CVDs). Based on previous studies, laminarin, a polysaccharide found in brown algae, has hypolipidemic activity, but its underlying mechanism has not been elucidated. In this study, we investigated the effect of laminarin on intestinal cholesterol uptake in vitro, as well as the lipid and morphological parameters in an in vivo model of high-fat diet (HFD)-fed mice, and addressed the question of whether Niemann\u2013Pick C1-like 1 protein (NPC1L1), a key transporter mediating dietary cholesterol uptake, is involved in the mechanistic action of laminarin. In in vitro studies, BODIPY-cholesterol-labeled Caco-2 cells were examined using confocal microscopy and a fluorescence reader. The results demonstrated that laminarin inhibited cholesterol uptake into Caco-2 cells in a concentration-dependent manner (EC50 = 20.69 \u03bcM). In HFD-fed C57BL\/6J mice, laminarin significantly reduced the serum levels of total cholesterol (TC), total triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). It also decreased hepatic levels of TC, TG, and total bile acids (TBA) while promoting the excretion of fecal cholesterol. Furthermore, laminarin significantly reduced local villous damage in the jejunum of HFD mice. Mechanistic studies revealed that laminarin significantly downregulated NPC1L1 protein expression in the jejunum of HFD-fed mice. The siRNA-mediated knockdown of NPC1L1 attenuated the laminarin-mediated inhibition of cholesterol uptake in Caco-2 cells. This study suggests that laminarin significantly improves dyslipidemia in HFD-fed mice, likely by reducing cholesterol uptake through a mechanism that involves the downregulation of NPC1L1 expression.<\/jats:p>","DOI":"10.3390\/md21120624","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T12:01:00Z","timestamp":1701259260000},"page":"624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Laminarin Reduces Cholesterol Uptake and NPC1L1 Protein Expression in High-Fat Diet (HFD)-Fed Mice"],"prefix":"10.3390","volume":"21","author":[{"given":"Zhuoqian","family":"He","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9261-5293","authenticated-orcid":false,"given":"Verena M.","family":"Dirsch","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"},{"name":"Institute of Innovative Drugs, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kewei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"},{"name":"Institute of Innovative Drugs, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"ref_1","unstructured":"WHO (World Health Organization) (2023, January 01). Cardiovasvular Diseases (CVDs). Available online: http:\/\/www.who.int\/cardiovascular_diseases\/en\/."},{"key":"ref_2","first-page":"7533","article-title":"Research on mechanism of PCS in damaging vascular endothelial cells and promoting formation of atherosclerosis via TLR4\/TREM-1","volume":"22","author":"Zhang","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5483","DOI":"10.1021\/acs.biochem.6b00342","article-title":"Cholesterol Biosynthesis: A Mechanistic Overview","volume":"55","author":"Cerqueira","year":"2016","journal-title":"Biochemistry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1016\/S0140-6736(16)31357-5","article-title":"Interpretation of the evidence for the efficacy and safety of statin therapy","volume":"388","author":"Collins","year":"2016","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nrcardio.2016.164","article-title":"Dyslipidaemia: Balancing the benefits and risks of statin therapy","volume":"13","author":"Lim","year":"2016","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1080\/10408398.2019.1634517","article-title":"Hypoglycemic effects of bioactive ingredients from medicine food homology and medicinal health food species used in China","volume":"60","author":"Gong","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1039\/c3fo60295h","article-title":"Origin and concept of medicine food homology and its application in modern functional foods","volume":"4","author":"Hou","year":"2013","journal-title":"Food Funct."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.arcmed.2018.01.004","article-title":"Hypolipidemic Components from Medicine Food Homology Species Used in China: Pharmacological and Health Effects","volume":"48","author":"Song","year":"2017","journal-title":"Arch. Med. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Li, Y., Zheng, Y., Zhang, Y., Yang, Y., Wang, P., Imre, B., Wong, A.C.Y., Hsieh, Y.S.Y., and Wang, D. (2021). Brown Algae Carbohydrates: Structures, Pharmaceutical Properties, and Research Challenges. Mar. Drugs, 19.","DOI":"10.3390\/md19110620"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1111\/1541-4337.12494","article-title":"Alginate Oligosaccharides: Production, Biological Activities, and Potential Applications","volume":"18","author":"Liu","year":"2019","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10529-005-6177-9","article-title":"Anti-apoptotic activity of laminarin polysaccharides and their enzymatically hydrolyzed oligosaccharides from Laminaria japonica","volume":"28","author":"Kim","year":"2006","journal-title":"Biotechnol. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.ijbiomac.2019.07.031","article-title":"Selenium nanoparticles fabricated in laminarin polysaccharides solutions exert their cytotoxicities in HepG2 cells by inhibiting autophagy and promoting apoptosis","volume":"137","author":"Cui","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4254","DOI":"10.1039\/D1FO00311A","article-title":"Polysaccharides from Laminaria japonica: An insight into the current research on structural features and biological properties","volume":"12","author":"Luan","year":"2021","journal-title":"Food Funct."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1021\/acs.jafc.1c07483","article-title":"Laminaria japonica Polysaccharide Suppresses Atherosclerosis via Regulating Autophagy-Mediated Macrophage Polarization","volume":"70","author":"Li","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1039\/C9FO02994J","article-title":"Enzymatic preparation of a low-molecular-weight polysaccharide rich in uronic acid from the seaweed Laminaria japonica and evaluation of its hypolipidemic effect in mice","volume":"11","author":"Li","year":"2020","journal-title":"Food Funct."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1600456","DOI":"10.1002\/mnfr.201600456","article-title":"Alleviating VLDL overproduction is an important mechanism for Laminaria japonica polysaccharide to inhibit atherosclerosis in LDLr(\u2212\/\u2212) mice with diet-induced insulin resistance","volume":"61","author":"Zha","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Andre, R., Pacheco, R., Bourbon, M., and Serralheiro, M.L. (2021). Brown Algae Potential as a Functional Food against Hypercholesterolemia: Review. Foods, 10.","DOI":"10.3390\/foods10020234"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1126\/science.1093131","article-title":"Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption","volume":"303","author":"Altmann","year":"2004","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1146\/annurev.physiol.69.031905.160725","article-title":"Regulation of intestinal cholesterol absorption","volume":"69","author":"Wang","year":"2007","journal-title":"Annu. Rev. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.cmet.2008.04.001","article-title":"The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1","volume":"7","author":"Ge","year":"2008","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1146\/annurev-physiol-012110-142233","article-title":"Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport","volume":"73","author":"Jia","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1161\/01.CIR.0000034044.95911.DC","article-title":"Inhibition of intestinal cholesterol absorption by ezetimibe in humans","volume":"106","author":"Sudhop","year":"2002","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0195-668X(02)00807-2","article-title":"Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia","volume":"24","author":"Knopp","year":"2003","journal-title":"Eur. Heart J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.ijbiomac.2022.08.059","article-title":"Low-molecular-weight fucoidan bidirectionally regulates lipid uptake and cholesterol efflux through the p38 MAPK phosphorylation","volume":"220","author":"Sun","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5124","DOI":"10.1039\/C9FO00619B","article-title":"The fucoidan from the brown seaweed Ascophyllum nodosum ameliorates atherosclerosis in apolipoprotein E-deficient mice","volume":"10","author":"Yin","year":"2019","journal-title":"Food Funct."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5782","DOI":"10.1021\/acs.jafc.9b01321","article-title":"Fucoidan A2 from the Brown Seaweed Ascophyllum nodosum Lowers Lipid by Improving Reverse Cholesterol Transport in C57BL\/6J Mice Fed a High-Fat Diet","volume":"67","author":"Yang","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s11745-013-3853-8","article-title":"LXR driven induction of HDL-cholesterol is independent of intestinal cholesterol absorption and ABCA1 protein expression","volume":"49","author":"Kannisto","year":"2014","journal-title":"Lipids"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/mnfr.201500541","article-title":"Anti-inflammatory and anti-chemotactic effects of dietary flaxseed oil on CD8(+) T cell\/adipocyte-mediated cross-talk","volume":"60","author":"Monk","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.physbeh.2008.01.001","article-title":"Water-soluble dietary fibers and cardiovascular disease","volume":"94","author":"Theuwissen","year":"2008","journal-title":"Physiol. Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cmet.2016.10.001","article-title":"Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion","volume":"24","author":"Jakulj","year":"2016","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.redox.2017.11.002","article-title":"(-)-Epicatechin protects the intestinal barrier from high fat diet-induced permeabilization: Implications for steatosis and insulin resistance","volume":"14","author":"Cremonini","year":"2018","journal-title":"Redox Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1111\/j.1463-1326.2010.01261.x","article-title":"Potential therapeutic uses for ezetimibe beyond lowering LDL-c to decrease cardiovascular events","volume":"12","author":"Ahmed","year":"2010","journal-title":"Diabetes Obes. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1093\/jn\/135.10.2305","article-title":"Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe","volume":"135","author":"During","year":"2005","journal-title":"J. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1021\/acs.jnatprod.1c00881","article-title":"Evodiamine Lowers Blood Lipids by Up-Regulating the PPARgamma\/ABCG1 Pathway in High-Fat-Diet-Fed Mice","volume":"84","author":"Hou","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1161\/ATVBAHA.112.301187","article-title":"Ezetimibe inhibits hepatic Niemann-Pick C1-Like 1 to facilitate macrophage reverse cholesterol transport in mice","volume":"33","author":"Xie","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/21\/12\/624\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:33:55Z","timestamp":1760132035000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/21\/12\/624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,29]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["md21120624"],"URL":"https:\/\/doi.org\/10.3390\/md21120624","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,29]]}}}