Impact of insulin resistance on the progression of chronic liver diseases.
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 Long-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, alpha-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-beta1. 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.
Kaji
Kosuke
K
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Yoshiji
Hitoshi
H
Kitade
Mitsuteru
M
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Yoshii
Junichi
J
Yanase
Koji
K
Namisaki
Tadashi
T
Yamazaki
Masaharu
M
Moriya
Kei
K
Tsujimoto
Tatsuhiro
T
Kawaratani
Hideto
H
Akahane
Takemi
T
Uemura
Masahito
M
Fukui
Hiroshi
H
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D003094:Collagen / Q000032:analysis; D004052:Diethylnitrosamine / Q000494:pharmacology; D018450:Disease Progression; D005947:Glucose / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008113:Liver Neoplasms / Q000503:physiopathology*; D008297:Male; D009389:Neovascularization, Pathologic; D051381:Rats; D020334:Rats, Inbred OLETF; D015291:Transforming Growth Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; D004052:Diethylnitrosamine; D015291:Transforming Growth Factors; D003094:Collagen; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat; D005947:Glucose