Deletion of angiotensin II type I receptor reduces hepatic steatosis.
OBJECTIVE
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.
Nabeshima
Yoshitaka
Y
Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Tazuma
Susumu
S
Kanno
Keishi
K
Hyogo
Hideyuki
H
Chayama
Kazuaki
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020868:Gene Silencing; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000235:genetics; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D017931:DNA Primers; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan