Patients treated with
highly active antiretroviral therapy may develop metabolic side effects such as
hyperlipidemia,
insulin resistance, lipoatrophy and
lactic acidosis. The pathophysiology of these metabolic abnormalities is unknown, although some, e.g.,
lactic acidosis and lipoatrophy, are more associated with
nucleoside use while
protease inhibitors (PIs) have been shown to contribute to
hyperlipidemia and
insulin resistance. Identifying new PIs that are not associated with
dyslipidemia has been hindered by the lack of mechanistic information and the unavailability of relevant animal models. In order to understand the molecular mechanism behind the
hyperlipidemia associated with other
protease inhibitors, and to develop a more effective, faster screen for compounds with this liability, we have analyzed expression profiles from PI-treated animals. Previously, we have shown that treatment of rats with
ritonavir results in increases in the expression of proteasomal subunit genes in the liver. We show this increase is similar in rats treated with
bortezomib, a
proteasome inhibitor. In addition, we have treated rats with additional
protease inhibitors, including
atazanavir, which is associated with lower rates of
lipid elevations in the clinic when administered in the absence of
ritonavir. Our results indicate a strong correlation between proteasomal induction and
lipid elevations, and have allowed us to develop a rapid screen for identifying novel PIs that do not induce the
proteasome.