title: Dual effects on HDL metabolism by cholesteryl ester transfer protein inhibition in HepG2 cells.
abstract: Cholesteryl ester transfer protein (CETP) promotes reverse cholesterol transport via exchange of cholesteryl ester and triglyceride among lipoproteins. Here, we focused on HDL metabolism during inhibition of CETP expression by using CETP antisense oligodeoxynucleotides (ODNs) in HepG2 cells. CETP secretion was decreased by 70% in mRNA levels and by 52% in mass 20 h after ODNs against CETP were delivered to HepG2 cells. Furthermore, as a consequence of the downregulation of CETP, the expression of scavenger receptor class B type I (SR-BI), an HDL receptor, was also reduced by approximately 50% in mRNA and protein levels, whereas the apolipoprotein A-I (apoA-I) expression and secretion were increased by 30 and 92%, respectively. In a functional study, the selective uptake of (125)I-[(14)C]cholesteryl oleate-labeled HDL(3) was decreased. Cholesterol efflux to apoA-I and HDL(3) was significantly increased by 88 and 37%, respectively. Moreover, the CE levels in cells after antisense treatment were elevated by 20%, which was related to the about twofold increase of cholesterol esterification and increased acyl-CoA:cholesterol acyltransferase 1 mRNA levels. Taken together, these findings suggest that although acute suppression of CETP expression leads to an elevation in cellular cholesterol stores, apoA-I secretion, and cellular cholesterol efflux to apoA-I, the return of HDL-CE to hepatocytes via an SR-BI pathway was inhibited in vitro. Thus antisense inhibition of hepatic CETP expression manifests dual effects: namely, increased formation of HDL and suppression of catabolism of HDL-CE, probably via the SR-BI pathway.
authors.affiliation: Molecular Genetics of Cardiovascular Disorders, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Huang
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Kawashiri
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.forename: Toshinori
authors.initials: T
authors.lastname: Higashikata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
mesh_terms: D000577:Amides; D016632:Apolipoprotein A-I / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004952:Esters; D006023:Glycoproteins; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D016632:Apolipoprotein A-I; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D018076:DNA, Complementary; D004952:Esters; D006023:Glycoproteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; C411602:dalcetrapib