114 Adiponectin is an anti-inflammatory polypeptide specific to adipose tissue that is decreased in insulin-resistant states and has been shown to inhibit angiogenesis via modulation of apoptosis in an animal model.115, 116 These complex factors related to an insulin-resistant state, promote uninhibited cell growth and appear to play a significant role in the development of HCC in the setting of NASH. The development of NASH is also associated with oxidative stress and the

release of reactive oxygen species (ROS) which likely contributes to the development of HCC. An insulin resistant obese mouse model demonstrated that ROS production is increased in the mitochondria of hepatocytes with fatty infiltration, and that oxidative stress may be implicated Ceritinib in hepatic hyperplasia.7, 117 During carcinogenesis, epithelial hyperplasia and dysplasia generally precede cancer Selleckchem IWR-1 by many years.7, 118 The oxidative stress may favor tumorigenesis through steatosis, inflammation, and cell proliferation, or it may induce cancer-promoting mutations directly. Trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, has been shown to cause mutations of the p53 tumor suppressor gene which is associated with more than half of human cancers including HCC.119 Nuclear respiratory factor-1 (Nrf1) is an essential transcription factor important in mediating oxidative stress.

In an animal model, Xu et al. demonstrated that hepatocytes lacking transcription factor Nrf1 had increased susceptibility to oxidative stress. The hepatic histology in cases lacking Nrf1 demonstrated steatosis, apoptosis, necrosis, inflammation, and fibrosis. The specimens ultimately developed hepatic cancer related to the oxidative stress.120 Hepatocarcinogenesis in NASH may also be partially mediated by increased release of inflammatory and inhibitory cytokines such as TNF-α, IL-6, and NF-κB.79, 121-123 Evidence suggests a complex molecular interplay related to these inflammatory cytokines that MCE leads to hepatocyte death, compensatory proliferation, and ultimately carcinogenesis.122 NF-κB regulates immune and inflammatory

responses and is activated in many tumors, inhibiting apoptosis.123 A recent study by Luedde et al. demonstrated that inhibition of NF-κB in mouse livers induced steatohepatitis and ultimately HCC by sensitizing hepatocytes to spontaneous apoptosis. This chronic cycle of injury, cell death, and regeneration through compensatory cellular proliferation likely contributes to the development of hepatocellular carcinoma.123 The c-Jun amino-terminal kinase 1 (JNK1) has also recently been linked to obesity, insulin resistance, NASH, and HCC development. JNK1 is a ubiquitously expressed, mitogen-activated protein kinase. Obesity is associated with abnormally elevated JNK activity.124 Free fatty acids, TNF-α, and ROS released in the setting of hyperinsulinemia are all potent activators of JNK, which in turn phosphorylates IRS-1.