The incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly rising and has become one of the most common causes of liver disease worldwide. Moreover, NAFLD acts as a risk factor for development of tumors of the gastro-intestinal tract, particularly hepatocellular carcinoma (HCC). It is also evident that visceral obesity is a crucial risk factor for the onset of NAFLD. Additionally, findings suggest that deposition of ectopic fat, including visceral obesity and fatty liver causes dysfunction of the adipose tissue with impaired production of adipocytokines. These increased adipocytokines further results in an increase in pro-inflammatory cytokines.

Adipokines are generally divided into those that enhance the onset of NAFLD and secondly into those that inhibit the development of NAFLD. The association between these two groups of adipokines can result either in a beneficial or harmful effect on NAFLD progression. For example, an antagonist link exists between adiponectin, with impeding action and TNF-α with enhancing action, causing opposite effects on insulin resistance and NAFLD. Usually a homeostasis occur between two groups under normal conditions, which can be chnaged by hypertrophy or hyperplasia of adipocytes, resulting in chronic state of inflammation, insulin resistance and development of NAFLD. 

Adiponectin, a potent cytokine has an insulin sensitizing, anti-inflammatory and anti-steatotic activity in hepatocytes through increasing oxidation of free fatty acids and decreasing gluconeogenesis, free fatty acid flow and de novo lipogenesis. Moreover, TNF-α, another vital pro-inflammatory cytokine in NAFLD promotes insulin resistance and its The excessive release from both the hypertrophic adipocytes and Kuppfer cells is indicative of the early events of hepatic damage. Besides, TNF-α triggers the production of other chemo-attractant cytokines in the hepatocytes, which in turn stimulates inflammatory cells. Therefore, raised levels of TNF-α and reduced levels of adiponectin are the required key conditions for the development of insulin resistance and NAFLD. Besides, these adipokines are also involved in the development of both intra and extra hepatic tumors. Adiponectin are known to cause antitumor activity by activating the AMP protein kinase (AMPK), an inhibitor of tumor cell growth that activates the caspase signaling pathway causing apoptosis of endothelial cells. Apart from activation of AMPK, adiponectin also exerts its anti-tumor action by inhibiting TNF-α, included in both tumor proliferation and angiogenesis. Thus, it is evident that obesity-related chronic state of low-grade inflammation and the presence of NAFLD creates a microenvironment favorable to the development of cancer.

Source: Divella R, Mazzocca A, Daniele A, Sabbà C, Paradiso A. Obesity, Nonalcoholic Fatty Liver Disease and Adipocytokines Network in Promotion of Cancer. Int J Biol Sci. 2019;15(3):610-616. Published 2019 Jan 1.