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. Supplementary material for this article can be found on the HEPATOLOGY website

Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice

“…However, the ob/ob mice liver is not an ideal model to study NASH; due to the lack of leptin in these mice, full activation of stellate cells does not occur, thereby preventing development of steatohepatitis and frank fibrosis. 29,31,32 In accordance, ␣ smooth muscle actin-positive stellate cells were not observed in livers from ob/ob mice (data not shown).…”

Parental Obesity and Offspring Serum Alanine and Aspartate Aminotransferase Levels: The Framingham Heart Study

“…Leptin is thought to be an important regulator of fat and energy metabolism (33). and several studies have shown that leptin may play a key role in regulating hepatic fibrosis (34,35) and progression of NASH (36). Our findings raise the possibility that genes involved in the pathogenesis of early-onset obesity may also be associated with abnormal ALT levels.…”

Hepatic fibrosis developing in morbid obesity independent of steatohepatitis: new mechanism or the Rube Goldberg machine?

“…Angiogenesis is associated with hepatic inflammation [7], hepatic fibrosis [8], the formation of portosystemic collateral vessels [9], and hepatic carcinogenesis [10]. In animal models of steatohepatitis, the expression of vascular endothelial growth factor (VEGF) and angiogenesis occurred in parallel to fibrosis and carcinogenesis [11]. In human tissue, angiogenesis, measured by CD 34-positive staining cells, occurred in NASH, but not normal liver or bland steatosis [12,13].…”