{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T10:53:04Z","timestamp":1761216784735,"version":"3.30.0"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":6056,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,2]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Amyloid fibrils of diverse origin are known to disturb vital cellular functions and induce cell death. In this study, the effects of amyloid fibrils from the C\u2013terminal fragment (C\u201336) of cleaved \u03b1<jats:sub>1<\/jats:sub> \u2013antitrypsin (AAT) on low\u2013density lipoprotein (LDL) metabolism were investigated in HepG2 cells. Treatment of the cells with C\u201336 fibrils (10 \u03bcmol\/L) enhanced <jats:sup>125<\/jats:sup>I\u2013LDL binding and uptake 10 to 15 times, and highly up\u2013regulated levels of LDL receptor mRNA, as compared with control cells. Competition experiments using excess of unlabeled LDL and blockage experiments with a monoclonal LDL receptor antibody diminished or completely abolished the stimulatory effects of fibrils on LDL binding and LDL receptor mRNA levels, suggesting that fibrils act via the LDL receptor pathway. However, C\u201336 fibrils had no significant effect on [2\u2013<jats:sup>14<\/jats:sup>C]acetate incorporation into cholesterol biosynthesis and cholesterol ester formation, but inhibited<jats:sup>125<\/jats:sup>I\u2013LDL degradation by 20% and reduced bile acid biosynthesis up to 48% in a dose\u2013dependent manner. Preincubation of the cells with fibrils before the addition of LDL totally abolished the LDL inhibitory effect on unesterified cholesterol synthesis, further confirming the LDL receptors to be the target for C\u201336 fibrils. Moreover, the expression of sterol regulatory element binding protein\u20131 (SREBP\u20131) was found to increase twofold and more after 24 hours of incubation of the cells with several concentrations of C\u201336 fibrils. Our study suggests that the cytotoxicity of C\u201336 fibrils on HepG2 cells is associated with perturbed intracellular cholesterol homeostasis, induced through fibril\u2013stimulated expression of the LDL receptors via the sterol\u2013responsive element<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.510290217","type":"journal-article","created":{"date-parts":[[2004,7,27]],"date-time":"2004-07-27T23:39:45Z","timestamp":1090971585000},"page":"434-442","update-policy":"http:\/\/dx.doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":14,"title":["Effects of Fibrillar C\u2013Terminal Fragment of Cleaved \u03b11\u2013Antitrypsin on Cholesterol Homeostasis in Hepg2 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