The pathological conditions of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are the major risk factors for hepatocellular carcinoma (HCC). Exposure to DNA-damaging agents such as ionizing radiation is another risk factor for HCC; calorie restriction (CR), however, effectively delays the onset of radiation-induced HCC. We investigated whether NASH is relevant to radiation-induced HCC and the cancer-preventing effect of CR. Eight-day-old male B6C3F1 mice were irradiated with 3.8 Gy of X-rays and then fed a standard diet or 30% CR diet from 49 days of age until necropsy, which was performed from 56 to 600 days with ~100-day intervals to assess both pathological changes and gene expression levels. We found that early-life exposure to radiation accelerated lipid accumulation and NASH-like histopathological changes in the liver, accompanied by accelerated development of HCC. CR ameliorated the changes in lipid metabolism in the liver and reversed the NASH-like pathology, which effectively delayed HCC development. Gene-expression profiling revealed the radiation-related activation and CR-related suppression of the peroxisome proliferator-activated receptor gamma/Cd36 pathway of transmembrane fatty-acid translocation before development of the NASH-like state. Thus, early-life exposure to radiation affects lipid metabolism and induces a steatoinflammatory microenvironment that favors HCC development. Therefore, targeting this pathway by CR (or measures that mimic CR) may be a promising strategy for preventing HCC caused by either radiation or other DNA-damaging agents.
Keywords: calorie restriction; hepatocellular carcinoma; ionizing radiation; nonalcoholic steatohepatitis.
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