Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects.
Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin-angiotensin system are intimately linked. We evaluated the role of the renin-angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats. Components of the renin-angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-beta, alpha 1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis.
Kurita
Seiichiro
S
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
Takamura
Toshinari
T
Ota
Tsuguhito
T
Matsuzawa-Nagata
Naoto
N
Kita
Yuki
Y
Uno
Masafumi
M
Nabemoto
Satoko
S
Ishikura
Kazuhide
K
Misu
Hirofumi
H
Ando
Hitoshi
H
Zen
Yoh
Y
Nakanuma
Yasuni
Y
Kaneko
Shuichi
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control; D008297:Male; D008715:Methionine / Q000172:deficiency; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D047228:Angiotensin II Type 1 Receptor Blockers; D005227:Fatty Acids; D007093:Imidazoles; D012333:RNA, Messenger; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C437965:olmesartan; D008715:Methionine