The Adenosine Monophosphate (AMP) Analog, 5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR) Inhibits Hepatosteatosis and Liver Tumorigenesis in a High-Fat Diet Murine Model Treated with Diethylnitrosamine (DEN)
Jianlong Gao, Rui Xiong, Dan Xiong, Wenxing Zhao, Sheng Zhang, Tao Yin, Xinhua Zhang, Guozhen Jiang, Zhengyu Yin
(Department of Minimally Invasive Interventional Oncology, Hubei Cancer Hospital, Wuhan, Hubei, China (mainland))
Med Sci Monit 2018; 24:8533-8543
The development and progression of hepatocellular carcinoma (HCC) are associated with obesity and hepatosteatosis. AMP-activated protein kinase (AMPK) regulates metabolic homeostasis. This study aimed to investigate the effects of treatment with the adenosine monophosphate (AMP) analog, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) on hepatosteatosis in a mouse model fed a high-fat diet (HFD), and on hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in the HFD mouse model.
MATERIAL AND METHODS: Male C57BL/6 male mice from two weeks of age were fed a high-fat diet, resulting in hepatosteatosis. HFD mice (15–20 per group) were treated with AICAR and without AICAR. HFD mice were treated with DEN, with and without AICAR. Mouse liver tissues were examined histologically using lipid histochemical stains, immunohistochemistry, and immunofluorescence. Levels of cytokines, alanine transaminase (ALT), triacylglyceride (TAG), and apoptosis were determined. Western blot was used to detect AMPK, pAMPK, STAT3, and pSTAT3. Real-time polymerase chain reaction (RT-PCR) detected expression of the ACL, FAS, CD36, ATGL, CPT1, and IL6 genes.
RESULTS: In the HFD mouse model, AICAR treatment inhibited hepatic lipid synthesis and IL-6 expression. In the DEN-treated mice, AICAR treatment reduced tumorigenesis, IL-6 signaling, and STAT3 activation. Short-term AICAR treatment had no significant effect in advanced HCC.
CONCLUSIONS: In an HFD mouse model, treatment with AICAR reduced the development of hepatosteatosis, and following treatment with the liver carcinogen, DEN, AICAR reduced the development of HCC. These preliminary findings support further studies on the role of AICAR in fatty liver disease and HCC.
Keywords: 2,5-Dimethoxy-4-Methylamphetamine, AMP-Activated Protein Kinases, Carcinoma, Hepatocellular