Oxidative stress and Liver X Receptor agonist induce hepatocellular carcinoma in Non‐alcoholic steatohepatitis model

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Background and Aim The incidence of non‐alcoholic steatohepatitis (NASH)‐related hepatocellular carcinoma (HCC) is progressively increasing. However, the pathophysiology and etiology of NASH progression to HCC are unknown. We hypothesized that steatosis was the key factor in NASH‐related hepatocarcinogenesis and aimed to evaluate the effects of long‐term liver X receptor (LXR) agonist stimulation on hepatic steatosis induced by a high‐fat diet and oxidative stress. Methods We used an LXR agonist (T0901317) and CCl 4 to induce hepatic steatosis and oxidative stress, respectively. C57BL/6 mice fed with a high‐fat diet were treated with either T0901317 + CCl 4 (T09 + CCl 4 group) or CCl 4 alone (CCl 4 group). T0901317 (2.5 mg/kg) and CCl 4 (0.1 mL/kg) were intraperitoneally administered twice weekly for 24 weeks. Results The liver‐to‐body weight ratio was significantly higher in the T09 + CCl 4 group than in the CCl 4 group. Mice in the T09 + CCl 4 group exhibited abnormal lipid metabolism and NASH‐like histopathological features. Additionally, all mice in the T09 + CCl 4 group developed liver tumors diagnosed as well‐differentiated HCC. The genes identified via microarray analysis were related to NASH and HCC development. Conclusions By combining long‐term LXR agonist stimulation with oxidative stress and a high‐fat diet, we successfully reproduced liver conditions in mice similar to those in humans with NASH and progression to HCC. Our results provide new insight into NASH‐related HCC progression and therapy.