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.