{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:50:29Z","timestamp":1760241029285,"version":"build-2065373602"},"reference-count":21,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T00:00:00Z","timestamp":1573430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The bile acid-phospholipid conjugate ursodeoxycholyl-lysophosphatidylethanolamide (UDCA-LPE) was shown to have anti-inflammatory, antisteatotic, and antifibrotic properties, rendering it as a drug targeting non-alcoholic steatohepatitis (NASH). On a molecular level, it disrupted the heterotetrameric fatty acid uptake complex localized in detergent-resistant membrane domains of the plasma membrane (DRM-PM). However, its mode of action was unclear. Methodologically, UDCA-LPE was incubated with the liver tumor cell line HepG2 as well as their isolated DRM-PM and all other cellular membranes (non-DRM). The membrane cholesterol and phospholipids were quantified as well as the DRM-PM protein composition by Western blotting. The results show a loss of DRM-PM by UDCA-LPE (50 \u00b5M) with a 63.13 \u00b1 7.14% reduction of phospholipids and an 81.94 \u00b1 8.30% reduction of cholesterol in relation to mg total protein. The ratio of phospholipids to cholesterol changed from 2:1 to 4:1, resembling those of non-DRM fractions. Among the members of the fatty acid uptake complex, the calcium-independent membrane phospholipase A2 (iPLA2\u03b2) abandoned DRM-PM most rapidly. As a consequence, the other members of this transport system disappeared as well as the DRM-PM anchored fibrosis regulating proteins integrin \u03b2-1 and lysophospholipid receptor 1 (LPAR-1). It is concluded that UDCA-LPE executes its action by iPLA2\u03b2 removal from DRM-PM and consequent dissolution of the raft lipid platform.<\/jats:p>","DOI":"10.3390\/ijms20225631","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T04:07:07Z","timestamp":1573531627000},"page":"5631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Bile Acid-Phospholipid Conjugate Ursodeoxycholyl-Lysophosphatidylethanolamide (UDCA-LPE) Disintegrates the Lipid Backbone of Raft Plasma Membrane Domains by the Removal of the Membrane Phospholipase A2"],"prefix":"10.3390","volume":"20","author":[{"given":"Wolfgang","family":"Stremmel","sequence":"first","affiliation":[{"name":"Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Staffer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, University Hospital of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gert","family":"Fricker","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0931","authenticated-orcid":false,"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1172\/JCI0216390","article-title":"Cholesterol, lipid rafts, and disease","volume":"110","author":"Simons","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1096\/fj.14-249763","article-title":"Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: Implications for nonalcoholic steatohepatitis","volume":"28","author":"Stremmel","year":"2014","journal-title":"FASEB J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Su, J., Gan-Schreier, H., Goeppert, B., Chamulitrat, W., Stremmel, W., and Pathil, A. (2018). Bivalent ligand UDCA-LPE inhibits pro-fibrogenic integrin signalling by inducing lipid raft-mediated internalization. Int J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103254"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/hep.22955","article-title":"Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide as a hepatoprotective agent","volume":"50","author":"Chamulitrat","year":"2009","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.jhep.2010.07.028","article-title":"The synthetic bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide suppresses TNF\u03b1-induced liver injury","volume":"54","author":"Pathil","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.plipres.2015.04.003","article-title":"Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment","volume":"59","author":"Escriba","year":"2015","journal-title":"Prog. Lipid Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.bbamem.2007.03.026","article-title":"Use of cyclodextrins to manipulate plasma membrane cholesterol content: Evidence, misconceptions and control strategies","volume":"1768","author":"Zidovetzki","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3933","DOI":"10.1242\/jcs.092015","article-title":"The roles of flotillin microdomains-endocytosis and beyond","volume":"124","author":"Otto","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6130","DOI":"10.1021\/cr200085w","article-title":"Phospholipase A2 enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention","volume":"111","author":"Dennis","year":"2011","journal-title":"Chem. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41467-018-03193-0","article-title":"The structure of iPLA(2)\u03b2 reveals dimeric active sites and suggests mechanisms of regulation and localization","volume":"9","author":"Malley","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1002\/hep.25531","article-title":"Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease","volume":"55","author":"Pathil","year":"2012","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e0197836","DOI":"10.1371\/journal.pone.0197836","article-title":"Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury","volume":"13","author":"Ludwig","year":"2018","journal-title":"PLoS ONE"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5113","DOI":"10.1111\/bph.12837","article-title":"Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-\u03b21\/Smad2\/3 signalling","volume":"171","author":"Pathil","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.bbalip.2017.05.013","article-title":"The overall fatty acid absorption controlled by basolateral chylomicron excretion under regulation of p-JNK1","volume":"1862","author":"Stremmel","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell. Biol. Lipids"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1053\/j.gastro.2009.09.015","article-title":"Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition","volume":"138","author":"Kluwe","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1055\/s-2001-17556","article-title":"Matrix as a modulator of hepatic fibrogenesis","volume":"21","author":"Schuppan","year":"2001","journal-title":"Semin. Liver Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ceb.2006.08.011","article-title":"Integrin-regulated FAK-Src signaling in normal and cancer cells","volume":"18","author":"Mitra","year":"2006","journal-title":"Curr. Opin. Cell. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.1111\/j.1440-1746.2006.04659.x","article-title":"Molecular mechanisms of hepatic fibrogenesis","volume":"22","author":"Parsons","year":"2007","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1159\/000320583","article-title":"Pressure activates Src-dependent FAK-Akt and ERK1\/2 signaling pathways in rat hepatic stellate cells","volume":"26","author":"Wu","year":"2010","journal-title":"Cell Physiol. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1242\/jcs.169409","article-title":"Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor","volume":"128","author":"Jang","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3446","DOI":"10.1038\/sj.emboj.7601204","article-title":"Dynamics in the plasma membrane: How to combine fluidity and order","volume":"25","author":"Marguet","year":"2006","journal-title":"EMBO J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:33:31Z","timestamp":1760189611000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,11]]},"references-count":21,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20225631"],"URL":"https:\/\/doi.org\/10.3390\/ijms20225631","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2019,11,11]]}}}