title: The HIV protease inhibitor ritonavir increases lipoprotein production and has no effect on lipoprotein clearance in mice.
abstract: This study examined the effect of human immunodeficiency virus (HIV) protease inhibitor therapy on lipoprotein production and catabolism in vivo. The HIV protease inhibitor ritonavir was given to C57BL/6 mice fed either a basal low-fat diet or a Western type high-fat diet. Fasted mice were injected with Triton WR1339 followed by hourly blood collection to monitor lipoprotein production. Results showed that ritonavir increased VLDL triglyceride production by 30% over a 4 h period when mice were fed the low-fat basal diet. The ritonavir effect was more pronounced under high-fat feeding conditions, with a 2-fold increase in VLDL triglyceride production rate. Ritonavir did not alter hepatic expression levels of diacylglycerol acyltransferase or microsomal triglyceride transfer protein, but increased hepatic apolipoprotein B (apoB) secretion rates under both low- and high-fat dietary conditions. In contrast to its effect on lipoprotein production, ritonavir did not alter triglyceride-rich lipoprotein clearance from circulation under either dietary condition. Taken together, these results indicate that the hyperlipidemic effect of HIV protease inhibitors is a direct result of increased hepatic lipoprotein production. The mechanism appears to be related to their role in preventing proteasome-mediated degradation of apoB and activated sterol regulatory element binding proteins in the liver.
authors.affiliation: Center for Lipid and Arteriosclerosis Studies, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Riddle
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Schildmeyer
authors.forename: Cam
authors.initials: C
authors.lastname: Phan
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Fichtenbaum
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
mesh_terms: D000217:Acyltransferases / Q000235:genetics; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D006678:HIV / Q000201:enzymology*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008074:Lipoproteins / Q000096:biosynthesis* / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D004041:Dietary Fats; D017320:HIV Protease Inhibitors; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D000217:Acyltransferases; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D019438:Ritonavir