title: Liver transcriptomic changes associated with ritonavir-induced hyperlipidemia in sensitive and resistant strains of rats.
abstract: Ritonavir (RTV) and other protease inhibitors (PIs) used for the treatment of human immunodeficiency virus (HIV) infection are associated with elevated serum triglycerides (TG) and cholesterol in some patients. A rat strain (Sprague-Dawley or SD) commonly used in toxicology studies is not sensitive to RTV-induced hyperlipidemia, making mechanistic studies and the identification of novel, lipid-neutral PIs challenging. The objective of this study was to identify a rat strain that mirrors human PI-associated hyperlipidemia. RTV was administered at 100 mg/kg/day for 5 days to a panel of 14 rat strains estimated to cover approximately 86% of the known genetic variance in rats. Increased serum TG and cholesterol levels occurred only in two rat strains, including LEW x BN rats. Livers from LEW x BN (sensitive) and SD (resistant) rats were then evaluated using microarrays to investigate differences in the transcriptomic response to RTV. Several genes, including some involved in bile acid biosynthesis, gluconeogenesis, and carbohydrate metabolism, were differentially regulated between the two strains. In particular, cytochrome P450 7A1 (CYP7A1), a key enzyme for cholesterol metabolism, was down-regulated in the sensitive and up-regulated in resistant rats. Collectively, these results demonstrate the utility of a genetically diverse rat panel to identify strains with clinical relevance for a particular adverse effect. Furthermore, the genome-wide transcriptomic analysis suggests that RTV-induced hyperlipidemia is at least in part due to changes in hepatic lipid biosynthesis and metabolism. These findings will facilitate the discovery of novel, lipid-neutral HIV PIs and the identification of relevant biomarkers for this adverse event.
authors.affiliation: Abbott Laboratories, Abbott Park, IL, USA. yi.yang@abbott.com
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Dahly-Vernon
authors.forename: Eric A G
authors.initials: EA
authors.lastname: Blomme
authors.forename: Jie
authors.initials: J
authors.lastname: Lai-Zhang
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Yvette A
authors.initials: YA
authors.lastname: Harrington
authors.forename: Steven H
authors.initials: SH
authors.lastname: Nye
authors.forename: Darin L
authors.initials: DL
authors.lastname: Evans
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling / Q000662:veterinary*; D005786:Gene Expression Regulation / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D006949:Hyperlipidemias / Q000139:chemically induced* / Q000235:genetics*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000009:adverse effects*
chemical_list: D017320:HIV Protease Inhibitors; D019438:Ritonavir