Regulation of Peroxisome Proliferator–Activated Receptor γ Activity by Losartan Metabolites

Abstract

Two active metabolites of the angiotensin type 1 (AT 1 ) receptor blocker losartan have been described previously, EXP3174 and EXP3179. Whereas EXP3174 is the main antihypertensive AT 1 receptor–blocking metabolite, the role of EXP3179 is widely unknown. Recently, a subgroup of AT 1 receptor blockers has been identified as ligands for the peroxisome proliferator–activated receptor γ (PPAR-γ). Here we characterize the PPAR-γ–activating properties of the 2 active losartan metabolites. PPAR-γ activity was measured with a chimeric Gal4-DNA–binding domain–hPPARγ-ligand–binding domain (LBD) fusion protein on a Gal4-dependent luciferase reporter system. EXP3179 prominently induced the activation of the PPAR-γ–LBD reaching a maximum at 100 μmol/L with a 7.1±1-fold induction ( P 50 μmol/L). Consistent with the activation of PPAR-γ, EXP3179 potently induced 3T3-L1 adipocyte differentiation, a typical PPAR-γ–dependent cell function, and markedly stimulated PPAR-γ target gene expression. EXP3174 failed to regulate differentiation or PPAR-γ target gene expression. The present study characterizes the active losartan metabolite EXP3179 as a partial PPAR-γ agonist. PPAR-γ activation by EXP3179 may help us to understand the beneficial metabolic effects of losartan observed in clinical trials.