Nonalcoholic fatty liver disease promotes hepatocellular carcinoma through direct and indirect effects on hepatocytes

Hepatocellular carcinoma (HCC) is the sixth most frequent neoplasm and the second leading cause of cancer‐related deaths worldwide. Nonalcoholic fatty liver disease (NAFLD), a common disorder in obese people, has been identified as an important risk factor for HCC. Following the increasing prevalence of obesity, it is expected that the contribution of NAFLD to HCC's incidence worldwide will grow. Recently, a number of studies have been published, which help us better understand cellular and molecular mechanisms of how NAFLD promotes hepatocarcinogensis. Inflammatory cytokines, ER stress and circadian dysregulation, which mediate hepatocyte injury and NAFLD progression, have been identified to promote malignant transformation of hepatocytes. Besides these ‘intrinsic’ effects, lipid dysregulation dramatically affects the liver local microenvironment. The reshaped immune environment has also been found to contribute to the NAFLD‐mediated hepatocarcinogenesis. This review explores recent findings of both ‘intrinsic’ effects on hepatocytes and the role of the local environment in NAFLD‐promoted HCC development. Nonalcoholic fatty liver disease promotes HCC through both direct effects on hepatocytes, and indirect effects on the environment shaping this into a protumor milieu. NAFLD‐associated events such as the increase of inflammatory cytokines alter gene expression profile of hepatocytes and contribute to malignant transformation. NAFLD also changes the population and functions of liver nonparenchymal cells and favors tumor development.