Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats.

Abstract

Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH.

• Authors: Mitsuteru Kitade, Hitoshi Yoshiji, Hideyuki Kojima, Yasuhide Ikenaka, Ryuichi Noguchi, Kosuke Kaji, Junichi Yoshii, Koji Yanase, Tadashi Namisaki, Kiyoshi Asada, Masaharu Yamazaki, Tatsuhiro Tsujimoto, Takemi Akahane, Masahito Uemura, Hiroshi Fukui
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 44 Issue 4 Pg. 983-91 (Oct 2006) ISSN: 0270-9139 [Print] United States
• PMID: 17006938 (Publication Type: Journal Article)

Chemical References

• Leptin
• Platelet Endothelial Cell Adhesion Molecule-1
• Vascular Endothelial Growth Factors
• Glutathione S-Transferase pi
• Gstp1 protein, rat
• Choline

Topics

• Animals
• Carcinoma, Hepatocellular (etiology)
• Choline (administration & dosage)
• Disease Models, Animal
• Disease Progression
• Fatty Liver (pathology, physiopathology)
• Fibrosis (etiology)
• Glutathione S-Transferase pi (metabolism)
• Leptin (physiology)
• Male
• Neovascularization, Pathologic (physiopathology)
• Oxidative Stress
• Platelet Endothelial Cell Adhesion Molecule-1 (analysis)
• Rats
• Rats, Zucker
• Vascular Endothelial Growth Factors (metabolism)