Impact of insulin resistance on the progression of chronic liver diseases

被引:38
作者
Kaji, Kosuke [1 ]
Yoshiji, Hitoshi [1 ]
Kitade, Mitsuteru [1 ]
Ikenaka, Yasuhide [1 ]
Noguchi, Ryuichi [1 ]
Yoshii, Junichi [1 ]
Yanase, Koji [1 ]
Namisaki, Tadashi [1 ]
Yamazaki, Masaharu [1 ]
Morina, Kei [1 ]
Tsujimoto, Tatsuhiro [1 ]
Kawaratani, Hideto [1 ]
Akahane, Takemi [1 ]
Uemura, Masahito [1 ]
Fukui, Hiroshi [1 ]
机构
[1] Nara Med Univ, Dept Internal Med 3, Nara 6348522, Japan
关键词
hepatocellular carcinoma; angiogenesis; hepatic stellate cells; glucose; vascular endothelial growth factor;
D O I
10.3892/ijmm_00000088
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Recent studies have revealed a close relationship between insulin resistance (IR) and the progression of chronic liver diseases. although relatively little is known regarding the possible mechanisms involved. The aim of this study was to elucidate the impact of IR on the development of liver fibrosis and hepatocarcinogenesis using obese diabetic Otsuka Lona-Evans Tokushima Fatty (OLETF) rats. Liver fibrosis development and glutathione-S-transferase placental form (GST-P)-positive pre-neoplastic lesions were both markedly accelerated in OLETF rats, being induced by pig serum and diethylnitrosamine (DEN). respectively. In the fibrosis experiment. u-smooth muscle actin-positive activated hepatic stellate cells (HSCs) also significantly increased in OLETF rats along with augmentation of the hepatic collagen content and transforming growth factor-beta(1). Our in vitro study showed that both glucose and insulin stimulated the proliferation of activated HSCs. and the combination treatment exerted an additive effect. In the DEN model, neovascularization, which plays a pivotal role in hepatocarcinogenesis. was up-regulated in OLETF rats almost in parallel with pre-neoplastic lesion development and a potent angiogenic factor. vascular endothelial growth factor. High glucose and insulin also significantly augmented the in vitro neovascularization Via extracellular signal-regulated kinase 1/2 phosphorylation. Similar to the effect on the activated HSCs, co-existence of both factors exerted a more potent effect than either single factor. In conclusion, these results indicated that the IR status directly accelerated liver fibrosis development and hepatocarcinogenesis at least partly through the stimulation of activated HSC proliferation and hepatic neovascularization, respectively, in the rat.
引用
收藏
页码:801 / 808
页数:8
相关论文
共 40 条
[21]   COMPARATIVE HISTOCHEMICAL INVESTIGATION OF THE GLUTATHIONE-S-TRANSFERASE PLACENTAL FORM AND GAMMA-GLUTAMYL-TRANSPEPTIDASE DURING N-NITROSOBIS(2-HYDROXYPROPYL)AMINE-INDUCED PANCREATIC CARCINOGENESIS IN HAMSTERS [J].
OBARA, T ;
MAKINO, T ;
URA, H ;
YOKOSE, Y ;
KINUGASA, T ;
MOORE, MA ;
SATO, K ;
KONISHI, Y .
CARCINOGENESIS, 1986, 7 (05) :801-805
[22]   Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis [J].
Ota, Tsuguhito ;
Takamura, Toshinari ;
Kurita, Seiichiro ;
Matsuzawa, Naoto ;
Kita, Yuki ;
Uno, Masafumi ;
Akahori, Hiroshi ;
Misu, Hirofumi ;
Sakurai, Masaru ;
Zen, Yoh ;
Nakanuma, Yasuni ;
Kaneko, Shuichi .
GASTROENTEROLOGY, 2007, 132 (01) :282-293
[23]   Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C [J].
Petit, JM ;
Bour, JB ;
Galland-Jos, C ;
Minello, A ;
Verges, B ;
Guiguet, M ;
Brun, JM ;
Hillon, P .
JOURNAL OF HEPATOLOGY, 2001, 35 (02) :279-283
[24]   PATHOGENESIS OF GLUCOSE-INTOLERANCE AND DIABETES-MELLITUS IN CIRRHOSIS [J].
PETRIDES, AS ;
VOGT, C ;
SCHULZEBERGE, D ;
MATTHEWS, D ;
STROHMEYER, G .
HEPATOLOGY, 1994, 19 (03) :616-627
[25]   Cytokine receptors and signaling in hepatic stellate cells [J].
Pinzani, M ;
Marra, F .
SEMINARS IN LIVER DISEASE, 2001, 21 (03) :397-416
[26]   Fibrosis accelerates the development of enzyme-altered lesions in the rat liver [J].
Sakaida, I ;
Hironaka, K ;
Uchida, K ;
Suzuki, C ;
Kayano, K ;
Okita, K .
HEPATOLOGY, 1998, 28 (05) :1247-1252
[27]  
SATO T, 1995, DIABETOLOGIA, V38, P1033
[28]   Hepatocellular carcinoma [J].
Schafer, DF ;
Sorrell, MF .
LANCET, 1999, 353 (9160) :1253-1257
[29]   D-glucose and insulin stimulate migration and tubular formation of human endothelial cells in vitro [J].
Shigematsu, S ;
Yamauchi, K ;
Nakajima, K ;
Iijima, S ;
Aizawa, T ;
Hashizume, K .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1999, 277 (03) :E433-E438
[30]   Effects of Sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats [J].
Shimizu, I ;
Ma, YR ;
Mizobuchi, Y ;
Liu, F ;
Miura, T ;
Nakai, Y ;
Yasuda, M ;
Shiba, M ;
Horie, T ;
Amagaya, S ;
Kawada, N ;
Hori, H ;
Ito, S .
HEPATOLOGY, 1999, 29 (01) :149-160