Telmisartan attenuates progression of steatohepatitis in mice: role of hepatic macrophage infiltration and effects on adipose tissue.
OBJECTIVE
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are the hepatic manifestation of metabolic syndrome. However, its therapeutic strategy has not been established. Recently, an angiotensin II type 1 receptor blocker, telmisartan (Tel), has received a great deal of attention as a therapeutic tool for metabolic syndrome. The aim of this study was to investigate the efficacy and mechanisms of Tel on a murine NASH model.


METHODS
C57BL/6 mice were fed a methionine- and choline-deficient high-fat diet (MCDHF) or a standard diet with/without the administration of Tel (10 mg/kg/day) for 8 weeks.


RESULTS
MCDHF feeding induced marked steatohepatitis with macrophage infiltration. Tel attenuated liver steatosis with decreased hepatic triglycerides (P<0.05) and fibrogenesis with decreased type I collagen and transforming growth factor-beta1 mRNA expressions (P<0.05). Tel also suppressed the infiltration of macrophages into the liver and decreased hepatic monocyte chemoattractant protein-1 and its receptor (CC-chemokine receptor 2; CCR2) mRNA expressions, especially CCR2. In vitro, Tel suppressed CCR2 expression, which was induced by low-density lipoprotein. The size of adipocyte in visceral fat tissue was reduced with an increased serum adiponectin concentration in the Tel group.


CONCLUSIONS
In this study, we revealed that Tel attenuated steatohepatitis progression by suppressing the macrophage infiltration into the liver. Tel also affected the reduction of adipocyte size and elevation of serum adiponectin. Tel might serve as a new therapeutic strategy for NASH.
Kudo
Hiroshi
H
Third Department of Internal Medicine, University of Toyama, Toyama, Japan.
Yata
Yutaka
Y
Takahara
Terumi
T
Kawai
Kengo
K
Nakayama
Yasuhiro
Y
Kanayama
Masami
M
Oya
Takeshi
T
Morita
Seiichi
S
Sasahara
Masakiyo
M
Mann
Derek A
DA
Sugiyama
Toshiro
T
D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D052242:Adiponectin / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D048429:Cell Size; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications / Q000188:drug therapy; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050152:Intra-Abdominal Fat / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D000077333:Telmisartan; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D052242:Adiponectin; C499919:Adipoq protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D012333:RNA, Messenger; D054390:Receptors, CCR2; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D008715:Methionine; D000077333:Telmisartan