Metformin Actions on the Liver: Protection Mechanisms Emerging in Hepatocytes and Immune Cells against NASH-Related HCC

Abstract

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to the global epidemic of obesity and type 2 diabetes mellitus (T2DM). Notably, NAFLD can progress from the mildest form of simple steatosis to nonalcoholic steatohepatitis (NASH) that increases the risk for hepatocellular carcinoma (HCC), which is a malignancy with a dismal prognosis and rising incidence in the United States and other developed counties, possibly due to the epidemic of NAFLD. Metformin, the first-line drug for T2DM, has been suggested to reduce risks for several types of cancers including HCC and protect against NASH-related HCC, as revealed by epidemical studies on humans and preclinical studies on animal models. This review focuses on the pathogenesis of NASH-related HCC and the mechanisms by which metformin inhibits the initiation and progression of NASH-related HCC. Since the functional role of immune cells in liver homeostasis and pathogenesis is increasingly appreciated in developing anti-cancer therapies on liver malignancies, we discuss both the traditional targets of metformin in hepatocytes and the recently defined effects of metformin on immune cells.

Keywords: HCC; MDSC; NAFLD; NASH; T cell; macrophage; metformin; myeloid-derived suppressor cell; type 2 diabetes mellitus.

Figure 1

Pathogenesis of NASH and NASH-related HCC and the possible effect of metformin on these processes. NAFLD can progress from the mildest form of simple steatosis to NASH, which is defined by hepatic cell damage and inflammation that are absent in the simple steatosis stage. The current theory acknowledges the development of NASH as a result of “multiple hits” that overload and stress the hepatocyte. The chronic inflammation, cell damage, and wound healing processes in the NASH condition cause fibrosis and cirrhosis. While simple steatosis is not a major risk factor for HCC, NASH conditions, especially those with cirrhosis, increase HCC risk. Although there is disagreement regarding whether metformin can inhibit NAFLD progression, preclinical and clinical studies have provided evidence that metformin use can reduce the risk of NAFLD/NASH-related HCC and suppress HCC progression.

Figure 2

Factors and cells changed by metformin, which mediates the liver-protecting effect against HCC development in the NASH condition. The mechanism by which metformin inhibits the development of NASH-related HCC is multi-factorial. Metformin directly impacts on hepatocytes, hepatic progenitor cells, and HCC cells, which suppress malignant transformation and cancer progression. Besides influencing those cells that go through the malignant transformation directly, metformin also changes the activity and population of immune cells including macrophages, T cells, and MDSCs, suppressing the HCC development.