The Bile Acid Sensor FXR Protects against Dyslipidemia and Aortic Plaques Development Induced by the HIV Protease Inhibitor Ritonavir in Mice Andrea Mencarelli1, Sabrina Cipriani1, Barbara Renga1, Daniela Francisci2, Giuseppe Palladino 1 , Eleonora Distrutti3, Franco Baldelli2, Stefano Fiorucci1* 1 Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facolta` di Medicina e Chirurgia, Perugia, Italy, 2 Dipartimento di Medicina Sperimentale e Scienze Biochimiche, University of Perugia, Facolta` di Medicina e Chirurgia, Perugia, Italy, 3 Azienda Ospedaliera di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy Abstract Background: Although human immunodeficiency virus (HIV)–related morbidity and mortality rates in patients treated with a combination of high active antiretroviral therapy (HAART) have declined, significant metabolic/vascular adverse effects associated with the long term use of HIV protease inhibitors (PIs) have emerged as a significant side effect. Here we illustrate that targeting the bile acid sensor farnesoid X receptor (FXR) protects against dyslipidemia and vascular injury induced HIV- PIs in rodents. Methodology/Principal Findings: Administration of the HIV PI ritonavir to wild type mice increased plasma triacylglycerols and cholesterol levels and this effect was exacerbated by dosing ritonavir to mice harbouring a disrupted FXR. Dyslipidemia induced by ritonavir associated with a shift in the liver expression of signature genes, Sterol Regulatory Element-Binding Protein (SREBP)- 1 and fatty acid synthase. Treating wild type mice with the FXR agonist (chenodeoxycholic acid, CDCA) protected against development of dyslipidemia induced by ritonavir. Administration of ritonavir to ApoE2/2 mice, a strain that develop spontaneously atherosclerosis, increased the extent of aortic plaques without worsening the dyslipidemia. Treating these mice with CDCA reduced the extent of aortic plaques by 70% without changing plasma lipoproteins or the liver expression of signature genes. A beneficial effect on aortic plaques was also obtained by treating ApoE2/2 mice with gemfibrozil, a PPARa agonist. FXR activation counter-regulated induction of expression/activity of CD36 caused by HIV-PIs in circulating monocytes and aortic plaques. In macrophages cell lines, CDCA attenuated CD36 induction and uptake of acetylated LDL caused by ritonavir. Natural and synthetic FXR ligands reduced the nuclear translocation of SREBP1c caused by ritonavir. Conclusions/Significance: Activation of the bile acid sensor FXR protects against dyslipidemia and atherosclerotic caused by ritonavir, a widely used HIV PI. From a mechanistic stand point it appears that besides reducing the liver expression of genes involved in fatty acid synthesis, FXR activation counter-regulates the expression/activity of CD36 on monocytes. FXR ligands might hold promise in the treatment dyslipidemia induced by ritonavir. Citation: Mencarelli A, Cipriani S, Renga B, Francisci D, Palladino G, et al. (2010) The Bile Acid Sensor FXR Protects against Dyslipidemia and Aortic Plaques Development Induced by the HIV Protease Inhibitor Ritonavir in Mice. PLoS ONE 5(10): e13238. doi:10.1371/journal.pone.0013238 Editor: Maurizio Pesce, Centro Cardiologico Monzino, Italy Received June 3, 2010; Accepted September 8, 2010; Published October 8, 2010 Copyright: 2010 Mencarelli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: All authors have applied for a use patent in Italy. This patent describes the use of CDCA, the natural FXR ligand described in this manuscript, as a potential treatment for dyslipidemia caused by HIV protease inhibitors. The study was not supported by any commercial entity and has no commercial bias. Please note that the patent is not submitted yet and is not granted yet. The patent does not contain any matter composition and does not include protection of any property by the authors. It does not interfere with the ethics of the study’s conduct and interpretation of data or their representation. * E-mail: fiorucci@unipg.it Introduction Protease inhibitors (PI) as a part of highly active anti-retroviral therapy (HAART) have been used successfully in the treatment of human immunodeficiency virus (HIV) infection. Incorporation of HIV protease inhibitors in the HAART causes profound and sustained suppression of viral replication, significantly reduces the morbidity and mortality, and prolongs the lifespan of patients with HIV infection [1,2]. HAART has changed the clinical profile of HIV infection from a sub-acute lethal disease to a chronic ambulatory disease [2,3]. Despite its efficacy in controlling the disease progression, the use of PI therapy associates with an increased risk of development of premature atherosclerosis. This is particularly true in younger patients (men under the age of 34 and women under the age of 44) [1–4]. Although the mechanism underlying HIV PI-induced atherosclerosis remains to be fully identified, an increasing body of evidence suggests that ttreatment of HIV-infected patients with HIV PIs causes a dyslipidemia which contributes to the development of cardiovascular diseases [4]. A significant increase in plasma triacylglycerols and total cholesterol concentrations, often associated with abnormal body fat distribution and peripheral insulin resistance (hyperinsulinemia, hyperglycemia and diabetes mellitus), has been detected in HIV PIs-treated patients [5–8]. There is evidence that such pro- atherogenetic lipid profile induced by PIs in linked to the effect these agents exert on the Sterol Regulatory Element-Binding PLoS ONE | www.plosone.org 1 October 2010 | Volume 5 | Issue 10 | e13238