title: Indinavir alters sterol and fatty acid homeostatic mechanisms in primary rat hepatocytes by increasing levels of activated sterol regulatory element-binding proteins and decreasing cholesterol 7alpha-hydroxylase mRNA levels.
abstract: Human immunodeficiency virus protease inhibitors induce hyperlipidemia in many patients treated with these drugs. We examined the effects of indinavir on cholesterol and bile acid homeostatic mechanisms in a primary rat hepatocyte (PRH) culture model. In PRH, indinavir up-regulated (2.5-fold) 3-hydroxy-3-methylglutaryl-Coenzyme A reductase mRNA levels 24hr after drug addition. In these same experiments, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels, the rate-limiting enzyme in bile acid biosynthesis, was decreased up to 10-fold. Fatty acid synthase mRNA levels were up-regulated more than 3-fold under these conditions. Indinavir did not alter CYP7A1 transcriptional activity, but decreased CYP7A1 mRNA half-life in PRH from 1.5hr to less than 0.5hr. Sterol regulatory element-binding protein-1 (SREBP-1) mature form was increased approximately 6-fold by this drug. Indinavir-induced mRNA changes and SREBP-1 mature protein levels were significantly abated by the addition of cholesterol, solubilized in beta-cyclodextrin, to culture medium. Indinavir markedly decreased endogenous cholesterol esterification and increased cholesterol in intracellular membranes in primary hepatocytes. Indinavir gavaged into intact mice also markedly increased SREBP-1 and SREBP-2 (mature forms) in hepatic nuclei. CYP7A1 mRNA was also decreased approximately 52% in indinavir-treated animals. We propose that indinavir disrupts cellular cholesterol homeostasis by increasing SREBP's and decreasing CYP7A1 mRNA.
authors.affiliation: Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kris
authors.initials: K
authors.lastname: Williams
authors.forename: Yi Ping
authors.initials: YP
authors.lastname: Rao
authors.forename: Ramesh
authors.initials: R
authors.lastname: Natarajan
authors.forename: W Michael
authors.initials: WM
authors.lastname: Pandak
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
mesh_terms: D000818:Animals; D001692:Biological Transport; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols / Q000378:metabolism*; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D012333:RNA, Messenger; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D014157:Transcription Factors; D014107:Tosyllysine Chloromethyl Ketone; D019469:Indinavir; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase