BACKGROUND/AIMS: A distinct subgroup of angiotensin II type 1 receptor (AT1R) blockers (ARBs) have been reported to suppress the development of hepatic steatosis. These effects were generally explained by selective peroxisome proliferator-activated receptor (PPAR) gamma modulating properties of ARBs, independent of their AT1R blocking actions. Here, we provide genetic evidence of the direct role for AT1R in hepatic steatosis. METHODS: The effect of AT1R deletion on steatohepatitis was investigated in AT1a(-/-) mice. Furthermore, the influence of AT1R inhibition by telmisartan as well as gene silencing of AT1R by siRNA was assessed in an in vitro experiment using HepG2 cells. RESULTS: Compared to wild-type (WT), AT1a(-/-) mice fed methionine-choline deficient (MCD) diet resulted in negligible lipid accumulation in the liver with marked induction of PPARalpha mRNA. In vitro experiments also demonstrated reduced cellular lipid accumulation by telmisartan and AT1R knockdown following exposure of long chain fatty acids. This is presumably explained by the observation that the expression of PPARalpha and its target genes were significantly up-regulated in specific siRNA treated HepG2 cells. CONCLUSIONS: Our data indicate, in addition to pharmacological effect of ARBs on PPARgamma activation, a key biological role for AT1R in the regulation of hepatic lipid metabolism.
BACKGROUND/AIMS: A distinct subgroup of angiotensin II type 1 receptor (AT1R) blockers (ARBs) have been reported to suppress the development of hepatic steatosis. These effects were generally explained by selective peroxisome proliferator-activated receptor (PPAR) gamma modulating properties of ARBs, independent of their AT1R blocking actions. Here, we provide genetic evidence of the direct role for AT1R in hepatic steatosis. METHODS: The effect of AT1R deletion on steatohepatitis was investigated in AT1a(-/-) mice. Furthermore, the influence of AT1R inhibition by telmisartan as well as gene silencing of AT1R by siRNA was assessed in an in vitro experiment using HepG2 cells. RESULTS: Compared to wild-type (WT), AT1a(-/-) mice fed methionine-choline deficient (MCD) diet resulted in negligible lipid accumulation in the liver with marked induction of PPARalpha mRNA. In vitro experiments also demonstrated reduced cellular lipid accumulation by telmisartan and AT1R knockdown following exposure of long chain fatty acids. This is presumably explained by the observation that the expression of PPARalpha and its target genes were significantly up-regulated in specific siRNA treated HepG2 cells. CONCLUSIONS: Our data indicate, in addition to pharmacological effect of ARBs on PPARgamma activation, a key biological role for AT1R in the regulation of hepatic lipid metabolism.
Authors: Leigh Goedeke; Frances M Vales-Lara; Michael Fenstermaker; Daniel Cirera-Salinas; Aranzazu Chamorro-Jorganes; Cristina M Ramírez; Julie A Mattison; Rafael de Cabo; Yajaira Suárez; Carlos Fernández-Hernando Journal: Mol Cell Biol Date: 2013-04-01 Impact factor: 4.272
Authors: Kenneth E Bernstein; Frank S Ong; Wendell-Lamar B Blackwell; Kandarp H Shah; Jorge F Giani; Romer A Gonzalez-Villalobos; Xiao Z Shen; Sebastien Fuchs; Rhian M Touyz Journal: Pharmacol Rev Date: 2012-12-20 Impact factor: 25.468