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

Int J Mol Sci. 2021 May 9;22(9):5016. doi: 10.3390/ijms22095016.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / prevention & control
  • DNA Damage
  • Disease Progression
  • Disease Susceptibility
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Liver / drug effects*
  • Liver / metabolism*
  • Liver Neoplasms / etiology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / prevention & control
  • Macrophages / metabolism
  • Metformin / pharmacology*
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Oxidative Stress
  • Protective Agents / pharmacology
  • Risk Factors

Substances

  • Hypoglycemic Agents
  • Protective Agents
  • Metformin